Pituitary Disorders of Childhood: Diagnosis and Clinical Management [1st ed.] 978-3-030-11338-4;978-3-030-11339-1

Table of contents :
Front Matter ....Pages i-xiii
Front Matter ....Pages 1-1
Embryologic and Genetic Disorders of the Pituitary Gland (Louise C. Gregory, Mehul T. Dattani)....Pages 3-27
Genetics of Hypopituitarism (Mariam Gangat, Sally Radovick)....Pages 29-37
Front Matter ....Pages 39-39
Adamantinomatous Craniopharyngioma: Genomics, Radiologic Findings, Clinical, and Prognosis (Hermann L. Müller, Juan Pedro Martinez-Barbera)....Pages 41-70
Prolactinomas (Takara L. Stanley, Madhusmita Misra)....Pages 71-87
Cushing Disease: Diagnosis and Treatment (Christina Tatsi, Constantine A. Stratakis)....Pages 89-114
Surgery for Cushing’s Disease (Brooke Swearingen)....Pages 115-120
Gigantism and Acromegaly (Angeliki Makri, Maya Lodish)....Pages 121-139
TSH-Secreting Pituitary Adenomas (Andrea Gerardo Antonio Lania, Nazarena Betella, Davide Milani)....Pages 141-154
Molecular Predictors of Clinical Behavior in Pituitary Adenohypophysial Tumors (Shereen Ezzat, Sylvia L. Asa)....Pages 155-172
Nonpituitary Sellar Masses and Infiltrative Disorders (Shilpa Mehta, Benjamin Cohen, Brenda Kohn)....Pages 173-197
Front Matter ....Pages 199-199
Posterior Pituitary Disorders: Anatomy and Physiology, Central Diabetes Insipidus (CDI), and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) (Colin Patrick Hawkes, Adriana Herrera, Brenda Kohn, Shana E. McCormack, Craig A. Alter)....Pages 201-225
Front Matter ....Pages 227-227
Congenital Hypogonadotropic Hypogonadism (Isolated GnRH Deficiency) (Cheng Xu, Nelly Pitteloud)....Pages 229-250
Genetics of Delayed Puberty (Sasha Howard, Leo Dunkel)....Pages 251-268
Hypothalamic Amenorrhea (Rula V. Kanj, Catherine M. Gordon)....Pages 269-277
Front Matter ....Pages 279-279
Neuro-Ophthalmic Diseases and Endocrinologic Function (Mary-Magdalene Ugo Dodd, Gena Heidary)....Pages 281-296
Front Matter ....Pages 297-297
Brain Irradiation Paradigms for Childhood Central Nervous System Tumors (Benjamin T. Cooper, Ralph E. Vatner, Helen A. Shih)....Pages 299-320
Front Matter ....Pages 321-321
Hypothalamic: Pituitary Dysfunction as a Late Effect of Childhood Cancer, Brain Tumors, and Their Treatments (Wassim Chemaitilly)....Pages 323-340
Front Matter ....Pages 341-341
Pituitary Response to Traumatic Brain Injury (Rayhan A. Lal, Andrew R. Hoffman)....Pages 343-352
Back Matter ....Pages 353-362

Citation preview

Contemporary Endocrinology Series Editor: Leonid Poretsky

Brenda Kohn Editor

Pituitary Disorders of Childhood Diagnosis and Clinical Management

Contemporary Endocrinology Series Editor Leonid Poretsky Division of Endocrinology Lenox Hill Hospital New York, NY, USA

More information about this series at http://www.springer.com/series/7680

Brenda Kohn Editor

Pituitary Disorders of Childhood Diagnosis and Clinical Management

Editor Brenda Kohn Division of Pediatric Endocrinology New York University New York, NY USA

ISSN 2523-3785     ISSN 2523-3793 (electronic) Contemporary Endocrinology ISBN 978-3-030-11338-4    ISBN 978-3-030-11339-1 (eBook) https://doi.org/10.1007/978-3-030-11339-1 Library of Congress Control Number: 2019935846 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Humana Press imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Series Editor Foreword

Because of its crucial role in regulating multiple endocrine functions, the pituitary gland is known in endocrine parlance as the “master gland.” Normal pituitary function is particularly important in childhood—a period of rapid growth and development. The subject of pituitary disorders of childhood, therefore, is an extremely important topic for physicians who provide medical care for the children and families affected by these conditions. This volume, edited by Dr. Brenda Kohn, is an encyclopedic compilation of recent scientific research and clinical guidelines that are essential for the recognition and care of children with congenital and acquired disorders of the pituitary gland. It addresses embryology and genetics, pituitary tumors and non-pituitary tumors that may affect pituitary function, hypothalamic/pituitary functional deficiencies, the effects of childhood cancer treatment and of traumatic brain injury, among other issues. In her preface, Dr. Kohn states that the book is intended for pediatric endocrinologists, pediatric neuro-endocrinologists and pediatric neurooncologists. This text is essential reading for all physicians involved in the care of children with disorders of the pituitary gland. In my view, this volume is also of immense interest to endocrinologists treating adults, since the consequences of childhood pituitary diseases commonly persist into adulthood and require a lifetime of endocrinological follow-up. The authors of every chapter possess an international reputation in their fields. Like Dr. Kohn, they should be congratulated on a remarkable accomplishment. New York, NY, USA 

Leonid Poretsky

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Preface

Pituitary Disorders of Childhood: Diagnosis and Clinical Management focuses on clinical disorders of the pituitary gland in children with specific emphasis on state-­ of-­the-art diagnostic and treatment modalities for pediatric pituitary disorders, highlighting the newest scientific advances in genomics and molecular biology that clinician-scientists caring for children need to know. Recent advances in neuroimaging of the pituitary gland and optic nerve pathways, the molecular characterization of pituitary tumors and genetic alterations involved in familial and sporadic pituitary tumorigenesis, advances in the neurobiology and genetics of growth and puberty, and results of long-term outcome data of treatment modalities, including CNS radiation, are described in detail. Pituitary Disorders of Childhood is intended as an educational read-through and reference text for pediatric endocrinologists, pediatric neurologists, and pediatric neuro-oncologists involved in the care of children with pituitary disorders. As of its publication, it is informative and current, and it is anticipated to maintain its scientific value in the foreseeable future. It is hoped that scientific breakthroughs discussed in this text will serve as a foundation for future and ongoing research. I am grateful to Kristopher Spring, Senior Editor at Springer Nature, for inviting me to initiate this text and to Daniel Dominguez and Portia Wong, Developmental Editors for Springer Nature, for the pleasure of working with them. The dedication of this text is twofold: It is dedicated to the basic scientists, translational researchers, and clinical physician-scientists whose research continues to advance the care of children with pituitary disorders. Many have contributed chapters to this text, and it has been an honor and a privilege to partner with the physicians and scientists who have shared their research by contributing to this text. For that, I am truly grateful. Above all, this book is dedicated to the children and families whom we care for and who entrust us on a daily basis with the mission to provide state-of-the-­art care for the children, which will enable the balance of a positive therapeutic outcome and optimal quality of life. New York, NY, USA 

Brenda Kohn, MD

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Contents

Part I Embryologic and Genetic Disorders of the Pituitary Gland 1 Embryologic and Genetic Disorders of the Pituitary Gland ����������������   3 Louise C. Gregory and Mehul T. Dattani 2 Genetics of Hypopituitarism  ��������������������������������������������������������������������  29 Mariam Gangat and Sally Radovick Part II Acquired Pituitary Disorders: Pituitary Tumors and Nonpituitary Sellar Masses 3 Adamantinomatous Craniopharyngioma: Genomics, Radiologic Findings, Clinical, and Prognosis  ����������������������������������������  41 Hermann L. Müller and Juan Pedro Martinez-Barbera 4 Prolactinomas  ��������������������������������������������������������������������������������������������  71 Takara L. Stanley and Madhusmita Misra 5 Cushing Disease: Diagnosis and Treatment ��������������������������������������������  89 Christina Tatsi and Constantine A. Stratakis 6 Surgery for Cushing’s Disease  ���������������������������������������������������������������� 115 Brooke Swearingen 7 Gigantism and Acromegaly  ���������������������������������������������������������������������� 121 Angeliki Makri and Maya Lodish 8 TSH-Secreting Pituitary Adenomas  �������������������������������������������������������� 141 Andrea Gerardo Antonio Lania, Nazarena Betella, and Davide Milani 9 Molecular Predictors of Clinical Behavior in Pituitary Adenohypophysial Tumors ���������������������������������������������������������������������� 155 Shereen Ezzat and Sylvia L. Asa

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Contents

10 Nonpituitary Sellar Masses and Infiltrative Disorders ������������������������� 173 Shilpa Mehta, Benjamin Cohen, and Brenda Kohn Part III Posterior Pituitary Disorders 11 Posterior Pituitary Disorders: Anatomy and Physiology, Central Diabetes Insipidus (CDI), and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) �������������������������������� 201 Colin Patrick Hawkes, Adriana Herrera, Brenda Kohn, Shana E. McCormack, and Craig A. Alter Part IV Functional Hypothalamic-Pituitary Hormone Deficiencies 12 Congenital Hypogonadotropic Hypogonadism (Isolated GnRH Deficiency)  �������������������������������������������������������������������� 229 Cheng Xu and Nelly Pitteloud 13 Genetics of Delayed Puberty �������������������������������������������������������������������� 251 Sasha Howard and Leo Dunkel 14 Hypothalamic Amenorrhea  ���������������������������������������������������������������������� 269 Rula V. Kanj and Catherine M. Gordon Part V Neuro-Opthalmic Diseases 15 Neuro-Ophthalmic Diseases and Endocrinologic Function ������������������ 281 Mary-Magdalene Ugo Dodd and Gena Heidary Part VI CNS Radiation 16 Brain Irradiation Paradigms for Childhood Central Nervous System Tumors  �������������������������������������������������������������������������� 299 Benjamin T. Cooper, Ralph E. Vatner, and Helen A. Shih Part VII Childhood Cancer Treatment 17 Hypothalamic: Pituitary Dysfunction as a Late Effect of Childhood Cancer, Brain Tumors, and Their Treatments ���������������� 323 Wassim Chemaitilly Part VIII Traumatic Brain Injury 18 Pituitary Response to Traumatic Brain Injury �������������������������������������� 343 Rayhan A. Lal and Andrew R. Hoffman Index  ������������������������������������������������������������������������������������������������������������������ 353

Contributors

Craig  A.  Alter, MD  Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Sylvia  L.  Asa, MD, PhD  Pathology, University Health Network, University of Toronto, Toronto, ON, Canada Nazarena Betella, MD  Department of Biomedical Sciences, Endocrinology Unit, Humanitas Research Hospital and Humanitas University, Rozzano, Italy Wassim Chemaitilly, MD  Division of Endocrinology, St. Jude Children’s Research Hospital, Memphis, TN, USA Benjamin  Cohen, MD  Division of Radiology, NYU Langone Medical Center, New York, NY, USA Benjamin T. Cooper, MD  Radiation Oncology, NYU Langone Health, New York, NY, USA Mehul T. Dattani, MBBS, DCH, FRCPCH, FRCP, MD  Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK Mary-Magdalene  Ugo  Dodd, MD, MSc  Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Leo  Dunkel, MD, PhD  Paediatric Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK Shereen Ezzat, MD  Medicine, University Health Network, University of Toronto, Toronto, ON, Canada Mariam Gangat, MD  Pediatric Endocrinology, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ, USA Catherine  M.  Gordon, MD, MS  Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

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Contributors

Louise C. Gregory, PhD  Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK Colin Patrick Hawkes, MD, PhD  Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Gena  Heidary, MD, PhD  Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Adriana Herrera, MD  Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Andrew R. Hoffman, MD  Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA Sasha Howard, MBBS, PhD  Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK Rula V. Kanj, MD  Division of Pediatric and Adolescent Gynecology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Brenda Kohn, MD  Division of Pediatric Endocrinology and Diabetes, New York University – Langone Medical Center, Hassenfeld Children’s Hospital, New York, NY, USA Rayhan A. Lal, MD  Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA Division of Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA, USA Andrea Gerardo Antonio Lania, MD, MhD  Department of Biomedical Sciences, Endocrinology Unit, Humanitas Research Hospital and Humanitas University, Rozzano, Italy Maya Lodish, MD  Division of Pediatric Endocrinology, University of California, San Francisco, San Francisco, CA, USA Angeliki Makri, MD, MSc  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA Juan Pedro Martinez-Barbera, PhD  UCL Great Ormond Street Institute of Child Health, Developmental Biology and Cancer, Birth Defects Research Centre, London, UK Shana E. McCormack, MD, MTR  Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Shilpa Mehta, MD  Division of Pediatric Endocrinology, NYU Langone Medical Center, New York, NY, USA

Contributors

xiii

Davide  Milani, MD  Neurocenter, Neurosurgery Unit, Humanitas Research Hospital, Rozzano, Italy Madhusmita Misra, MD, MPH  Pediatric Endocrinology, Massachusetts General Hospital, Boston, MA, USA Hermann  L.  Müller, MD  Department of Pediatrics and Pediatric Hematology/ Oncology, Klinikum Oldenburg AöR, Medical Campus University Oldenburg, Oldenburg, Germany Nelly  Pitteloud, MD  Service of Endocrinology, Diabetes and Metabolism, University Hospital, CHUV, Lausanne, Switzerland Sally Radovick, MD  Department of Pediatrics, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ, USA Helen A. Shih, MD, MS, MPH  Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA Takara  L.  Stanley, MD  Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA Constantine  A.  Stratakis, MD, D(Med)Sc  Eunice Kennedy Shriver, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA Brooke  Swearingen, MD  Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA Christina  Tatsi, MD, PhD  Eunice Kennedy Shriver, National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA Ralph  E.  Vatner, MD, PhD  Department of Radiation Oncology, University of Cincinnati and Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Cheng Xu, MD, PhD  Endocrinology, Diabetology & Metabolism Service, Internal Medicine Department, Lausanne University Hospital, Lausanne, Switzerland

Part I

Embryologic and Genetic Disorders of the Pituitary Gland

Chapter 1

Embryologic and Genetic Disorders of the Pituitary Gland Louise C. Gregory and Mehul T. Dattani

Hypothalamo-Pituitary Development The mature pituitary gland is a central regulator responsible for controlling growth, metabolism, reproduction and development and homeostasis through the regulation and function of other endocrine glands in the body [1]. The pituitary gland is situated within the sella turcica recess of the sphenoid bone at the base of the brain and consists of three lobes derived from two adjacent ectodermal layers: the anterior and intermediate lobes from the oral ectoderm and the posterior lobe from the neural ectoderm [2, 3]. Hypothalamo-pituitary (HP) development is dependent on the communication between the oral ectoderm and the overlying neural ectoderm. This occurs through a complex spatio-temporal genetic cascade of transcription factors and signalling molecules that may be either intrinsic or extrinsic to the developing Rathke’s pouch, the primordium of the anterior pituitary (AP) [4]. A series of tightly regulated steps that result in cell proliferation and differentiation give rise to the five different specialized AP cell types that secrete six hormones: somatotrophs [growth hormone (GH)], thyrotrophs [thyroid-stimulating hormone (TSH)], gonadotrophs [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], lactotrophs [prolactin (PRL)] and the corticotrophs [adrenocorticotropic hormone (ACTH)] [5] (Fig. 1.1). The synthesis of each one of the six anterior pituitary hormones is regulated by specific hypothalamic peptides. Many of these ligands travel via the hypophyseal portal system from the hypothalamus into the bloodstream, a transport system that allows rapid communication and migration of hormones to the anterior pituitary. The ligands bind to their respective receptors on each specific anterior pituitary cell type, giving rise to the six hormones that have targets elsewhere in the body, and play distinct roles in endocrine regulation (Fig. 1.1). L. C. Gregory · M. T. Dattani (*) Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_1

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L. C. Gregory and M. T. Dattani

Hypothalamus SHH GLI2 OTX2 HESX1 SOX2 SOX3 ARNT2 KCNQ1 RNPC3

Melanotrophs (MSH)

PCSK1 TBX19

TRH

POMC

Rathke’s pouch

GHRH

Gonadotrophs (FSH, LH) KCNQ1 PNPLA6 RNPC3

Thyrotrophs (TSH)

TA GA

F1

U1

PO LHX3 LHX4

RP progenitor cells

TRHR

TSHB IGSF1

2

HESX1 GLI2 OTX2 SOX2 IFT172

Proliferating cells

PROP1

POU1F1

Differentiating cells

PO

U1

PCSK1 TBX19

Somatotrophs (GH) GH1 IGSF1 KCNQ1

GHRHR

F1

Lactotrophs (PRL) IGSF1

Corticotrophs (ACTH) POMC

Fig. 1.1  A flowchart illustrating human embryonic hypothalamo-pituitary development. A complex spatio-temporal genetic cascade of transcription factors and signalling molecules, intrinsic or extrinsic, to the developing Rathke’s pouch. A series of tightly regulated steps result in cell proliferation and differentiation to give rise to the five different specialized anterior pituitary cell types that secrete six hormones. Specific peptides derived from the hypothalamus regulate the synthesis of these hormones by binding to their respective receptors on each anterior pituitary cell type

 uman Conditions Arising from Disordered Hypothalamo-­ H Pituitary Development Congenital hypopituitarism (CH) is characterized by deficiencies in one or more of these six hormones, with GH being the most frequently occurring hormone deficiency and often seen in isolation [4]. It is a syndrome with a wide variation in severity and may present early in the neonatal period or later in childhood. Midline and craniofacial structural abnormalities are often associated with CH, giving rise to a range of highly variable disorders, ranging from fatality to holoprosencephaly

1  Embryologic and Genetic Disorders of the Pituitary Gland

5

(HPE), septo-optic dysplasia (SOD) and Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism (HH) with anosmia [6]. Thus, disordered embryogenesis can cause variable phenotypes involving a range of craniofacial midline defects, associated with HP disorders. All causative genes for congenital hypopituitarism and related disorders and their inheritance patterns are listed in Table 1.1 and are discussed throughout this chapter.

Isolated Growth Hormone Deficiency Growth hormone-releasing hormone (GHRH) is released from the hypothalamus and binds to its receptor (GHRHR) on somatotroph cells. This results in the synthesis and release of GH, in the presence of the transcription factor POU1F1 [7]. GH then binds to its receptors on target tissues, primarily the liver, leading to the release of insulin-like growth factor 1 (IGF1) and its binding protein, IGFBP3. The most common isolated deficiency is congenital isolated GH deficiency (IGHD) that has an incidence between 1/4000 and 1/10,000 live births. The majority of cases are sporadic, with a small percentage (3–30%) of familial cases, the aetiology being unknown in most patients [8, 9]. Short stature, ranging from moderate to severe, is the essential phenotypic feature in IGHD and is associated with a poor growth velocity with delayed skeletal maturation. Children with GHD are usually treated with recombinant human GH (rhGH) and generally respond well [9]. A number of genetic forms of GHD have been described. Autosomal recessive IGHD type IA patients present with severe growth failure in the first 6 months of life with undetectable GH concentrations. These patients frequently develop anti-GH antibodies after receiving exogenous GH, which prevent the growth response anticipated after rhGH therapy [10]. Heterogeneous homozygous GH1 deletions, most frequently measuring 6.7 kb in length, were first described and remain the most common GH1 gene alteration in patients with IGHD type IA [11], with other severe loss-of-function GH1 mutations described subsequently (Table 1.1). Type IB GHD is associated with recessive mutations in GH1 and GHRHR, the latter also known as Sindh dwarfism [12]. Missense, frameshift, nonsense or splice site mutations may occur in GH1 in patients from consanguineous pedigrees and specific ethnic backgrounds, for example, IVS4 + 1G → T, p.G120 V and p.C182X, respectively [5, 13, 14]. Type IB GHD due to GHRHR mutations is not a classical IGHD phenotype, in that these patients have minimal facial hypoplasia and no microphallus but do manifest anterior pituitary hypoplasia (APH) on magnetic resonance imaging (MRI) [15]. Patients that harbour GHRHR mutations are usually from consanguineous pedigrees from Brazil or the Indian subcontinent [16]. The vast majority of GHRHR mutations are associated with complete loss of function, for example, p.W273S and p.A176V [8, 17], and usually affect cAMP production, such as the p.K329E substitution that fails to show any cAMP response following GHRH treatment in in  vitro studies [18]. The first, and still the most common, GHRHR mutation is p.E72X resulting in a truncated protein devoid of both the

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Table 1.1  Genes associated with congenital hypopituitarism and related phenotypes, and their inheritance patterns Gene GH1

Phenotype IGHD type IA IGHD type IB IGHD type II GHRHR IGHD type IB RNPC3 IGHD TSHB TSHD TRHR

TSHD

IGSF1

TSHD, hypoprolactinemia, transient GHD; usually with macroorchidism TSHD IAD IAD; early-onset obesity and red hair pigmentation IAD, GHD, TSHD, DI

TBL1X TBX19 POMC PCSK1

TCF7L1 SOD HESX1 IGHD CPHD SOD SOX2 HH, anophthalmia/microphthalmia Hypothalamo-pituitary tumour SOX3 CPHD and absent infundibulum GHD OTX2 SOD CPHD IGHD LHX3 CPHD, short neck with limited rotation LHX4 CPHD PROP1 CPHD POU1F1 CPHD PROKR2 HH/KS SOD FGFR1 HH/KS SOD FGF8 HH/KS HPE SOD KAL1 HH/KS SOD KS

Inheritance Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive Autosomal recessive Compound heterozygous Autosomal recessive Compound heterozygous X-linked X-linked Autosomal recessive Autosomal recessive Compound heterozygous Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive Autosomal dominant X-linked Autosomal dominant: haploinsufficiency or dominant negative Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant Autosomal dominant Autosomal dominant Autosomal recessive X-linked

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Table 1.1 (continued) Gene GLI2

Phenotype HPE IGHD/ CPHD HH CDON PSIS GPR161 PSIS ROBO1 PSIS ARNT2 CPHD PNPLA6 Oliver–McFarlane and Laurence–Moon syndrome KCNQ1 GHD, maternally inherited gingival fibromatosis IFT172 GHD, retinopathy, metaphyseal dysplasia, renal failure (ciliopathies)

Inheritance Autosomal dominant: Haploinsufficiency Autosomal dominant Autosomal recessive Autosomal dominant Autosomal recessive Autosomal recessive Autosomal dominant Compound heterozygous

IGHD isolated growth hormone deficiency, TSHD thyroid-stimulating hormone deficiency, IAD isolated adrenocorticosteroid hormone deficiency, DI diabetes insipidus, SOD septo-optic dysplasia, CPHD combined pituitary hormone deficiency, HH hypogonadotropic hypogonadism, KS Kallmann syndrome, HPE holoprosencephaly, PSIS pituitary stalk interruption syndrome

transmembrane and intracellular domains (Wajnrajch et al. 1996). A recent study described a novel partial loss-of-function homozygous GHRHR mutation, p.P79L, which gives rise to an unusually mild form of IGHD in two unrelated families. The patients were compound homozygous, with a second homozygous variant in GHRHR, p.R4Q, which was not associated with functional impairment [19]. Heterozygous mutations in the GH1 gene commonly affect splicing resulting in exon skipping, leading to the most common autosomal dominant form of GHD, known as type II GHD [20] (Table 1.1). The shorter 17.5 kDa GH isoform, resulting from the skipping of exon 3, has been reported to exert a dominant negative effect on GH secretion, with expression levels directly related to severity of the disorder [21, 22]. Heterozygous GH1 missense mutations, such as p.E32A, p.R178H and p.R183H, have also been described in GHD type II. These patients have variable height deficit and severity, occasionally with a height within the normal range, and may develop additional pituitary hormone deficiencies over time, including ACTH, TSH and gonadotrophin deficiencies [8]. To date, no mutations in GHRH have been described in association with IGHD. In addition to GH1 and GHRHR, mutations have recently been reported in RNPC3 in patients with GHD. The RNA-binding region (RNA recognition motifs [RRM]) containing 3 on chromosome 1 encodes a 65 K protein component of the U12-type spliceosome. It contains two bipartite nuclear targeting sequences important for nuclear targeting for proteins, especially those functioning in the cell nucleus itself, and its two RRM motifs suggest that it may contact one of the small nuclear RNAs of the minor spliceosome [23]. Biallelic mutations in RNPC3 have been described in three sisters with severe IGHD and pituitary hypoplasia, where anomalies were identified in U11/U12 di-snRNP formation and the splicing of multiple U12-type introns in these patient cells [24]. Through RNA sequencing the

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authors identified a list of 21 genes with significantly decreased U12/U2 ratios in patient cells, as well as aberrant processing events including exon skipping and activation of cryptic U2-type splice sites [24]. A subset of the 21 genes were found to encode proteins with relevant functions in pituitary development, such as SPCS2 and SPCS3 that encode subunits of the signal peptidase complex, implicated in post-translational processing of preprohormones such as preproghrelin to proghrelin [24, 25], thus themselves becoming candidates for GHD.  However, the exact mechanism underlying the GH deficiency remains to be established. No murine model for Rnpc3 loss of function exists; however studies using a zebrafish mutant model with an induced lethal point mutation in rnpc3 have provided a useful and specific model of aberrant U12-type splicing in  vivo. Results showed that the formation of aberrant U11- and U12-containing snRNAs sufficiently impaired the efficiency of U12-type splicing to cause arrested development in the intestine, liver and pancreas. Analysis of the zebrafish transcriptome revealed that efficient mRNA processing is a critical process for the growth and proliferation of cells during vertebrate development [26]. Additionally, mutations have occasionally been described in IGHD patients in genes encoding early (HESX1, SOX2, SOX3 and OTX2) or late (PROP1 and POU1F1) transcription factors implicated in murine and human pituitary development [9, 27, 28].

Other Isolated Hormone Deficiencies and Abnormalities Congenital functional failure of a single lineage has been reported for all pituitary cell types, giving rise to isolated hormone deficiencies other than IGHD, such as isolated TSH deficiency (TSHD), isolated hypogonadotropic hypogonadism [IHH; LH and FSH deficiency] that may be part of KS, isolated ACTH deficiency (IAD) and, very rarely, isolated PRL deficiency (PRLD) [29]. Interestingly, an increased prolactin is more likely to occur in children with congenital hypopituitarism, particularly those with midline defects, as opposed to a decrease. Although rare, isolated PRLD also known as hypoprolactinaemia clinically manifests only in women as puerperal alactogenesis, namely, the failure of milk production during breastfeeding [30]. One such familial case involved a mother and daughter that had eight pregnancies cumulatively, all followed by puerperal alactogenesis resulting from isolated PRLD [31]. The aetiology of isolated PRLD is as yet unknown, and candidate genes often screened are those found to be mutated in patients with PRLD as part of combined pituitary hormone deficiency (CPHD) and that are known to be involved in the lineage differentiation of lactotrophs, such as POU1F1, PROP1, LHX3, LHX4, HESX1 and OTX2 [32] (Table 1.1). In TSHD, inadequate thyroid hormone biosynthesis occurs due to defective stimulation of the thyroid gland by TSH, therefore causing central, or secondary, hypothyroidism in the affected patients. In some rare cases, mutations in genes regulating TSH biosynthesis and secretion, namely, TSHB, TRHR and more recently IGSF1, have been described in patients with isolated TSHD [33, 34]. In addition, a homo-

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zygous frameshift mutation in PROP1 in a pedigree has been reported to be associated with isolated central hypothyroidism presenting at a young age [35], indicating that this well-known CPHD causative gene should also be considered in the diagnosis of TSHD. Mutations in TSHB, encoding the TSHβ subunit, have previously been identified in hypothyroid patients, with TSH concentrations that are highly variable, and not always detectable [36, 37]. The most frequently occurring TSHB mutation, c.373delT (C105Vfs114X) [37], causing secondary hypothyroidism is known as a mutational ‘hotspot’ in TSHB and has been identified in homozygous form in several populations worldwide [38]. It has also been identified in compound heterozygosity with p.Q49X [39], a 5.4kb TSHB deletion (c.1-4389_417*195delinsCTCA) and a missense p.M1P variant [40], amongst others. Screening using both T4 and TSH is a highly sensitive method for detecting congenital hypothyroidism in neonates and helps prevent mental retardation, which could be a consequence of delayed diagnosis [41]. Rare recessive biallelic inactivating mutations in TRHR, namely, p.S115T117del and p.A118T, have been reported in three affected individuals from two unrelated pedigrees with central congenital hypothyroidism (CCH), with absent TSH and prolactin responses to exogenous TRH [42, 43]. More recently, the p. P81R missense mutation described in isolated CCH highlights the importance of the second transmembrane helix in mediating TRH receptor activation via hormone binding, making it the first deleterious missense TRHR defect that gives rise to CCH [44]. In addition, a recently identified novel homozygous mutation, p.I131T, that decreases TRH affinity was identified in an overweight patient with CCH and normal stature [33]. More recently, IGSF1 mutations have been associated with an X-linked form of central hypothyroidism associated with macroorchidism; mutations include missense, nonsense, frameshift and submicroscopic gene deletions incorporating IGSF1 [34, 45]. Igsf1 is expressed in murine pituitary thyrotroph, lactotroph and somatotroph cells [34] and in Leydig and germ cells in murine/human testes, with very low levels in Sertoli cells [46]. Furthermore, the latter study implies that IGSF1 stimulates transcription of TRHR by negative modulation of the TGFβ1-Smad ­signalling pathway, thereby enhancing TSH synthesis and biopotency. In contrast, IGSF1 is suggested to downregulate the activin-Smad pathway, leading to reduced expression of FSHB secreted by gonadotropes. The authors describe a large hemizygous 207.873 Kb deletion on Chr. Xq26.2 associated with hypothyroidism with reduced TSH biopotency, increased secretion of FSH in neonatal minipuberty and macroorchidism from 3 years of age [46]. Macroorchidism does not appear to be a phenotypic feature in all patients with IGSF1 mutations [47], and interestingly, heterozygous female carriers of these IGSF1 mutations may sometimes manifest mild hypothyroidism [48]. Igsf1-deficient male mice (Igsf1_ex1male) show diminished pituitary and serum TSH concentrations, pituitary TRH receptor expression and triiodothyronine concentrations and increased body mass [34]. Recent studies have shown that Igsf1-deficient male mice with a loss-of-function mutation in the C-terminal domain exhibit reduced expression of the TSH subunit genes as well as

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TSH and TRH proteins. Addition of exogenous TRH resulted in TSH release, albeit to a significantly lesser extent than wild-type littermates [49]. The X-linked transducin β-like protein 1 (TBL1X) gene is a component of the thyroid hormone receptor-corepressor complex, mutations in which have been previously associated with sensorineural hearing loss [50]. In a recent study, six mutations in unrelated pedigrees with congenital isolated central hypothyroidism have been identified [51]. Like IGSF1, TBL1X is associated with an X-linked form of TSHD. Isolated ACTH deficiency (IAD) is a very rare and heterogeneous condition making diagnosis very difficult due to the varied clinical presentation. It may be lethal due to the hypocortisolism and has also been associated with neonatal hypoglycaemia, convulsions, hypercalcaemia [52] and/or cholestasis that can be associated with a 20% mortality rate if unrecognized [53, 54]. IAD patients have also presented with an empty sella and severe hyponatraemia [55]. TBX19, formally known as TPIT, plays a critical role in the terminal differentiation of the pituitary pre-pro-opiomelanocortin (POMC) lineages, namely, corticotrophs and melanotrophs. Mutations in TBX19 have been associated with early-onset IAD [56] and have been found in up to 2/3 of neonatal cases, with complete or severe loss of function as exemplified by studies of DNA binding and/or transactivation [57]. These TBX19 mutations are most often substitutions in the DNA-binding Tbox domain, thereby resulting in impaired DNA binding or protein-protein interaction. However, premature stop codons, aberrant splicing and chromosomal deletions have also been reported in this gene [58]. A recent study described compound heterozygosity in TBX19, with a novel frameshift p.Arg222Lysfs*4 mutation and the previously described p.R286X mutation, respectively, in a patient with IAD combined with recurrent respiratory tract infections. The authors concluded that adrenal insufficiency should be considered in patients with unexplained recurrent infections to prevent a delay in diagnosis [59]. The serial cleavage of POMC by prohormone convertases (PCs) generates ACTH in corticotrophs (PC1) and melanocyte-stimulating hormone (αMSH) in melanotrophs (PC2) that bind to the melanocortin receptors (MC2-R, MC1-R and MC4-R, respectively) [60–62]. POMC mutations have been reported in association with IAD. MC1-R function is known to contribute towards hair and skin pigmentation in both mice and humans [63]. ACTH is the only known ligand for MC2-R located in the adrenals [64]. Antagonistic studies on MC4-R signalling have revealed its involvement in the regulation of food intake and in the aetiology of severe obesity in mice [65], which occurs in the absence of the MC4-R ligand α-MSH. Therefore patients with POMC mutations usually have the distinct phenotypic hallmarks of early-onset obesity and red hair, in addition to adrenal insufficiency with hypocortisolism and hypoglycaemia. The first POMC mutations described were the compound heterozygous p.G7013  T/p.C7133Δ and the homozygous p.C3804A identified, respectively, in such patients [66]. Compound heterozygosity has also been described in PCSK1, encoding PC1, in a female patient with ACTH and gonadotrophin deficiency, with severe obesity and glucose dysregulation [67]. PC1 has since been described as being essential for the normal absorptive function of the

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human small intestine, with compound heterozygosity identified in a second patient with malabsorptive severe refractory neonatal diarrhoea as the predominant phenotype. This patient, similar to the first, also had obesity, hypoadrenalism, reactive hypoglycaemia and elevated circulating levels of specific prohormones [68]. PC1-­ null mice confirm defective POMC and proinsulin processing seen in PC1-deficient humans; however, mice are growth retarded rather than obese [69]. Subsequent PCSK1 mutations have since been identified in patients, such as the nonsense p.Arg80* loss-of-function mutation, which produces a truncated protein with only 2 exons out of 14, and that co-segregated with obesity in a three-generation family [70]. Furthermore, recent studies have generated PCSK1 (PC1)-deficient human embryonic stem cell (hESC) lines, differentiated into hypothalamic neurons, to investigate POMC processing. Results showed that unprocessed POMC increased and processed POMC-derived peptides in PCSK1 knockout hESC-derived neurons decreased in cells, which phenotypically copies the POMC processing reported in PC1-null mice and PC1-deficient patients [71]. PC1/3-deficient patients often manifest hypothyroidism and hypocortisolism. However some patients may also present with an elevated TSH and ACTH, respectively [72]. In rare cases, GHD and diabetes insipidus may also occur in these patients, thus broadening disease manifestation in PCSK1 insufficient patients [73].

Septo-Optic Dysplasia SOD, also known as de Morsier syndrome, occurs in 1/10,000 live births with equal prevalence in males and females. It is a heterogeneous disorder with a variable phenotype, loosely defined by any combination of the triad of optic nerve hypoplasia (ONH), midline neuroradiological abnormalities (such as agenesis of the corpus callosum and absence of the septum pellucidum) and pituitary hypoplasia with consequent endocrine deficits [74, 75]. Approximately 40% of SOD patients may actually present with normal endocrinology. Intriguingly, SOD is associated with a younger maternal age, when compared with mothers of children with isolated defects of the HP axis [76]. The reason for this maternal age effect is unknown but has been suggested to be associated with increased maternal drug and alcohol abuse [77, 78]. Approximately 75–80% of patients exhibit ONH, which may be unilateral or, more commonly, bilateral (88% as compared with 12% unilateral cases), and may be the first presenting feature with later onset of endocrine dysfunction [79]. In rare cases, the eye abnormality may be more severe, resulting in microphthalmia or anophthalmia [80], where one or both of the eyes are abnormally small or completely absent, respectively. The association of midline abnormalities with hypopituitarism has long been established, suggesting a common developmental origin of the hypothalamus and pituitary and the midline structures within the brain [81]. Mutations in the gene encoding the transcriptional repressor HESX1 were the first to be associated with the pathogenesis of rare cases of SOD [82, 83]. Significant insights into the pathogenesis of the disorder were provided

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by the original studies, whereby murine transgenesis resulted in murine phenotypes highly reminiscent of SOD. Thereafter, human mutations have been cloned into mouse models and studied in depth, such as the first HESX1 mutation (p.R160C) identified [84]. More recently, SOX2, SOX3 and OTX2 have been shown to be mutated in rarer forms of SOD, with severe bilateral eye defects including microphthalmia or anophthalmia in patients with SOX2 and OTX2 mutations, and abnormalities of the hypothalamus, pituitary and the infundibulum as well as the corpus callosum in patients with SOX3 mutations [85] (Table 1.1). Recently, mutations in genes implicated in KS have also been linked with SOD; for example, two heterozygous KAL1 mutations were identified in three females from two unrelated families with SOD [86]. Prior to this, three patients with SOD were reported to have heterozygous mutations in FGFR1 that altered receptor signalling, with one predicted to affect splicing [87]. The same report also identified a heterozygous loss-of-function mutation, p.R268C, in PROKR2. This variant had previously been implicated in normosmic HH and KS. The heterozygous missense FGF8 mutation, p.Q216E, has also been described in an SOD patient with microcephaly and neurological defects. Interestingly, FGF8 has also been implicated in a patient with semilobar HPE, diabetes insipidus and TSH and ACTH insufficiency [6], making this KS gene a new candidate for both SOD and HPE. More recently, a defined role for TCF7L1 in the aetiology of SOD has been described. Conditional deletion of murine Tcf7L1 results in forebrain defects and partially penetrant dwarfism [88]. Heterozygous missense TCF7L1 variants were then subsequently identified in two unrelated SOD patients [88]. SOD can be associated with a wide range of phenotypic variability, highlighting the complexity of the disorder and suggesting the impact of both genetic and environmental factors involved in the aetiology of the disease [89]. Other associated features include developmental delay, seizures, visual impairment, sleep disturbance, precocious puberty, obesity, anosmia, sensorineural hearing loss and cardiac anomalies [77]. The majority of cases remain aetiologically unexplained. The following section describes the role of the genes linked with this disorder and other CH syndromes to date.

HESX1 The transcription factor HESX1 is a member of the paired-like class of homeodomain proteins which acts as a transcriptional repressor essential for pituitary organogenesis [83]. Binding partners of human HESX1 such as transducing-like enhancer of split 1 (TLE1) (ortholog of Groucho in Drosophila), the nuclear corepressor (N-COR) and DNA methyltransferase 1 (DNMT1) can all form complexes to enable it to exert its repressive activity [90, 91]. Hesx1 is one of the earliest markers of murine pituitary development, expressed initially during gastrulation in the region fated to form the forebrain and ventral diencephalon, and is then restricted to Rathke’s pouch by embryonic day (E) 9.0 [92]. Hesx1 continues to be

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expressed in the developing AP until E12, when it then disappears in a spatiotemporal sequence that corresponds to progressive pituitary cell differentiation [4]. Hesx1 transcripts have totally disappeared from the entire ventral portion by E13, giving rise to the anterior lobe of the pituitary [93]. A homozygous null mutation in mice results in a phenotype that resembles SOD, with 5% of Hesx1 null mice exhibiting a severe phenotype with no AP [90]. This is consistent with an insertion mutation in exon 3 in the ‘Alu’ element of HESX1 which was identified in a patient with a retinal coloboma associated with aplasia of the AP. The reported patient had undetectable concentrations of all AP hormones [94]. Patients with HESX1 mutations have variably penetrant phenotypes ranging from isolated GHD, evolving hypopituitarism in the absence of midline and eye defects, through to SOD and pituitary aplasia [95]. Hesx1 null mice show great phenotypic variability with features that include a reduction in forebrain tissue, craniofacial dysplasia with a short nose and absence of developing optic vesicles. These mice also have a significantly decreased head size, absence of telencephalic vesicles, absence of olfactory placodes, hypothalamic and infundibular abnormalities, and aberrant morphogenesis of Rathke’s pouch [83]. Rathke’s pouch formation was variably affected, and abnormal bifurcations were apparent, resulting in multiple pituitary glands in a proportion of the mice [82, 83, 96]. Although of variable severity, both neonatal and adult homozygous mutant mice manifested phenotypes that presented with eye defects such as microphthalmia and anophthalmia, with abnormalities of the septum pellucidum and corpus callosum, closely resembling SOD in humans.

SOX2 and SOX3 SOX2 and SOX3 are members of the SOXB1 subfamily of ‘SRY-related HMG box’ transcription factors. They have an N-terminal domain of unknown function, a DNA- binding high mobility group (HMG) box domain and a longer C-terminal domain involved in transcriptional activation [97]. Members of the SOXB1 subfamily are expressed throughout the CNS and are amongst the earliest neural markers that play a role in neuronal determination [98]. Murine Sox3 is shown to be involved in neurogenesis through its expression in actively dividing undifferentiated neural progenitor cells, and this expression is maintained throughout development [99]. Expression of Sox3 is also seen in the ventral diencephalon, infundibulum and presumptive hypothalamus, a similar expression pattern to that of Wnt5a expression [100]. Sox3-deficient mice exhibit expanded BMP and FGF signalling domains as well as abnormalities in Rathke’s pouch [101], suggesting a possible mechanism underlying the hypopituitary phenotype in these mutants [102]. The mutant mice exhibited variable complex phenotypes including craniofacial abnormalities, midline CNS defects and a reduction in size and fertility [101]. Mutations in SOX3 are usually associated with infundibular hypoplasia and an ectopic or undescended PP and have been shown to result in aggresome formation and impaired transactivation

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[103]. Duplications within the Xq24-q27.3 region [104], incorporating SOX3, have long been associated with X-linked hypopituitarism and mental retardation. SOX3 was the only gene that was found to be expressed in the murine infundibulum out of three annotated in the smallest duplication (690Kb) to date. Submicroscopic SOX3-­ spanning duplications at position Xq27.1 have since been described in patients with variable hypopituitary phenotypes including CPHD, absence or hypoplasia of the infundibulum and an abnormality of the corpus callosum [85]. Polyalanine expansions of SOX3 were initially associated with X-linked mental retardation and IGHD in a French pedigree that harboured an in-frame duplication of 33 bp encoding for 11 alanines in the SOX3 gene [105]. A further SOX3 polyalanine expansion was later associated with loss of function in a transcriptional assay in an X-linked pedigree with hypopituitarism [85]. Additionally, a 2.31-Mb deletion on Xq27, again incorporating SOX3, was identified in a patient with haemophilia B due to the loss of factor IX and CH due to loss of SOX3, with the unusual phenotype of a persistent craniopharyngeal canal on MRI [106], a phenotype that was replicated in Sox3 null mice. Furthermore, an 18 bp deletion in the polyalanine tract of SOX3 (p.A243_ A248del6) was identified in a CH patient, resulting in an increase in transcriptional activation [107]. These data highlight the critical gene dosage of SOX3 in normal development of the diencephalon and infundibulum and consequently the AP. SOX2 is expressed in neural progenitor populations throughout the developing and adult CNS and is necessary to maintain their progenitor identity [108]. After gastrulation, murine Sox2 expression is restricted to the presumptive anterior neuroectoderm and, by E9.5, is expressed throughout the CNS, brain, sensory placodes, branchial arches, gut endoderm, oesophagus and trachea. Homozygous null Sox2 mice fail to survive and die shortly after implantation [109], whereas heterozygous mice manifest hypoplasia and abnormal morphology of the AP, with subsequent reduction in GH, LH, ACTH and TSH concentrations [110]. Other studies have shown that retinal progenitor cells with conditionally ablated Sox2 lose competence to both proliferate and terminally differentiate. Additionally, Sox2 hypomorphic/ null mice, with a 40% reduction of Sox2 expression compared to wild-type (WT) mice, present with variable microphthalmia as a result of aberrant neural progenitor differentiation. Furthermore, this study suggests that Sox2/SOX2 activity functions in a dose-dependent manner in retinal progenitor cell differentiation [111]. The first description of SOX2 mutations in humans was in a cohort of individuals with severe eye phenotypes. De novo mutations were associated with bilateral anophthalmia, or severe microphthalmia, with accompanying developmental delay, learning difficulties, oesophageal atresia and genital abnormalities in males [112]. SOX2 expression in humans is observed throughout the human brain, including the developing hypothalamus as well as Rathke’s pouch and the eye [80]. Following on from these studies, SOX2 mutations have also been associated with AP hypoplasia and hypogonadotropic hypogonadism (HH) [110] and are usually associated with loss of function. These de novo mutations result in a loss of DNA binding, nuclear localization or transcriptional activation, suggesting that the phenotypes arise as a result of haploinsufficiency of SOX2 during development. Conditional deletion of Sox2 mutant mice in the hypothalamus and pituitary is associated with impaired gonado-

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trophin secretion as well as TSH and GH deficiencies. This suggests a critical role for Sox2 in the hypothalamus and/or the developing pituitary, particularly with respect to GnRH neuron specification [113]. In addition, SOX2 haploinsufficiency has been implicated in the generation of slow-progressing pituitary tumours in patients [114]. Furthermore, a very recent study [115] has implicated a role for SOX2 in melanotrope cell fate acquisition, independent of its early role in promoting progenitor proliferation. This study showed that SOX2 is maintained at low levels in melanotropes [115] where its expression is likely regulated by P27 [116]. Murine cells expressing Sox2 and E-cadherin are found throughout the RP in embryos but persist scattered throughout the adult gland, predominantly within a narrow zone lining the pituitary cleft. These postnatal Sox2+ cells also express Sox9 and S100 [117]. Interestingly, both embryonic and adult Sox2+ pituitary progenitor/ stem cells have shown the ability to differentiate into all hormone-producing lineages, contributing to organ homeostasis during postnatal life. Furthermore, the targeted expression of oncogenic β-catenin in Sox2+ cells gives rise to pituitary tumours [118]. Therefore Sox2+ pituitary stem/progenitor cells not only seem to be involved in long-term physiological maintenance of the adult pituitary, but they also appear accountable for driving tumorigenesis in vivo.

OTX2 OTX2 (orthodenticle homeobox 2) is a transcription factor that is required for the formation of anterior structures and maintenance of the forebrain and has been implicated in 2–3% of anophthalmia-/microphthalmia-related syndromes in humans [82]. In mice, the expression of Otx2 is localized to developing neural and sensory structures of the brain such as the cerebellum, the eye, nose and ear and is required at multiple steps in brain development and neuronal differentiation [119]. Mice homozygous for mutations die from severe brain abnormalities after exhibiting malformations in both the forebrain and the eye due to impaired gastrulation. Heterozygous mice can display a range of phenotypes from normal to severe forms of eye/brain abnormalities such as anophthalmia and HPE [120]. During retinal development, Otx2 regulates retinal pigment epithelium specification and photoreceptor and bipolar cell differentiation and maturation, with expression being maintained in these three cell types throughout life [121]. Otx2 transcripts and protein are normally detectable at E10.5  in both the ventral diencephalon and Rathke’s pouch. By E12.5 Otx2 transcripts are undetectable in Rathke’s pouch but persist in the ventral diencephalon until E14.5, and by E16.5, no Otx2 transcripts are detected in either structure [122]. A previous study showed that Otx2 expression persisted in Rathke’s pouch until E16.5 in Prop1-mutant mice, 4 days after the peak of Prop1 expression and 2 days after any pituitary defects become apparent [122]. This study suggests that Prop1 regulates expression of other factors that suppress Otx2, implying a role for Otx2 in murine pituitary development. Another study reported an HH phenotype in GnRH-neuron-Otx2 knockout mice [123]. These murine data are

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consistent with human OTX2 phenotypes, which are highly variable and include IGHD, hypopituitarism and HH, usually, but not invariably, associated with severe ocular malformations [124]. Furthermore, OTX2 regulates expression of transcription factors HESX1 and POU1F1, thereby influencing anterior pituitary development. In vitro functional analysis showed that mutant Otx2 abolished activation of the HESX1 promoter and was hypomorphic on the POU1F1 promoter [125]. Despite this knowledge, the precise role of OTX2 in hypothalamo-pituitary development still remains unclear [3]. In addition, in  vivo otocephaly gene suppression studies show that OTX2 loss-of-function mutations modify otocephaly and/or dysgnathia phenotypes in humans when in the presence of a second known otocephaly gene mutation. This suggests that mutant OTX2 contributes to the severity of craniofacial defects, such as those affecting the lower jaw [126].

GLI2 The GLI family zinc finger 2 (GLI2) transcription factor is a component of the SHH signalling pathway, known to be implicated in HPE and other midline neurodevelopmental anomalies [127, 128]. Unlike mutated SHH, described to specifically cause HPE, mutated GLI2 is also associated with CH in the absence of midline brain defects [129]. These patients have variable phenotypes ranging from IGHD to complex CPHD, in combination with variable polydactyly, cleft lip/palate, diabetes insipidus, dysmorphic features and an ectopic posterior pituitary on MRI [130– 132]. Truncated GLI2 is often reported in such cases, for example, p.L788fsX794, p.L694fsX722 and p.E380X, respectively [130], with complete loss of the C-terminal activator domain. In addition, haploinsufficient missense mutations such as p.E518K [129] and p.R516P [133], for example, have been implicated in the aetiology of CH in these patients. Incomplete or variable penetrance may also be apparent for GLI2 mutations, where a heterozygous mutation with functional consequences in the child is present in the unaffected parent or a parent with a mild form of the disease, respectively [129].

Pituitary Stalk Interruption Syndrome Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or discontinuous pituitary stalk, pituitary gland insufficiency and APH and/or an EPP on MRI. Interestingly, a novel missense mutation in CDON, another member of the SHH signalling pathway that causes HPE, has been reported in a patient with PSIS, with neonatal hypoglycaemia and cholestasis associated with GH, TSH, and ACTH deficiencies, without HPE [134]. This again demonstrates how mutated members of this crucial pathway may elicit other hypopituitary-related phenotypes, aside from their more established association with HPE. GPR161, encoding the orphan G

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protein-­coupled receptor 161, a transmembrane protein, has also been implicated in PSIS.  Whole exome sequencing revealed a homozygous missense mutation, p.L19Q, in a consanguineous family with two affected siblings with PSIS [135]. Despite the lack of functional analysis, prediction models and the hypothesis that GPR161 interacts with GLI2, GLI3 and the SHH pathway suggest a possible involvement of this gene in the aetiology of patients with PSIS [135]. ROBO1 is a receptor involved in Slit/Robo signalling that essentially controls embryonic axon guidance and branching in the nervous system during development [136]. ROBO1 is another gene that has recently been implicated in PSIS; a novel heterozygous frameshift, a nonsense and a missense mutation (p.A977Qfs*40, p.Y1114* and p.C240S, respectively) were identified in five affected patients. Ocular anomalies including hypermetropia with strabismus and ptosis were present in four out of five patients with PSIS (two familial and one sporadic case) [137]. Known CH causative genes including LHX4, OTX2, HESX1, SOX3, and PROKR2 have also been described to be mutated in rare cases of PSIS [28, 138, 139].

ARNT2 ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) is a member of the basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. This protein forms heterodimers with sensor proteins from the same family that then bind regulatory DNA sequences. Arnt2(-/-) null murine embryos die perinatally and exhibit impaired hypothalamic development [140]. Recent studies showed expression of ARNT2 within the CNS, including the hypothalamus, as well as the renal tract during human embryonic development. A homozygous frameshift ARNT2 mutation has been described in several individuals born to a highly consanguineous pedigree with congenital hypopituitarism. These patients exhibit GH, TSH and ACTH deficiencies associated with diabetes insipidus, progressive neurological abnormalities with microcephaly, renal tract abnormalities and post-retinal visual pathway dysfunction, indicating the essential role of ARNT2 in HP development and postnatal brain growth [141]. The disorder appears to be lethal, with several individuals dying in the first few years of life.

PNPLA6 Mutations in the PNPLA6 gene, , encoding neuropathy target esterase (NTE), are known to be associated with a spectrum of rare neurodegenerative conditions, including spastic paraplegia type 39 (SPG39), Gordon–Holmes syndrome (GHS) and Boucher–Neuhäuser syndrome (BNHS) [142, 143]. This gene has recently been implicated in two distinct neurodegenerative disorders: Oliver–McFarlane and Laurence–Moon syndromes. The phenotypes are characterized by

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chorioretinopathy, spinocerebellar ataxia, spastic paraplegia, learning difficulties, and trichomegaly. These disorders include pituitary dysfunction with a small anterior pituitary on MRI, including variable GHD and HH.  In humans, embryonic expression studies show PNPLA6 transcript expression in the developing eye, pituitary and brain. Significant reduction of NTE enzymatic activity was observed in fibroblast cells derived from Oliver–McFarlane syndrome patients. Additionally, full rescue of the pnpla6 morphant zebrafish was achieved using wild-type PNPLA6 mRNA, compared to only partial rescue with mutant PNPLA6 mRNAs [144]. These data signify that defective recessive PNPLA6 alleles can give rise to rare distinct phenotypes with variable neurodegenerative manifestations (Table 1.1).

KCNQ1 The paternally imprinted gene KCNQ1 encodes the alpha subunit of the voltage-­ gated ion channel Kv7.1, previously implicated in cardiac arrhythmia syndromes amongst other heart defects [145]. It is expressed in mouse and human somatotroph and gonadotroph cells in the postnatal pituitary, in hypothalamic GHRH neurons during murine development and in the human hypothalamus [146]. Mutations in KCNQ1 (p.R116L and p.P369L) have recently been described in patients with GHD, maternally inherited gingival fibromatosis and accompanying mild craniofacial dysmorphic features [146] (Table  1.1). Phenotypic variability is apparent in patients harbouring mutations, even between monozygotic twins where one had more severe growth failure during childhood than the other. This study demonstrates how ion channels are clinically relevant regulators of pituitary function in humans, which supports previous data implicating voltage-gated potassium channel currents in pituitary cells [147–149].

IFT172 The IFT172 gene encodes a subunit of the intraflagellar transport (IFT) subcomplex IFT-B, necessary for ciliary assembly and maintenance. Mutations in IFT172 have previously been associated with skeletal ciliopathies, with or without polydactyly, that in turn are often associated with retinal, cerebellar or hepatorenal malformations [150–152]. Interestingly, a patient with early growth retardation, APH and an EPP on their MRI harboured compound heterozygous mutations in IFT172, p.C1727R and a novel splice site mutation in intron 4 and c.337–2A >C, identified through WES.  This patient manifested retinopathy associated with metaphyseal dysplasia and hypertension with renal failure, indicative of a ciliopathy [153]. This was the first report of an IFT172 mutation present in a patient who presented with GHD in early childhood, signifying the role of ciliary function in pituitary development and the bridge between early-onset growth failure and ciliopathies (Table 1.1).

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Furthermore, Alström syndrome, a rare autosomal recessive disease characterized by multiorgan dysfunction and associated with GHD, is caused by a mutation in ALMS1, encoding a protein that localizes to the centrosomes and basal bodies of ciliated cells [154].

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117. Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci U S A. 2008;105(8):2907–12. 118. Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, et  al. Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell. 2013;13(4): 433–45. 119. Frantz GD, Weimann JM, Levin ME, McConnell SK.  Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J Neurosci. 1994;14(10): 5725–40. 120. Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J. A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development. 1996;122(1):243–52. 121. Housset M, Samuel A, Ettaiche M, Bemelmans A, Beby F, Billon N, et al. Loss of Otx2 in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration. J Neurosci. 2013;33(24):9890–904. 122. Mortensen AH, MacDonald JW, Ghosh D, Camper SA.  Candidate genes for panhypopituitarism identified by gene expression profiling. Physiol Genomics. 2011;43(19): 1105–16. 123. Diaczok D, DiVall S, Matsuo I, Wondisford FE, Wolfe AM, Radovick S.  Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. Mol Endocrinol (Baltimore, Md). 2011;25(5):833–46. 124. Gorbenko Del Blanco D, Romero CJ, Diaczok D, de Graaff LC, Radovick S, Hokken-­ Koelega AC.  A novel OTX2 mutation in a patient with combined pituitary hormone deficiency, pituitary malformation, and an underdeveloped left optic nerve. Eur J Endocrinol. 2012;167(3):441–52. 125. Tajima T, Ohtake A, Hoshino M, Amemiya S, Sasaki N, Ishizu K, et  al. OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J Clin Endocrinol Metab. 2009;94(1): 314–9. 126. Chassaing N, Sorrentino S, Davis EE, Martin-Coignard D, Iacovelli A, Paznekas W, et  al. OTX2 mutations contribute to the otocephaly-dysgnathia complex. J Med Genet. 2012;49(6):373–9. 127. Roessler E, Du YZ, Mullor JL, Casas E, Allen WP, Gillessen-Kaesbach G, et  al. Lossof-­ function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A. 2003;100(23): 13424–9. 128. Roessler E, Ermilov AN, Grange DK, Wang A, Grachtchouk M, Dlugosz AA, et al. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum Mol Genet. 2005;14(15):2181–8. 129. Gregory LC, Gaston-Massuet C, Andoniadou CL, Carreno G, Webb EA, Kelberman D, et al. The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clin Endocrinol (Oxf). 2015;82(5):728–38. 130. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Vasques GA, Leite CC, et al. Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab. 2010;95(11): E384–91. 131. Franca MM, Jorge AA, Carvalho LR, Costalonga EF, Otto AP, Correa FA, et al. Relatively high frequency of non-synonymous GLI2 variants in patients with congenital hypopituitarism without holoprosencephaly. Clin Endocrinol (Oxf). 2013;78(4):551–7. 132. Bear KA, Solomon BD, Antonini S, Arnhold IJ, Franca MM, Gerkes EH, et al. Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly. J Med Genet. 2014;51(6):413–8.

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133. Flemming GM, Klammt J, Ambler G, Bao Y, Blum WF, Cowell C, et al. Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency. J Clin Endocrinol Metab. 2013;98(3):E567–75. 134. Bashamboo A, Bignon-Topalovic J, Rouba H, McElreavey K, Brauner R. A nonsense mutation in the hedgehog receptor CDON associated with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2016;101(1):12–5. 135. Karaca E, Buyukkaya R, Pehlivan D, Charng WL, Yaykasli KO, Bayram Y, et  al. Whole-­ exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2015;100(1):E140–7. 136. Blockus H, Chedotal A. The multifaceted roles of Slits and Robos in cortical circuits: from proliferation to axon guidance and neurological diseases. Curr Opin Neurobiol. 2014;27:82–8. 137. Bashamboo A, Bignon-Topalovic J, Moussi N, McElreavey K, Brauner R.  Mutations in the human ROBO1 gene in pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2017;102(7):2401–6. 138. Diaczok D, Romero C, Zunich J, Marshall I, Radovick S. A novel dominant negative mutation of OTX2 associated with combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2008;93(11):4351–9. 139. Reynaud R, Jayakody SA, Monnier C, Saveanu A, Bouligand J, Guedj AM, et al. PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab. 2012;97(6):E1068–73. 140. Keith B, Adelman DM, Simon MC. Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt. Proc Natl Acad Sci U S A. 2001;98(12):6692–7. 141. Webb EA, AlMutair A, Kelberman D, Bacchelli C, Chanudet E, Lescai F, et al. ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies. Brain: J Neurol. 2013;136(Pt 10):3096–105. 142. Rainier S, Bui M, Mark E, Thomas D, Tokarz D, Ming L, et al. Neuropathy target esterase gene mutations cause motor neuron disease. Am J Hum Genet. 2008;82(3):780–5. 143. Topaloglu AK, Lomniczi A, Kretzschmar D, Dissen GA, Kotan LD, McArdle CA, et  al. Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J Clin Endocrinol Metab. 2014;99(10):E2067–75. 144. Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, et al. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015;52(2):85–94. 145. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12(1):17–23. 146. Tommiska J, Kansakoski J, Skibsbye L, Vaaralahti K, Liu X, Lodge EJ, et al. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nat Commun. 2017;8(1):1289. 147. Stojilkovic SS, Tabak J, Bertram R. Ion channels and signaling in the pituitary gland. Endocr Rev. 2010;31(6):845–915. 148. Stojilkovic SS, Bjelobaba I, Zemkova H. Ion channels of pituitary gonadotrophs and their roles in signaling and secretion. Front Endocrinol. 2017;8:126. 149. Xu R, Roh SG, Loneragan K, Pullar M, Chen C. Human GHRH reduces voltage-gated K+ currents via a non-cAMP-dependent but PKC-mediated pathway in human GH adenoma cells. J Physiol. 1999;520(Pt 3):697–707. 150. Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, et al. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007;39(6):727–9.

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151. Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A, Brackman D, et al. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet. 2011;89(5):634–43. 152. Waters AM, Beales PL.  Ciliopathies: an expanding disease spectrum. Pediatr Nephrol (Berlin, Germany). 2011;26(7):1039–56. 153. Lucas-Herald AK, Kinning E, Iida A, Wang Z, Miyake N, Ikegawa S, et al. A case of functional growth hormone deficiency and early growth retardation in a child with IFT172 mutations. J Clin Endocrinol Metab. 2015;100(4):1221–4. 154. Romano S, Maffei P, Bettini V, Milan G, Favaretto F, Gardiman M, et  al. Alstrom syndrome is associated with short stature and reduced GH reserve. Clin Endocrinol (Oxf). 2013;79(4):529–36.

Chapter 2

Genetics of Hypopituitarism Mariam Gangat and Sally Radovick

Key Points • Coordinated temporal and spatial expression of numerous transcription factors is essential for normal pituitary gland development and function. • The pituitary gland is responsible for the production of hormones that play a crucial role in growth, metabolism, puberty and reproduction, lactation, and stress response. • Several mutations in patients with hypopituitarism have been identified; however, the vast majority of patients remain labeled idiopathic. • Next-generation sequencing technology is expanding our understanding of the underlying genetic mechanisms of hypopituitarism and has the potential of revolutionizing clinical care.

Case Presentation A 5-year and 3-month-old boy was referred to the pediatric endocrinology clinic for evaluation of short stature. Other than his height, his parents did not have any concerns and reported him to be a healthy child. His birth history was normal with a weight of 3.4 kg and length of 49 cm, without a history of jaundice or hypoglycemia. His height measurement was 94  cm (−3.6 SDS) with a midparental target M. Gangat (*) Pediatric Endocrinology, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ, USA e-mail: [email protected] S. Radovick Department of Pediatrics, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ, USA © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_2

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height of 178  cm, and weight was 14  kg (−0.17 SDS), resulting in a BMI of 15.84 kg/m2 (63rd percentile). A review of his growth charts from the pediatrician showed a poor growth velocity since birth. On exam, he had an absence of dysmorphic features or midline defects and normal-appearing external male genitalia without a micropenis. His initial screening laboratory studies revealed a normal complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), celiac panel, and urine analysis; however, low levels of serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGF-BP3)) were seen. His bone age X-ray showed delayed skeletal maturation. Growth hormone stimulation testing with arginine and clonidine revealed subnormal growth hormone levels with a peak level less than 5 ng/mL. MRI imaging revealed a hypoplastic anterior pituitary with a normally positioned stalk and posterior bright spot. In light of the imaging, further laboratory workup was ordered, which revealed a low free T4 level of 0.6 ng/dL, with an inappropriately normal TSH of 1.8 μIU/mL, and a low prolactin level. No other pituitary abnormalities were found with appropriately prepubertal gonadotropin levels and a normal AM cortisol level of 15.2 μg/ dL. The patient was started on injections of recombinant growth hormone at a dose of 0.6 mg daily as well as levothyroxine orally, resulting in a significant improvement in growth velocity.

I ntroduction and Clinical Presentation of Hormone Deficiencies The pituitary gland lies in the hypophyseal fossa, the deepest part of the sella turcica, located in the sphenoid bone of the neurocranium. It is comprised of two distinct structures, the adenohypophysis (anterior and intermediate lobes) and neurohypophysis (posterior lobe), which differ in embryologic origin. The anterior originates from Rathke’s pouch, an invagination of the oral ectoderm, while the posterior lobe arises from the neuroectoderm. Numerous transcription factors act in a coordinated temporal and spatial sequence during pituitary development and ultimately result in the differentiation of specific pituitary cell lineages. The anterior lobe has five distinct cell types that produce six hormones: somatotrophs (growth hormone [GH]), thyrotrophs (thyrotropin also known as thyroid-stimulating hormone, [TSH]), gonadotrophs (luteinizing hormone [LH] and follicle-stimulating hormone, [FSH]), lactotrophs (prolactin), and corticotrophs (adrenocorticotropin, [ACTH]). These hormones play a crucial role in growth, metabolism, puberty and reproduction, lactation, and stress response. Combined pituitary hormone deficiency (CPHD), defined as the deficiency of more than one anterior pituitary hormone, is associated with severe morbidity and can be life-threatening. The clinical presentation varies depending on age as well as the number and severity of hormone deficiencies. Many findings are non-specific, especially in the newborn period, mandating a high index of suspicion, particularly in patients with midline defects.

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Newborns with growth hormone deficiency (GHD) may not show overt growth failure and, however, may present with hypoglycemia and prolonged jaundice. When combined with gonadotropin deficiency, genitourinary abnormalities such as microphallus and cryptorchidism can be seen. Children present with growth failure evidenced by poor growth velocity, short stature, and an increased weight-to-height ratio. Pulsatile secretion and the short half-life of GH limit the use of random serum GH levels. However, IGF-1, the primary mediator of the actions of GH, and its most abundant carrier protein, IGF-BP3, are stable throughout the day and therefore useful screening labs. Growth hormone stimulation testing, although imperfect, [1] can be performed using several protocols [2] and can aid in establishing the diagnosis of GHD. Recombinant growth hormone is the treatment of choice and is commonly administered once daily via subcutaneous injections. Although congenital hypothyroidism (CH) due to TSH deficiency is rare, early diagnosis and treatment are critical to prevent adverse neurological outcomes [3]. Infants can present with myxedema, hypotonia, hoarse cry, poor feeding, macroglossia, umbilical hernia, large fontanels, hypothermia, and prolonged jaundice. Some symptoms overlap with those seen in childhood such as lethargy, constipation, and dry skin. Additional features seen in children include poor linear growth, cold intolerance, brittle hair, and a decline in academic performance. Newborn screening protocols for CH vary by state, and central hypothyroidism can be missed with primary TSH with backup thyroxine (T4) measurements [3]. If suspected, free or total T4 should be assessed since TSH can be inappropriately normal. Levothyroxine (synthetic form of T4) is the treatment of choice. Hypogonadotropic hypogonadism resulting from deficient secretion of LH and FSH can lead to genitourinary abnormalities as discussed above in boys; however, the prevalence of these findings at birth is low, suggesting maternal hCG has an important role in fetal testosterone production. Newborn girls have normal-­ appearing external genitalia. Within the first few months of life, infants experience a transient activation of the hypothalamic-pituitary-gonadal axis. This process, sometimes referred to as “mini-puberty,” leads to penile and testicular growth in males and maturation of ovarian follicles in females; however, the biological relevance remains unclear [4]. Low gonadotropin and sex steroid levels during this brief window can lead to early identification of congenital hypogonadotropic hypogonadism. Failure to undergo pubertal development with its associated growth spurt is seen later in childhood and adolescence and is the most common presentation of isolated hypogonadotropic hypogonadism. Prepubertal serum concentrations of sex steroid hormones along with low or “normal” serum LH and FSH concentrations are seen. A prepubertal biochemical profile is also seen in constitutional delay of growth and puberty, making the distinction between these two conditions challenging. Sex steroid treatment goals include attainment of secondary sex characteristics, normal growth spurt, and fertility preservation. The main physiologic role of prolactin is for lactation. Isolated prolactin deficiency is rare, and therefore identified patients often have manifestations of other pituitary hormone deficiencies [5].

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ACTH deficiency (secondary adrenal insufficiency) results in cortisol deficiency, the primary glucocorticoid secreted by the adrenal cortex. Cortisol is essential for stress response and has significant effects on carbohydrate, protein, and fat metabolism as well as anti-inflammatory effects. Generally, the presentation of anterior pituitary hormone deficiencies is similar to primary deficiencies of the target organs they control; however, there are two distinct differences between primary and secondary adrenal insufficiency. ACTH deficiency does not lead to mineralocorticoid deficiency, as this pathway is primarily regulated by the ­renin-angiotensin-­aldosterone system, and therefore does not result in salt wasting, hyperkalemia, and volume contraction. However, hyponatremia can be seen in secondary adrenal insufficiency due to inappropriate secretion of vasopressin [6]. Second, ACTH deficiency is not associated with hyperpigmentation, which results from high circulating ACTH and other melanocyte-stimulating hormone levels. Initial laboratory studies should include cortisol (measured around 8 am once diurnal patterns are established) and ACTH levels. Low-dose (1  μg) cortrosyn (synthetic ACTH) stimulation testing can aid in confirming the diagnosis. In an adrenal crisis, emergency treatment is crucial, starting with fluid resuscitation, intravenous glucose, and parenteral glucocorticoid treatment. Chronic treatment may require oral glucocorticoid replacement at physiologic doses, typically lower compared to treatment of primary adrenal failure, with stress dosing as needed. Clinical status, weight gain, and growth velocity need to be monitored closely to avoid overtreatment. Patients with partial ACTH deficiency may only need glucocorticoid treatment at times of increased physiologic stress.

PROP1 Prophet of Pit-1 (Prop1) is a pituitary-specific transcription factor that plays a critical role in the differentiation of somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs. The human PROP1 gene, located at chromosomal position 5q35, has at least 3 exons encoding 226 amino acid proteins and spans less than 4  kb of genomic DNA. It contains both a paired-like DNA-binding protein and a C-terminal transactivation domain [7]. Mutations in the PROP1 gene are the most frequent genetic defects identified in patients with CPHD [8]. In a study of 10 unrelated CPHD kindreds, 55% (11 of 20) of the PROP1 alleles had the 301-302delAG deletion in exon 2. The same study evaluated 21 sporadic cases of CPHD, and although only 12% of the PROP1 alleles were 301delAG, when the sporadic cases were subdivided into a multiple hypopituitary group and a multiple hypothalamic group based on TRH stimulation testing, the frequency increased to 50% in the hypopituitary group [8]. Analysis of a tightly linked polymorphic marker, D5S408, led the authors to conclude that these deletions may be independent recurring mutations rather than being inherited from a single common founder mutation [8]. A later study of 73 individuals with CPHD found that 35 patients had PROP1 gene defects, including 3 missense

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mutations, 2 frameshift mutations, and 1 splice site mutation [9]. Three tandem repeats of the dinucleotides GA at location 296–302 were identified as a hot spot [9]. Mutations typically involve the DNA-binding homeodomain; however, a mutation affecting the transactivating domain resulting in a truncated protein with only 34% activity of that of the wild-type PROP1 has been reported, suggesting a critical functional role of the C-terminal end of the transcription factor in proteinDNA interaction [10]. Studies on the Ames dwarf (df) mouse, which harbors a missense mutation in the Prop1 gene, leading to attenuated DNA-binding and transactivation capacity, show that Prop1 messenger RNA (mRNA) is expressed in the developing pituitary gland before Pit-1 mRNA expression, with maximal expression by e12.0 [11]. Prop1 plays a critical role in the expression of Pit1 and the development of Pit1-dependent cell lineages (somatotroph, lactotroph, and thyrotroph) in early pituitary organogenesis [11]. PROP1 involvement in gonadotropin and ACTH deficiencies has been explored; however, the mechanisms remain unclear [12]. The first reports of humans with CPHD due to mutations of the PROP1 gene found that in contrast to individuals with POU1F1 mutations, gonadotropin deficiency is present and therefore affected individuals do not enter puberty spontaneously, suggesting a direct or indirect role for PROP1 in gonadotroph ontogenesis [13]. Interestingly, isolated hypogonadotropic hypogonadism was the initial presentation in three brothers from a consanguineous family found to be homozygous for a nonsense mutation (W194X) in the PROP1 gene [14]. A retrospective analysis of nine CPHD patients with known PROP1 mutations found that all patients developed progressive decline with age in anterior pituitary function, including adrenal insufficiency. All patients developed at least partial adrenal insufficiency and eventually needed hydrocortisone replacement at a mean age of 18.4 +/− 3.5 years [15]. Further, evaluation of a large consanguineous Indian CPHD pedigree with homozygosity for a 13-bp deletion in exon 2 predicted to generate a null allele revealed severe cortisol deficiency in two patients. These data suggest a role for PROP1 in the differentiation and/or maintenance of corticotroph cells and highlight that the impairment of the pituitaryadrenal axis in CPHD patients does not exclude an underlying PROP1 gene defect [16]. Phenotypic variability, even among patients with the same mutation, has been described. A study of five patients with CPHD, homozygous for the R120C mutation, showed that each patient followed a different pattern and time scale in the development of pituitary hormone deficiencies; the age at diagnosis was dependent on the severity of symptoms. Although all five patients eventually presented with gonadotropin deficiency, they all entered puberty, and two females experienced menarche [17]. The most consistent feature is short stature; however, normal growth and attainment of normal adult height have been reported [10, 18]. One such patient was a female with expected hypogonadotropic hypogonadism, who continued to grow until age 20 years at which time she reached a normal adult height. The lack of circulating estrogen delaying epiphyseal fusion and resulting in a prolonged period of growth was noted among the contributing factors [18].

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Magnetic resonance imaging (MRI) of the brain in most patients showed some degree of anterior pituitary hypoplasia with a normal-appearing stalk and posterior pituitary; however, normal and even pituitary enlargement has been reported [19, 20]. It has also been shown that pituitary morphology can change over time in patients with PROP1 mutations. MRI imaging on an 8-year-old female with severe short stature, homozygous for the 301AG deletion, initially showed pituitary gland enlargement (8 mm in height). Repeat imaging at age 15 years showed a significantly reduced pituitary height of 2 mm [20].

POU1F1 (PIT1) POU1F1 (also known as PIT1) is pituitary-specific transcription factor essential for the development of the somatotroph, lactotroph, and thyrotroph cell lineages [21]. It is a founding member of the POU family of transcription factors, characterized by two protein domains, the POU-homeodomain and the POU-specific domain, both necessary for high-affinity DNA binding [21]. The human POU1F1 gene is located on chromosome 3p11 and contains six exons [22]. Most patients are homozygous for a recessive mutation or have a dominant negative mutation in codon 271, a well-recognized hot spot [23]; however, compound heterozygosity has also been described [24, 25]. An additional hot spot, E230K, has been suggested, as this mutation was identified in five different pedigrees; however, most were Maltese, bringing into question a founder effect [23]. A recent study explored the underlying molecular mechanisms of Pit1-mediated gene activation and found that the R271W mutation results in loss of Pit1 association with beta-­ catenin and SATB1. This association is required for binding of Pit1-occupied enhancers to a nuclear matrin-3-rich network/architecture, which is a key event in effective activation of gene transcription [26]. The first reports of POU1F1 mutations in humans were described in 1992 by four independent groups, all of which described patients with growth hormone, prolactin, and thyrotropin deficiency [27–30]. This triad of hormone deficiencies has been well described in association with POU1F1 gene mutations with the majority of patients presenting with growth failure secondary to growth hormone deficiency [24]. Wide variability with respect to thyrotropin deficiency has been described. An infant born to a mother, both heterozygous for the R271W mutation, highlighted the importance of transplacental thyroxine transfer. At birth, both the infant and mother had undetectable serum thyroxine levels, resulting in significant respiratory, cardiovascular, and neurological morbidity, as well as delayed bone maturation in the infant [31]. While this study reported severe congenital hypothyroidism, other studies have shown preservation of TSH secretion, even into the third decade of life [23]. MRI imaging in patients with POU1F1 mutations shows either a small or normal anterior pituitary, with a normal posterior pituitary [25].

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Case Continued Ongoing clinical and biochemical monitoring revealed delayed puberty secondary to hypogonadotropic hypogonadism, without associated anosmia. Genetic testing revealed a 2-bp deletion in exon 2 of the PROP1 gene. Key Points • POU1F1 mutations are associated with the classic triad of growth hormone, prolactin, and thyrotropin deficiency; in addition to this triad, PROP1 mutations can include gonadotropin and cortisol deficiency. • There can be phenotypic variability in the age at presentation and severity of hormone deficiencies; therefore, monitoring for progressive pituitary decline is critical. • MRI pituitary imaging shows either a hypoplastic or normal-sized anterior pituitary is those with POU1F1 mutations, while a hypoplastic, normal, or even enlarged anterior pituitary is seen in patients with PROP1 mutations; further pituitary morphology can change over time in patients with PROP1 gene mutations including spontaneous involution of pituitary hyperplasia. • Despite phenotypic variability, establishing the genotype in patients with CPHD is important as it can guide clinical decision-making including predicting disease progression and avoidance of unnecessary surgery and can facilitate genetic counseling.

Future Considerations Pituitary gland development is a complex orchestrated process that results in essential hormone production. Advances in molecular genetics have identified mutations within genes encoding pituitary transcription factors in patients with isolated or syndromic hypopituitarism, expanding our understanding of the underlying molecular basis. However, the vast majority of affected patients remain labeled as idiopathic, presumably due to mutations yet to be identified as well as modifier genes and environmental factors. Next-generation sequencing (NGS), including whole-­ genome sequencing (WGS) and whole-exome sequencing (WES), are now being used in clinical care [32]. The less expensive of the two, WES, provides coverage of more than 95% of exons, which contain 85% of disease-causing mutations in Mendelian disorders [33]. Ethical concerns have been raised including the assessment of significance and the need for user-friendly software in the analysis of the raw sequence [33]. Nonetheless, WES and eventually WGS hold the potential of exponentially increasing our knowledge of the genetic basis of hypopituitarism and personalizing preventive, diagnostic, and therapeutic patient care.

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References 1. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, et al. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab. 1995;80(5):1532–40. 2. Biller BM, Samuels MH, Zagar A, Cook DM, Arafah BM, Bonert V, et  al. Sensitivity and specificity of six tests for the diagnosis of adult GH deficiency. J Clin Endocrinol Metab. 2002;87(5):2067–79. 3. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, Brown RS; Public Health Committee, Lawson Wilkins Pediatric Endocrine Society, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006;117(6):2290–2303. 4. Kuiri-Hanninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr. 2014;82(2):73–80. 5. Mukherjee A, Murray RD, Columb B, Gleeson HK, Shalet SM. Acquired prolactin deficiency indicates severe hypopituitarism in patients with disease of the hypothalamic-pituitary axis. Clin Endocrinol. 2003;59(6):743–8. 6. Oelkers W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N Engl J Med. 1989;321(8):492–6. 7. Duquesnoy P, Roy A, Dastot F, Ghali I, Teinturier C, Netchine I, et al. Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency. FEBS Lett. 1998;437(3):216–20. 8. Cogan JD, Wu W, Phillips JA 3rd, Arnhold IJ, Agapito A, Fofanova OV, et al. The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J Clin Endocrinol Metab. 1998;83(9):3346–9. 9. Deladoey J, Fluck C, Buyukgebiz A, Kuhlmann BV, Eble A, Hindmarsh PC, et al. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab. 1999;84(5):1645–50. 10. Reynaud R, Barlier A, Vallette-Kasic S, Saveanu A, Guillet MP, Simonin G, et al. An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain. J Clin Endocrinol Metab. 2005;90(8):4880–7. 11. Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O'Connell SM, et  al. Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature. 1996;384(6607):327–33. 12. Nakamura Y, Usui T, Mizuta H, Murabe H, Muro S, Suda M, et  al. Characterization of Prophet of Pit-1 gene expression in normal pituitary and pituitary adenomas in humans. J Clin Endocrinol Metab. 1999;84(4):1414–9. 13. Wu W, Cogan JD, Pfaffle RW, Dasen JS, Frisch H, O'Connell SM, et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet. 1998;18(2):147–9. 14. Reynaud R, Chadli-Chaieb M, Vallette-Kasic S, Barlier A, Sarles J, Pellegrini-Bouiller I, et al. A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies. J Clin Endocrinol Metab. 2004;89(11):5779–86. 15. Bottner A, Keller E, Kratzsch J, Stobbe H, Weigel JF, Keller A, et al. PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab. 2004;89(10):5256–65. 16. Agarwal G, Bhatia V, Cook S, Thomas PQ. Adrenocorticotropin deficiency in combined pituitary hormone deficiency patients homozygous for a novel PROP1 deletion. J Clin Endocrinol Metab. 2000;85(12):4556–61. 17. Fluck C, Deladoey J, Rutishauser K, Eble A, Marti U, Wu W, et  al. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C). J Clin Endocrinol Metab. 1998;83(10):3727–34.

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18. Arroyo A, Pernasetti F, Vasilyev VV, Amato P, Yen SS, Mellon PL. A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty. Clin Endocrinol. 2002;57(2):283–91. 19. Fofanova O, Takamura N, Kinoshita E, Vorontsov A, Vladimirova V, Dedov I, et al. MR imaging of the pituitary gland in children and young adults with congenital combined pituitary hormone deficiency associated with PROP1 mutations. AJR Am J Roentgenol. 2000;174(2):555–9. 20. Mendonca BB, Osorio MG, Latronico AC, Estefan V, Lo LS, Arnhold IJ.  Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302  in the PROP1 gene. J Clin Endocrinol Metab. 1999;84(3):942–5. 21. Andersen B, Rosenfeld MG. POU domain factors in the neuroendocrine system: lessons from developmental biology provide insights into human disease. Endocr Rev. 2001;22(1):2–35. 22. Ohta K, Nobukuni Y, Mitsubuchi H, Ohta T, Tohma T, Jinno Y, et al. Characterization of the gene encoding human pituitary-specific transcription factor, Pit-1. Gene. 1992;122(2):387–8. 23. Turton JP, Reynaud R, Mehta A, Torpiano J, Saveanu A, Woods KS, et al. Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2005;90(8):4762–70. 24. Hendriks-Stegeman BI, Augustijn KD, Bakker B, Holthuizen P, van der Vliet PC, Jansen M.  Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1F1 gene. J Clin Endocrinol Metab. 2001;86(4):1545–50. 25. Radovick S, Cohen LE, Wondisford FE. The molecular basis of hypopituitarism. Horm Res. 1998;49(Suppl 1):30–6. 26. Skowronska-Krawczyk D, Ma Q, Schwartz M, Scully K, Li W, Liu Z, et  al. Required enhancer-matrin-3 network interactions for a homeodomain transcription program. Nature. 2014;514(7521):257–61. 27. Ohta K, Nobukuni Y, Mitsubuchi H, Fujimoto S, Matsuo N, Inagaki H, et al. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem Biophys Res Commun. 1992;189(2):851–5. 28. Pfaffle RW, DiMattia GE, Parks JS, Brown MR, Wit JM, Jansen M, et  al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science. 1992;257(5073):1118–21. 29. Radovick S, Nations M, Du Y, Berg LA, Weintraub BD, Wondisford FE. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science. 1992;257(5073):1115–8. 30. Tatsumi K, Miyai K, Notomi T, Kaibe K, Amino N, Mizuno Y, et al. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet. 1992;1(1):56–8. 31. de Zegher F, Pernasetti F, Vanhole C, Devlieger H, Van den Berghe G, Martial JA. The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency. J Clin Endocrinol Metab. 1995;80(11):3127–30. 32. Bick D, Dimmock D.  Whole exome and whole genome sequencing. Curr Opin Pediatr. 2011;23(6):594–600. 33. Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet. 2014;59(1):5–15.

Part II

Acquired Pituitary Disorders: Pituitary Tumors and Nonpituitary Sellar Masses

Chapter 3

Adamantinomatous Craniopharyngioma: Genomics, Radiologic Findings, Clinical, and Prognosis Hermann L. Müller and Juan Pedro Martinez-Barbera

Introduction Adamatinomatous craniopharyngiomas (ACPs) are rare embryonic malformations of the sellar/parasellar area with low histological grade (WHO Io). Tumours are comprised of solid components and cysts, which are filled with a fluid rich in lipids and pro-inflammatory signals. ACPs are associated with mutations in CTNNB1 (β-catenin) . Despite high overall survival rates (87–95% 20-year overall survival in ACP), patients with hypothalamic involvement of ACP show reduced overall survival. Quality of survival is impaired in long-term survivors due to sequelae caused by the anatomical proximity of ACPs to the optic chiasma and hypothalamic-­ pituitary axes [1–10]. Severe morbid obesity has relevant impact on long-term quality of survival and frequently occurs in ACP with hypothalamic involvement [11] (Fig. 3.1). Any clinical improvement in the prognosis of ACP patients will require risk-adapted neurosurgical and radiooncological treatment approaches conducted by a multidisciplinary team that provides medical as well as psychosocial support for these patients [3, 12].

H. L. Müller (*) Department of Pediatrics and Pediatric Hematology/Oncology, Klinikum Oldenburg AöR, Medical Campus University Oldenburg, Oldenburg, Germany e-mail: [email protected] J. P. Martinez-Barbera UCL Great Ormond Street Institute of Child Health, Developmental Biology and Cancer, Birth Defects Research Centre, London, UK © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_3

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p = 0.000 p = 0.001

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Fig. 3.1  Weight development in childhood-onset craniopharyngioma patients recruited in HIT Endo according to hypothalamic involvement. Body mass index (BMI) SDS is shown at time of diagnosis and at two intervals after diagnosis (8–12 years and more than 12 years). White boxes, BMI at diagnosis; hatched, 8–12-year follow-up; black, more than 12-year follow-up. The horizontal line in the middle of the box depicts the median. The top and bottom edges of the box, respectively, mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box lengths. (From Sterkenburg et al. [175], by permission of Oxford University Press)

Epidemiology ACPs are rare, with an overall incidence of 0.5–2 cases per million population per year. A bimodal age distribution has been observed, with highest incidence rate in children of ages 5–14 years (childhood-onset ACP) and adults of ages 50–74 years (adult ACP). Childhood-onset ACPs represent between 30% and 50% of all cases [13–18]. ACP can be detected during the whole paediatric age period, even in preand perinatal periods [15]. In population-based studies, no gender differences have been observed. ACP represents 1.2–4% of all paediatric brain tumours.

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Molecular Aetiology of ACP ACP is caused by mutations in CTNNB1 (gene encoding β-catenin) [19–24]. This distinguishes ACP from the papillary craniopharyngioma, a tumour of the elderly that is associated with mutations in BRAF [23]. The identified CTNNB1 mutations affect critical regulatory amino acids that control β-catenin stabilization and are predicted to cause its protein accumulation and over-activation of the WNT pathway. Indeed, nucleocytoplasmic accumulation of β-catenin is observed in most of human ACP tumours, usually in either single cells or small groups of cells that form clusters (hereafter referred to as “cell clusters”) [25]. Transcriptional targets of the WNT pathway such as AXIN2, LEF1, and BMP4 are mostly restricted to the cluster cells [26–28]. These cluster cells express some markers associated with stemness [29], and despite expressing oncogenic β-catenin, they are not cycling, as shown by the lack of expression of Ki67, a marker of proliferative cells [28]. Clusters are also observed in human ACP but not in any other tumour of the sellar region, including papillary craniopharyngioma [25, 30].

 ouse Models of ACP Demonstrate a Causative Role M of CTNNB1 Mutations The identification of the CTNNB1 mutations in human ACP does not prove causality. A valid manner to test whether mutations in CTNNB1 can lead to tumour formation is to generate genetically engineered mouse models (GEMMs) expressing an equivalent form of the mutant β-catenin. This approach has led to the generation of two GEMMs of ACP: an embryonic model, in which expression of oncogenic β-catenin is targeted to the embryonic precursors of the anterior pituitary, and an inducible model, where the cells expressing mutant β-catenin are Sox2+ stem cells of young adult mice [28, 31]. These mouse models develop tumours, which resemble some features of human ACP. For instance, murine tumours showed β-catenin-­ accumulating cell clusters with concomitant expression of Lef1, Axin2, and Bmp4, indicating the activation of the WNT pathway [28, 32]. Like the human clusters, the murine clusters do not express Ki67, suggesting exit of the cell cycle and also express stemness markers. These mouse models were able to predict the expression of genes that had not previously been involved in human ACP (e.g. sonic hedgehog (SHH) and CXCR4) [32, 33]. Moreover, gene expression profiling of human ACP has revealed the up-regulation of other genes and pathways [34, 35], many of which were shown to be expressed in the mouse models [32] (Fig. 3.2). At the radiological level, a comprehensive MRI study has shown the presence of solid components and large cysts in the mouse tumours, the latter being a common characteristic in many paediatric ACP tumours [36]. However, the mouse ­ tumours did not show calcification or deposits of wet keratin, and so far, infiltration of the tumour into the hypothalamus has not been observed. Overall, these

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H. L. Müller and J. P. Martinez-Barbera CXCR4/CXCL12 pathway upregulation

Expression of proinflammatory signals (IL6R, IL2RB, PTGS2)

Expression of matrix metaloproteinases (MMP9, MMP12)

Downregulation of cell adhesion molecules (CD44, Claudin1)

CTNNB1 mutations in human ACP WNT pathway up-regulation (AXIN2, LEF1)

SHH pathway upregulation (SHH, GLI1, PATCH1)

BMP pathway upregulation (BMP2, BMP4, BMP7)

EGF pathway upregulation (AREG, EGFR)

FGF pathway upregulation (FGF3, FGF4, FGF20)

Cell survival Cell Proliferation and differentiation Cell adhesion and migration Inflammation

Fig. 3.2  Genes and molecular pathways involved in human ACP.  Schematic outlining majorly deregulated genes and pathways in ACP, resulting from activating mutations in beta-catenin. Most, if not all, ACP tumours carry mutations in CTNNB1 (beta-catenin) directly resulting in the over-­ activation of the WNT/beta-catenin pathway. This is evidenced by the expression of target genes such as AXIN2 and LEF1. As the result of this initial oncogenic hit, defined as the driver mutation, several further genes and pathways become deregulated. These are likely to affect multiple biological processes such as cell proliferation, survival, differentiation, inflammation, angiogenesis, cell adhesion, and tumour infiltration among others. The colour code indicates the potential involvement of the deregulated pathways in these biological processes, as deducted from other cellular/ tumoural contexts. This assessment is not exclusive as many of the pathways may be involved either directly or indirectly in several or all of the processes indicated. Knowing whether the inhibition or stimulation of some of these pathways may be of therapeutic use requires robust preclinical data to confirm their pathogenic effects. For more details, see references [26, 32–35, 187, 188]. (From Müller et al. [10])

GEMMs have demonstrated a causal effect of the mutations in β-catenin and proven to be useful tools to study the pathogenesis of human ACP.

 ox2+ Pituitary Stem Cells Can Induce Tumour Formation S in a Paracrine Manner The pituitary gland of the mouse contains a population of Sox2+/Sox9+ cells that represent a stem cell reservoir. Genetic tracing experiments have demonstrated that Sox2+ve and Sox9+ve progeny populate all of the hormone-producing cells and

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contribute to normal cell turnover in the adult pituitary, thus demonstrating that they are stem cells in vivo [31, 37]. This is in agreement with previous observations showing that the clonogenic potential of the pituitary gland, defined as the cells capable of expanding clonally and differentiating in vitro, is contained within the Sox2+/Sox9+ cell compartment [32, 37]. A population of SOX2+/SOX9+ co-­ expressing cells also exist in the human embryonic pituitary, suggesting the existence of pituitary stem cells in the human gland [38]. The presence of these stem cells raises a question: are these involved in the pathogenesis of ACP? Mouse experiments have been performed by expressing oncogenic β-catenin in Sox2+ cells (inducible ACP model). This approach has demonstrated that mutated Sox2+ cells can cause tumourigenesis, but contrary to other cancer models where the tumour cells derive from the transformed stem cells, the results in the ACP mouse model indicate that the tumours are induced in a paracrine manner (Fig. 3.3). Recently, combining genetic and molecular approaches, the tumour-inducing potential of mutated Sox2+ cells have been associated with the paracrine activities of the cluster cells, which have been shown to be senescent in both mouse and human ACP [39]. This working model proposes that the clusters i

iii

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Fig. 3.3  Paracrine model for the involvement of pituitary stem cells in tumorigenesis. (i) Schematic representation of Sox2+ve stem cells (A) and Sox2-ve cells in the adult pituitary. Expression of oncogenic β-catenin in some Sox2+ve cells (A* in ii) results in transient proliferation and formation of β-catenin-accumulating cell clusters (A* in iii–vi) and the release of secreted factors to the surrounding cells (iii) leading to cell transformation (B’), proliferation (B’ in v), and tumour formation (B’ in vi). (From Müller et al. [10])

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secrete a plethora of growth factors as well as many pro-inflammatory cytokines/ chemokines, which create a tumour permissive environment that may cause tumour initiation and progression. The presence of inflammatory mediators has recently been characterized in human tumours [40]. These findings are important to understand the pathogenesis of human ACP and may offer an explanation to some clinical features observed in the patients. For instance, using a novel xenotransplant model for human ACP, the activity of the clusters have been shown to be important for controlling the ACP’s brain-invasive behaviour [41]. This is further supported by the 3D architecture of the tumour cells in human ACP, where cell clusters are distributed along the finger-like protrusions that invade the hypothalamus and surrounding structures [42]. The senescent cluster cells may be more resilient to the effect of irradiation and could reinitiate tumour development and cause relapse, a finding compatible with the clinical data showing a high relapse incidence of human ACP after radiotherapy [10]. Finally, the growth dynamics of the mouse tumours indicate that although the clusters are present at birth, no significant tumour growth is observed until several weeks of life [36, 39], an observation compatible with the peak of diagnosis of paediatric ACP at 5–14 years of age. This suggests that pre-tumoural lesions containing clusters could be present in the newborn pituitary, which could develop into full tumours after a long latency period, as seen in the murine models.

Imaging Studies Computerized tomography (CT) and magnetic resonance imaging (MRI) show that ACP is a tumour of the sellar and/or parasellar area frequently consisting of cystic parts. The most common location is suprasellar, with an intrasellar portion; only 20% are exclusively suprasellar and only 5% exclusively intrasellar [18, 43]. CT is the radiological method appropriate to detect calcifications, which are observed in up to 90% of these tumour tissues. The signal intensity of ACP tissue in MRI is variable and depends on the protein concentration of the cyst fluid. Cyst membranes and solid tumour appear isointense in T1-weighted MRI (Fig. 3.4). A combination of cystic, solid, and calcified tumour components is an important radiological clue to the diagnosis. The radiological differential diagnoses of sellar masses include xanthogranuloma, germinoma, Langerhans cell histiocytosis (LCH), Rathke cleft cyst, glioma, epidermoid tumour, thrombosis of arachnoidal cysts, colloidal cyst of the third ventricle, pituitary adenoma, aneurysms, and rare inflammatory variations [18, 44]. MRI before and after gadolinium application is the standard imaging for detection of ACP, further imaged by native CT to detect calcifications [18]. After preoperative detection of calcifications and complete resection confirmed by postoperative magnetic resonance imaging, a postsurgical native computerized tomography of the sellar/parasellar area (without contrast medium application) is recommended for definitive confirmation of complete resection [18]. For radiological follow-up

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b

d Fig. 3.4  Degree of obesity in relation to the location of childhood-onset craniopharyngioma. In both patients craniopharyngioma (as indicated by arrow on magnetic resonance imaging before surgery) could be completely resected. Both patients had complete hypopituitarism after surgery requiring endocrine substitution of all hypothalamic-pituitary axes. The patient depicted in (b) developed severe obesity due to hypothalamic lesions of suprasellar parts of craniopharyngioma (c). The patient depicted in (a) presented with a small tumour confined to the sellar region (d). After complete resection she kept normal weight without any eating disorders. (Adapted by permission from Müller et al. [189]. Copyright 2003)

­ onitoring, native MRI without application of gadolinium contrast medium is recm ommended due to recent reports on gadolinium deposits after frequent application. A major step towards potential standardization of preoperative staging in ACP is the comparison of published grading systems for assessment of hypothalamic damage/involvement in regard to prediction value for severe hypothalamic obesity as the main sequelae impairing quality of survival. Mortini et al. [45] have published one of the first studies, which identifies radiological variables linked to hypothalamic

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involvement on preoperative MRI, and correlate them with clinical features, long-­ term outcome, and prognosis. Additionally, Mortini et al. [45] analysed the sensitivity of three published grading systems [44, 46–48] for prediction of hypothalamic obesity in their single centre cohort. Hypothalamic hyperintensity in T2-weighted/ FLAIR images, unidentifiable pituitary stalk, dislocated chiasm, mammillary body involvement, retrochiasmatic tumour extension, and either infundibular recess or unrecognizable supraoptic recess have proven to be useful to define the hypothalamus invasion. Variables identified as factors with high and comparable prediction value for postoperative hypothalamic syndrome were the degree of hypothalamic involvement according to the classification described by Sainte-Rose and Puget [47], Van Gompel et al. [46], and Muller et al. [44, 48]. These results support the hypothesis that disease or treatment-related hypothalamic alterations have relevant negative impact on quality of survival and prognosis in ACP [49, 50].

Presenting Clinical Manifestations ACP is frequently diagnosed late—sometimes years after initial appearance of symptoms [24, 51]—with clinical symptoms often caused by increased intracranial pressure (e.g. nausea and headache) [52, 53]. Further initial manifestations are neuroendocrine (52–87%) and visual deficits (62–84%). Hormonal deficiencies are caused by tumour or treatment-related alterations to hypothalamic-pituitary axes that affect growth hormone secretion (75%), gonadotropins (40%), adrenocorticotropic hormone (ACTH) (25%), and thyroid-stimulating hormone (TSH) (25%). At the time of primary diagnosis, 40–87% of ACP patients present with at least one endocrine deficiency [54], and other endocrine symptoms such as central diabetes insipidus are observed preoperatively in 17–27% of all ACP patients [54, 55]. Müller et al. analysed anthropometric data such as weight and height obtained in routine checkups before diagnosis in 90 ACP patients [56] and reported on reduced growth rates—as an early manifestation of ACP—in infants as young as 12 months of age. Significant weight gain at the time of initial ACP diagnosis, a known risk factor for consecutive hypothalamic obesity, tended to occur later in history, i.e. shortly before diagnosis at a median age of 8 years. Hoffmann et  al. [57] analysed clinical symptoms and complaints at diagnosis and duration of history in 411 ACP patients. The authors observed that ACP is frequently diagnosed after very long duration of history, especially in older children and adolescents. However, late diagnosis, i.e. long duration of history before initial ACP diagnosis, was no significant risk factor for larger tumour volume, reduced survival rate, or impaired functional capacity. Symptoms in history indicating neurological deficit and visual impairment should be considered as clinical events necessitating rapid diagnostic workup. Reduced growth rates and weight gain are early events in patient history, which should lead to early consideration of ACP in differential diagnosis.

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Risk-Adapted Treatment Strategies Surgery The Necker group at Paris [47] published a surgical algorithm for treatment of ACP, which suggests a hypothalamus-sparing strategy risk-adapted based on a presurgical neuroradiological grading of hypothalamic tumour involvement [58]. Elowe-­ Gruau et  al. [47] reported that patients surgically treated according to this recommendation had comparable relapse rates and a lower prevalence of severe obesity than ACP patients after radical, gross total resection (28% versus 54%, respectively). The study of the Necker group is the first report proving efficacy and tolerability of such a hypothalamus-sparing approach by comparing ACP patients operated by the same experienced team at a single institution and thus minimizing the potential bias of neurosurgical experience on prognosis. Müller et al. [44, 48] reported on a risk-adapted treatment strategy based on pre- and postsurgical neuroradiological grading of hypothalamic alterations; the assessment of tumour extension towards the mammillary bodies was considered essential for their grading into anterior or posterior hypothalamic involvement/lesion. ACP patients with postsurgical lesions affecting posterior hypothalamic areas presented with increased body mass index (BMI) SDS and impaired self-assessed quality of life during long-term prospective follow-up. Based on the current literature, it is recommendable to have a multidisciplinary team able to discuss diagnostic and treatment strategies, adopting the most sophisticated approaches feasible based on sufficient in-house surgical, radiooncological, and psychosocial experience for treating patients with ACP [3, 8, 49, 59, 60].

Radiooncological Treatment Biological characteristics of ACP allow the option of using high-precision, three-­ dimensional conformation technology. A conventional, fractionated irradiation total target volume dose of 54 Gray has been established worldwide [61, 62]. For decades, radiooncological therapy using photon irradiation was the standard of treatment. Proton beam therapy is being increasingly used for the treatment of ACP. Treatment planning studies have shown that proton beam therapy may result in lower doses to critical organs, thereby minimizing the risk of neurocognitive, vascular, and optic nerve complications and of second cancers [63–65]. Whereas early clinical results of proton beam therapy in ACP are encouraging [66–69], clinical long-term outcome data are still limited in proton beam therapy compared to modern photon therapy. In the near future, long-term results should be available in due course with sufficient follow-up time.

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Instillation of Sclerosing Substances for Cystic Tumours A catheter insertion into a cystic ACP has the advantage of repetitive drainage of the ACP cyst and instillation of sclerosing substances into the cystic cavity. Instillation of bleomycin as a sclerosing substance into ACP cysts was used in the past [70]. Since severe neurotoxic side effects were observed due to cystic leakage of bleomycin into CSF [71], instillation of bleomycin is nowadays no more recommended. Intracystic instillation of interferon alpha is a promising therapeutic option for predominantly monocystic ACP [72–74].

Long-Term Outcome and Morbidities Pituitary Deficiencies Pituitary hormone deficiencies are frequent in ACP. At the time of initial ACP diagnosis, 40–87% of patients [54, 75–77] show at least one endocrine pituitary deficit. Seventeen to twenty seven percent [54, 76, 78] present with initial central diabetes insipidus. The frequency of postsurgical pituitary endocrine deficiencies increases due to treatment-related alterations of hypothalamic-pituitary axes [56, 75, 76, 78– 82]. Transient diabetes insipidus occurs in up to 80–100% of all cases after surgery [75, 83]. Permanent postsurgical central diabetes insipidus is observed in 40–93% [48, 55, 75, 76, 78, 81–84]. After transsphenoidal surgical approach, a lower risk for development of new hormonal deficiencies has been observed [77, 85]. Recovery from pituitary deficits after surgery is a rare event. Growth hormone (GH) deficiency is observed in 26–75% of ACP patients at the time of initial ACP diagnosis [54, 84], and reduced growth rates, one of the early clinical symptoms related to ACP, often occur years before ACP diagnosis [56]. GH deficiency is diagnosed in about 70–92% of patients following treatment for ACP [48, 56, 86, 87], and positive responses to GH substitution are observed in most cases [88]. Normal growth rates after ACP in spite of proven GH deficiency are reported in the literature [89]. In fact, patients with hypothalamic involvement of ACP have been reported to reach normal adult height more frequently than ACP patients without hypothalamic involvement [56]. Even though this observation of “growth without GH” has been described in ACP five decades ago [90], the pathophysiology of growth in these cases is still not clear, although leptin and insulin are postulated to play a role in this context.

Visual and Neurological Outcomes Due to suprasellar tumour location, ACP patients frequently present with visual deficits both of visual field and visual acuity. Visual impairment as an initial symptom related to ACP is observed in more than 50% of all ACP patients [54], with

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improvement of vision in 41–48% of patients after surgery [55, 75]. Risk factors for postsurgical visual impairment are severe presurgical visual deficiencies and prechiasmatic tumour location [75, 79]. Improvement in ophthalmological outcome has been reported in cases surgically treated via transsphenoidal approaches [55]. Neurological sequelae include cranial nerve deficits, epilepsy, hemiparesis, and cerebrovascular complications [78, 81, 87]. Most neurological sequelae are transient. The rate of long-term neurological sequelae is reported to be 8% [75]. This rate increases to 36% for tumours of large volume [78] and to 30% when both neurological and visual complications are present [83].

Hypothalamic Syndrome Clinical symptoms associated with hypothalamic syndrome, such as obesity, disturbances of circadian rhythm, daytime sleepiness, behavioural changes, and dysregulation of thirst, body temperature, heart rate, and/or arterial hypertension, have been found at the time of diagnosis in 35% of ACP [3, 4, 11, 91–94]. After ACP treatment, the rate of hypothalamic syndrome increases in some series up to 80% [5]. Weight gain in ACP frequently occurs years before diagnosis [56]. Obesity at the time of initial ACP diagnosis—a risk factor, highly predictive for the development of long-term obesity—has been observed in 12–19% of patients [4]. In patients at risk, BMI frequently increases early after primary surgical treatment, and most significant weight gain occurs during the first year post surgery (Fig. 3.5). The overall prevalence of severe obesity is high, reaching up to 55% [49, 95]. The association between morbid obesity and hypothalamic involvement and/or treatment-related hypothalamic lesions is well known in ACP [7, 96, 97]. By synchronizing circadian rhythms, hypothalamic nuclei play a dominant role in stabilizing the internal environment. Recent reports indicate that appropriate balance of the autonomous nervous system has significant impact on metabolic balance [98]. Adipose tissue is innervated by sympathetic nerve fibres controlling lipolysis. Also, lipogenesis in adipocytes is regulated by parasympathetic innervation of adipose tissue originating from sympathetic and parasympathetic origin located in the periventricular and suprachiasmatic nuclei (SCN) [97–99]. Accordingly, the SCN plays a major role in balancing circadian regulation of both parasympathetic and sympathetic branches of the autonomous nervous system [97]. Considering the high rate of ACP patients with treatment-related alterations of suprasellar structures, it is most likely that suprasellar ACP location and/or the treatment-related hypothalamic lesions result in SCN damage. This has major impact on central clock mechanisms resulting in a dysregulation predisposing to metabolic alterations [100]. Analysing self-assessment by nutritional diaries, Harz et al. [101] showed that ACP patients with hypothalamic obesity had a caloric intake similar to BMI-­ matched controls. A study on physical activity in long-term survivors of ACP using actimetric devices showed that ACP patients presented with reduced physical activity levels when compared with BMI-matched healthy controls [101]. Severe dys-

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a

b 10.00

10.00 p =0.23

9.00

9.00

8.00

8.00 p =0.18

7.00

7.00

D BMI SDS (36 mo postOP -at Dnx)

6.00

BMI SDS at diagnosis

5.00 4.00 3.00 2.00 1.00 0.00

6.00 5.00 4.00 3.00 2.00 1.00 0.00

–1.00

–1.00

–2.00

–2.00

–3.00

–3.00

–4.00

p =0.69

p =0.745

p =0.011

–4.00 p =0.033

–5.00

n = 18

Grade

0

23

61

1

2

Pre surgical hypoth. inv.

–5.00

n = 23

Grade

0

13 1

28 2

Post surgical hypoth. lesions

Fig. 3.5  Body mass index (BMI SDS) at diagnosis (a) and increases in BMI (ΔBMI SDS) during 36 months after surgery (b) in relation to presurgical hypothalamic involvement (a) and surgical hypothalamic lesions (b) of 117 childhood-onset craniopharyngioma patients recruited in KRANIOPHARYNGEOM 2000. The horizontal line in the middle of the box depicts the median. Edges of box mark the 25th and 75th percentile. Whiskers indicate the range of values that fall within 1.5 box lengths. (From Müller et al. [48])

regulations of circadian rhythms with increased daytime sleepiness have been observed in ACP patients suffering from hypothalamic obesity [100]. This patient group also presented with low, early morning and nocturnal melatonin saliva concentrations [102, 103], when compared with BMI-matched healthy controls. Impaired hypothalamic regulation of circadian melatonin secretion in ACP extending to the suprasellar area was hypothesized as pathogenic explanation. First experi-

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ences with melatonin substitution in ACP patients were promising: physical activity and daytime sleepiness improved and saliva melatonin concentrations normalized under melatonin medication [102]. A polysomnographic study on ACP patients suffering from severe daytime sleepiness revealed sleeping patterns typical for hypersomnia and secondary narcolepsy, i.e. frequent “sleep-onset REM phases” (SOREM) [100, 104, 105]. Treatment with central stimulating agents such as methylphenidate or modafinil improved daytime sleepiness in these ACP patients [105]. Accordingly, secondary narcolepsy should be taken into consideration as clinical significant sequelae in severely obese ACP patients [105]. Mason et al. [106] treated five severely obese ACP patients (age range: 6.0–9.8 years) with dextroamphetamine, a central stimulating agent, for the purpose of weight reduction. Under dextroamphetamine medication, patient BMI stabilized. The patients’ parents reported improvements in terms of alertness and physical activity in their children. Several reports [98, 107] hypothesized that decreased physical activity and consecutive severe obesity in ACP are associated with reduced central sympathetic output. Roth et  al. [108] reported on impaired concentrations of catecholamine metabolites in urine. The authors observed a clear association between urine concentrations of catecholamine metabolites and physical activity levels and the degree of obesity in ACP patients. It is well known that reduced metabolic rates, both in terms of resting and total energy expenditure, are influential on the development of severe obesity after ACP diagnosis and treatment. A lower resting energy expenditure (REE) was observed in paediatric and adult ACP patients when compared with healthy controls [109], and the energy intake/REE ratio was decreased in patients with ACP involving the third ventricle [110]. Further factors which potentially reduce physical activity levels are visual and neurological deficits [111, 112], increased daytime sleepiness [100, 102], and psychosocial impairments [49]. The gastrointestinal hormones ghrelin and peptide YY and their satiety-­regulating effects in obese ACP patients were analysed by Roemmler-Zehrer et al. [113]. The authors’ findings lead to the conclusion that reduced ghrelin secretion and impaired postprandial ghrelin suppression and severe hypothalamic obesity are associated with appetite dysregulation in ACP patients. Peptide YY levels in ACP were similar in the subgroups of normal weight, obese, and very obese ACP patients. Peripheral α-melanocyte-stimulating hormone and brain-derived neurotrophic factor are neuroendocrine factors with potential pathogenic roles in the development of obesity in ACP [114, 115]. Roth et al. [116] reported on elevated leptin concentrations in serum relative to BMI in ACP with suprasellar extension. The authors suggested that a dysfunction of hypothalamic receptors, that are part of the negative feedback loop with adipocyte-­ derived leptin, results in a failure of physiological appetite inhibition in these patients. Hoffmann et al. [117] reported on non-alcoholic fatty liver disease (NAFLD) , a previously underestimated, severe morbidity in ACP patients with hypothalamic obesity. In their ACP cohort, increased liver enzymes, elevated HOMA index, and

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radiological signs of NAFLD occurred in 50% of ACP patients with hypothalamic obesity. Sixty percent of all patients with NAFLD had been treated with stimulating agents for increased daytime sleepiness and hypersomnia as typical clinical manifestations of secondary narcolepsy. As liver toxicity of central stimulating agents is well described, Hoffmann et  al. [117] recommend that these central stimulating agents, appropriate for treatment of secondary narcolepsy, should be prescribed very judiciously in ACP patients. Oxytocin, a hypothalamic hormone, plays an important physiological role in regulation of body composition and behaviour. Daubenbüchel et al. [118] recently reported that ACP patients are secreting the hormone oxytocin, even when pituitary and hypothalamic structures show signs of disease- or treatment-related damage. However, in case of hypothalamic damage grade 1, which is characterized by lesions confined to anterior hypothalamic areas, ACP patients presented with a lower fasting oxytocin levels. In addition, changes in oxytocin levels before and after standardized breakfast correlated with BMI, demonstrating that ACP with hypothalamic obesity present with less variation in oxytocin secretion due to nutrition. First experiences with oxytocin treatment in ACP patients were promising with regard to neuropsychological [119] and weight-reducing effects [120].

Challenges in Treating Hypothalamic Obesity Morbid obesity in ACP patients with hypothalamic involvement is mainly nonresponsive to conventional lifestyle modifications due to the above-mentioned pathogenic mechanisms in appetite regulation, energy expenditure, and regulation central sympathetic tone [3, 4, 99, 121–124]. Recent trials on pharmaceutical treatment of morbid hypothalamic obesity in ACP patients report on mixed results [11]. Hamilton et  al. [125] assessed the effect of a combined diazoxide-metformin therapy in an open-label prospective trial on a small cohort of obese ACP patients (n  =  9). Combined diazoxide-metformin medication for 6 months resulted in reduced weight gain of patients with hypothalamic obesity. Initial pretreatment insulin levels predicted effectiveness of diazoxide and metformin medication. The treatment effect of a combination of metformin and fenofibrate on the metabolic status was analysed by Kalina et al. [126] in 22 ACP patients. The authors observed positive effects of the metformin and fenofibrate combination medication on dyslipidemia and homeostatic model assessment (HOMA) . Zoicas et  al. [127] treated eight adult patients with hypothalamic obesity (6 ACP) with GLP-1 analogues and observed a clinical relevant and sustained weight reduction associated with improvements in metabolic and cardiovascular risk profiles. Substitution therapy with recombinant growth hormone is efficient in promoting normal growth rates. However, clinically relevant weight-reducing effects are not reported in ACP with hypothalamic obesity [128, 129]. Positive effects of growth hormone substitution on quality of life have recently been reported in a prospective ACP trial focusing on short-term outcome 3 years after ACP diagnosis [130].

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Induced by vagal activation, ACP patients with hypothalamic obesity present with a parasympathetic predominance of their autonomic nervous system, associated with clinical symptoms such as daytime sleepiness and reduced heart rate variability [98]. Insulin secretion as well as adipogenesis is induced by direct parasympathetic activation of β cells. Insulin as a major anabolic hormone plays an important role for weight gain in hypothalamic obesity. Octreotide, a somatostatin analogue, suppresses insulin secretion. In a double-blinded, randomized controlled study in children with hypothalamic obesity, Lustig et al. [131] analysed octreotide treatment, observing moderate reductions in weight gain, which were however associated with considerable gastrointestinal side effects. Initial experiences with laparoscopic gastric banding (LAGB) in severely obese ACP patients showed good tolerability and weight reduction during shortterm follow-­up [132–134]. Immediately after bariatric procedure (LAGB) [134], an instant improvement of binge-eating behaviour was observed in ACP patients. However, LAGB failed to result in weight reduction during long-term follow-up. Nevertheless, relative weight stabilization could be achieved with regular followup monitoring [135]. In a systematic meta-analysis and review of the literature, Bretault et  al. [132] analysed the 12-month outcome after bariatric surgery for hypothalamic obesity due to ACP treatment. At 12 months after bariatric surgery, among 18 cases with follow-­up data, 6 patients presented with a more than 20% reduction of their initial weight; all had undergone either Roux Y gastric bypass (n  =  3), sleeve gastrectomy, (n  =  2), or biliopancreatic diversion (n  =  1). All patients who had lost less than 5% of their initial weight had undergone LAGB except one Roux Y gastric bypass case. These findings indicate that Roux Y gastric bypass, biliopancreatic diversion, and sleeve gastrectomy are the most efficient bariatric treatment options for hypothalamic obesity after ACP.  However, treatment with invasive, nonreversible bariatric methods—such as the abovementioned—is controversial in the paediatric population due to ethical, medical, and legal considerations [135–137]. Despite several promising therapeutic approaches [34], it must be pointed out that currently no therapy for ACP patients with hypothalamic obesity has been proven to be effective in randomized trials. Furthermore, rehabilitation programmes after ACP have not been shown to result in persistent long-term effects in terms of weight stabilization or weight reduction [138].

Eating Behaviour Hoffmann et al. [139] studied eating behaviour and the rate of eating disorders in 101 ACP survivors and 85 BMI-matched healthy controls. Severely obese ACP patients presented with a higher rate of pathological eating behaviour, more weight problems, and a higher rate of eating disorders, when compared with obese and normal weight or overweight ACP patients. However, ACP patients with different degrees of obesity presented with similar or even less pathological findings for

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eating disorders when compared with BMI-matched controls. The authors conclude that the observed differences in terms of eating disorders are not diseasespecific for ACP. Using functional magnetic resonance imaging (fMRI) , Roth et al. [140] studied pre- and post-meal responses to visual food cues in ACP patients’ brain regions of interest. Following a test meal, BMI-matched controls showed suppression of activation by high-calorie food cues, whilst ACP patients showed a trend towards higher activation in fMRI. These findings support the authors’ hypothesis that altered perception of food cues especially after food intake may be associated with hypothalamic obesity in ACP patients. Although hypothalamic obesity is the most frequent sequelae in ACP [141], diencephalic syndrome resulting in severe weight loss and cachexia can also occur as a rare hypothalamic dysregulation of body composition in ACP [142, 143]. Hoffmann et al. [143] analysed the incidence of diencephalic syndrome, its clinical manifestation before and after ACP diagnosis, and outcome in 485 ACP patients recruited in the German Childhood Craniopharyngioma Registry. Only 4.3% of all ACP patients presented with decreased BMI (61 Gray [159]. No cerebrovascular abnormalities associated with clinical symptoms or complications have been reported in other series of conventionally fractionated irradiation for ACP [62, 160–165]. In 10–29% of ACP

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patients, fusiform dilatations of the carotid artery (FDCA) have been detected on postoperative MRI after radical resection. The natural history of FDCA appears to be benign. Haemorrhage or stroke, as complications attributable to FDCA, has not been reported to date [166, 167]. A prospective study on long-term prognosis in ACP patients showed that FDCA had no significant impact on prognosis and clinical course of disease [168]. Cardiac risk factors have been reported in ACP patients. Mong et al. [169] analysed cardiac status in a small ACP cohort (n = 12). The authors showed that 50% of ACP patients presented with at least one abnormality of cardiac structure, function, or rhythm. Prolonged QT intervals were found in 25% of the analysed cohort.

Second Malignant Neoplasms Rajan et al. [160] reported no second malignancies in their large series (n = 173) after a median follow-up of 12 years post radiation. Overall, only 4 cases of second malignancies after ACP have been reported [67, 170–172]: two in-field glioblastomas [170, 172], one posterior fossa meningioma [67], and one in-field glioma with unknown grade of malignancy [171].

Survival and Late Mortality Overall mortality rates in CP are three to five times increased compared to general population [173, 174]. Sterkenburg et al. found an impaired 20-year overall survival rate in the subgroup with hypothalamic involvement of ACP [175, 176] (Fig. 3.6). Hypothalamic obesity due to hypothalamic involvement resulted in an impairment of long-term quality of life [175]. Disturbances of circadian rhythms such as daytime sleepiness, fatigue, [100, 102, 177], memory deficits [156, 178, 179], neuropsychological imbalances [91, 180–184], and pulmonary, gastrointestinal complaints (dyspnea, diarrhoea) [175], and cardiovascular morbidity [180] are clinically relevant long-term sequelae in ACP with hypothalamic obesity. Petito et al. [185] identified tumour volume as a prognostic factor showing that tumours with a diameter smaller than 3 cm were associated with increased survival rates. Daubenbüchel et  al. [176] prospectively analysed 163 long-term survivors of ACP for prognosis and outcome. The authors showed that initial hydrocephalus had no significant adverse impact on outcome. In ACP long-term survivors presenting with initial hypothalamic involvement, functional capacity and overall survival rates were significantly reduced. Progression-free survival rates were not related to initial hydrocephalus, primary hypothalamic involvement, or degree of initial resection. Accordingly, the authors conclude that radical neurosurgical resection is not recommended in ACP with primary hypothalamic involvement to prevent additional hypothalamic lesions [176].

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a –1,0 no HI, n = 82 (0.95 ± 0.04)

Overall survival

–0,8

–0,6 HI, n = 132 (0.84 ± 0.04) –0,4

–0,2 95%-CI: no HI: 0.87 – 1.0 HI: 0.76 – 0.92

–0,0 0

p =0.006

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20

30

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50

Follow-up time (years)

b –1,0

progression-free survival

–0,8 no HI, n = 53 (0.62 ± 0.09) –0,6

–0,4

HI, n = 85 (0.56 ± 0.07)

–0,2 95%-CI: no HI: 0.44 – 0.80 HI: 0.42 – 0.70

–0,0 0

10

p =0.673 20

30

40

Follow-up time (years)

Fig. 3.6  Kaplan-Meier analyses of 20-year overall survival (a) and 20-year progression-free survival (PFS) (b) of patients with childhood-onset craniopharyngioma recruited in HIT Endo related to hypothalamic involvement (HI). (From Sterkenburg et  al. [175], by permission of Oxford University Press)

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Conclusions In the case of hypothalamic involvement, radical gross total resection of ACP is not recommended. Based on the above-mentioned association between initial involvement/treatment-related lesions and long-term morbidity and quality of survival, ACP should be considered as a chronic, non-curable disease in most cases. Accordingly, treatment should be performed by multidisciplinary experienced teams in the context on national and international multicentre studies aiming at risk-­ adapted hypothalamus-sparing strategies and improvement of follow-up care. Due to the current lack of proven therapeutic options for hypothalamic syndrome and consecutive hypothalamic obesity, novel treatment approaches based on recent molecular findings are warranted [43]. The mouse models presented in this chapter are suitable tools to test novel therapies for these aggressive tumours [186]. Financial Disclosure  This manuscript was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. H.L. Müller is supported by the German Childhood Cancer Foundation, Bonn, Germany. This work was supported by the Medical Research Council (MRC) (Grants MR/M000125/1), Great Ormond Street Hospital for Children Charity/Children with Cancer UK (GOSHCC/CWCUK) (Grant W1055), and National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children National Health Service Foundation Trust and University College London. J.P.  Martinez-Barbera is a Great Ormond Street Hospital for Children’s Charity Principal Investigator.

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160. Rajan B, Ashley S, Gorman C, Jose CC, Horwich A, Bloom HJ, et al. Craniopharyngioma--a long-term results following limited surgery and radiotherapy. Radiother Oncol J Eur Soc Ther Radiol Oncol. 1993;26(1):1–10. 161. Stripp DC, Maity A, Janss AJ, Belasco JB, Tochner ZA, Goldwein JW, et al. Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults. Int J Radiat Oncol Biol Phys. 2004;58(3):714–20. 162. Karavitaki N, Brufani C, Warner JT, Adams CB, Richards P, Ansorge O, et  al. Craniopharyngiomas in children and adults: systematic analysis of 121 cases with long-term follow-up. Clin Endocrinol (Oxf). 2005;62(4):397–409. 163. Pemberton LS, Dougal M, Magee B, Gattamaneni HR. Experience of external beam radiotherapy given adjuvantly or at relapse following surgery for craniopharyngioma. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2005;77(1):99–104. 164. Moon SH, Kim IH, Park SW, Kim I, Hong S, Park CI, et  al. Early adjuvant radiotherapy toward long-term survival and better quality of life for craniopharyngiomas--a study in single institute. Child’s Nerv Syst. 2005;21(8-9):799–807. 165. Combs SE, Thilmann C, Huber PE, Hoess A, Debus J, Schulz-Ertner D.  Achievement of long-term local control in patients with craniopharyngiomas using high precision stereotactic radiotherapy. Cancer. 2007;109(11):2308–14. 166. Nagata T, Goto T, Ichinose T, Mitsuhashi Y, Tsuyuguchi N, Ohata K. Pathological findings of fusiform dilation of the internal carotid artery following radical dissection of a craniopharyngioma. J Neurosurg Pediatr. 2010;6(6):567–71. 167. Bendszus M, Sorensen N, Hofmann E, Roll E, Solymosi L. Fusiform dilatations of the internal carotid artery following surgery for pediatric suprasellar tumors. Pediatr Neurosurg. 1998;29(6):304–8. 168. Hoffmann A, Warmuth-Metz M, Lohle K, Reichel J, Daubenbuchel AM, Sterkenburg AS, et  al. Fusiform dilatation of the internal carotid artery in childhood-onset craniopharyngioma: multicenter study on incidence and long-term outcome. Pituitary. 2016;19(4): 422–8. 169. Mong S, Pomeroy SL, Cecchin F, Juraszek A, Alexander ME. Cardiac risk after craniopharyngioma therapy. Pediatr Neurol. 2008;38(4):256–60. 170. Regine WF, Mohiuddin M, Kramer S. Long-term results of pediatric and adult craniopharyngiomas treated with combined surgery and radiation. Radiother Oncol J Eur Soc Ther Radiol Oncol. 1993;27(1):13–21. 171. Hetelekidis S, Barnes PD, Tao ML, Fischer EG, Schneider L, Scott RM, et  al. 20-year experience in childhood craniopharyngioma. Int J Radiat Oncol Biol Phys. 1993;27(2): 189–95. 172. Habrand JL, Ganry O, Couanet D, Rouxel V, Levy-Piedbois C, Pierre-Kahn A, et  al. The role of radiation therapy in the management of craniopharyngioma: a 25-year experience and review of the literature. Int J Radiat Oncol Biol Phys. 1999;44(2):255–63. 173. Bulow B, Attewell R, Hagmar L, Malmstrom P, Nordstrom CH, Erfurth EM. Postoperative prognosis in craniopharyngioma with respect to cardiovascular mortality, survival, and tumor recurrence. J Clin Endocrinol Metab. 1998;83(11):3897–904. 174. Pereira AM, Schmid EM, Schutte PJ, Voormolen JH, Biermasz NR, van Thiel SW, et al. High prevalence of long-term cardiovascular, neurological and psychosocial morbidity after treatment for craniopharyngioma. Clin Endocrinol. 2005;62(2):197–204. 175. Sterkenburg AS, Hoffmann A, Gebhardt U, Warmuth-Metz M, Daubenbüchel AM, Müller HL.  Survival, hypothalamic obesity, and neuropsychological/psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes. Neuro Oncol. 2015;17(7):1029–38. 176. Daubenbuchel AM, Hoffmann A, Gebhardt U, Warmuth-Metz M, Sterkenburg AS, Muller HL. Hydrocephalus and hypothalamic involvement in pediatric patients with craniopharyngioma or cysts of Rathke’s pouch: impact on long-term prognosis. Eur J Endocrinol/Eur Fed Endocr Soc. 2015;172(5):561–9.

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177. Pickering L, Jennum P, Gammeltoft S, Poulsgaard L, Feldt-Rasmussen U, Klose M. Sleep-­ wake and melatonin pattern in craniopharyngioma patients. Eur J Endocrinol/Eur Fed Endocr Soc. 2014;170(6):873–84. 178. Ozyurt J, Lorenzen A, Gebhardt U, Warmuth-Metz M, Muller HL, Thiel CM. Remote effects of hypothalamic lesions in the prefrontal cortex of craniopharyngioma patients. Neurobiol Learn Mem. 2014;111:71–80. 179. Ozyurt J, Muller HL, Thiel CM. A systematic review of cognitive performance in patients with childhood craniopharyngioma. J Neuro-oncology. 2015;125(1):9–21. 180. Erfurth EM, Holmer H, Fjalldal SB. Mortality and morbidity in adult craniopharyngioma. Pituitary. 2013;16(1):46–55. 181. Roemmler-Zehrer J, Geigenberger V, Stormann S, Ising M, Pfister H, Sievers C, et al. Specific behaviour, mood and personality traits may contribute to obesity in patients with craniopharyngioma. Clin Endocrinol. 2015;82(1):106–14. 182. Zada G, Kintz N, Pulido M, Amezcua L. Prevalence of neurobehavioral, social, and emotional dysfunction in patients treated for childhood craniopharyngioma: a systematic literature review. PLoS One. 2013;8(11):e76562. 183. Crespo I, Santos A, Webb SM. Quality of life in patients with hypopituitarism. Curr Opin Endocrinol Diabetes Obes. 2015;22(4):306–12. 184. Crespo I, Valassi E, Santos A, Webb SM. Health-related quality of life in pituitary diseases. Endocrinol Metab Clin North Am. 2015;44(1):161–70. 185. Petito CK, DeGirolami U, Earle KM.  Craniopharyngiomas: a clinical and pathological review. Cancer. 1976;37(4):1944–52. 186. Apps JR, Martinez-Barbera JP. Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology. Brain Pathol. 2017;27(3):364–9. 187. Gomes DC, Jamra SA, Leal LF, Colli LM, Campanini ML, Oliveira RS, et al. Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas. Eur J Endocrinol. 2015;172(5):603–8. 188. Stache C, Holsken A, Fahlbusch R, Flitsch J, Schlaffer SM, Buchfelder M, et al. Tight junction protein claudin-1 is differentially expressed in craniopharyngioma subtypes and indicates invasive tumor growth. Neuro Oncol. 2014;16(2):256–64. 189. Müller HL, Kaatsch P, Warmuth-Metz M, et  al. Kraniopharyngeom im Kindes- und Jugendalter. Monatsschr Kinderheilkd: Springer Nature; 2003.

Chapter 4

Prolactinomas Takara L. Stanley and Madhusmita Misra

Introduction and Epidemiology Prolactinomas are pituitary adenomas comprised of lactotrophs, producing and secreting prolactin. Pituitary adenomas are quite rare in children, comprising only about 2–3% of the supratentorial tumors in this age group [1]. In prepubertal children, prolactinomas are rare, and the most common pituitary adenomas are corticotropinomas [2]. In peri- and postpubertal children, however, prolactinomas are the most common pituitary adenoma, comprising at least half of all adenomas in this age group [2–7]. Children are much more likely to present with macroprolactinomas than are adults [8]. Prolactinomas occur more frequently in females than in males, and females are more likely to present with microadenomas, whereas males are much more likely to present with macroadenomas [4, 6, 7]. This difference is likely a combination of a distinct pathological process in males and a tendency for earlier presentation and diagnosis in females due to menstrual irregularity [5]. Hyperprolactinemia is a much more common finding in the pediatric population than is prolactinoma. Prolactin is unique among pituitary hormones in that it is primarily regulated through tonic inhibition by dopamine. Thus, any sellar or suprasellar lesion that compresses the pituitary stalk, interrupting dopamine signaling, can cause hyperprolactinemia, as can multiple medications that antagonize dopamine signaling. Consequently, careful consideration of the differential diagnosis of elevated prolactin is a critical first step in the diagnosis of prolactinoma.

T. L. Stanley Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA M. Misra (*) Pediatric Endocrinology, Massachusetts General Hospital, Boston, MA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_4

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Table 4.1  Signs and symptoms of macroprolactinomas in children Symptoms of hyperprolactinemia Primary amenorrhea/delayed puberty Menstrual dysfunction Galactorrhea Gynecomastia (% of males) Symptoms caused by mass effect Headache Short stature Visual disturbances/visual field defect

Microprolactinomas

Macroprolactinomas

0–22 [4, 6, 7] 58–80 [4, 6, 7] 27–67 [4, 6, 7] (Reported in 1 male in 1 series) [7]

10–71 [4, 6, 7] 29–86 [4, 6, 7] 51–91 [4, 6–8] 31–44 [7, 8]

0–17 [4, 6, 7] 0–11 [4, 6, 7] 0 [4, 6, 7]

40–87 [4, 6–8] 0–16 [4, 6, 7] 17–47 [4, 6–8]

Presenting Signs and Symptoms of Prolactinomas Typical presenting symptoms of micro- and macroprolactinomas, as reported in multiple pediatric case series, are shown in Table 4.1 [3, 4, 6–8]. Microadenomas generally present due to clinical sequelae of elevated prolactin – namely, menstrual irregularity (rarely menorrhagia), hypogonadism, or galactorrhea – whereas macroadenomas present both with effects of hyperprolactinemia and with tumor-related mass effects. Micro- and macroprolactinomas commonly present in females with menstrual irregularity, and both may present with galactorrhea or delayed puberty in either sex [3]. Males may also present with gynecomastia [7, 8]. Macroprolactinomas commonly present with headaches, visual problems, growth delay, and insufficiency of other pituitary hormones [3, 8]. Tall stature or features of acromegaly may also occur in patients with tumors that co-secrete growth hormone (GH) and prolactin [3], depending on pubertal stage.

Diagnostic Approach Laboratory Evaluation Evaluation of the signs and symptoms described above should include a prolactin level as well as gonadotropins and gonadal steroids, thyroid-stimulating hormone (TSH), and free thyroxine (free T4), and other laboratory testing as appropriate. Although elevated serum prolactin prompts concern for prolactinoma, the differential diagnosis of hyperprolactinemia should be carefully considered first, as described below. Dynamic testing, such as stimulation with thyrotropin-releasing hormone, is not recommended in the evaluation of hyperprolactinemia [9].

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Evaluation of Elevated Serum Prolactin Children with hyperprolactinemia should undergo a comprehensive medical history to assess for causes not associated with pituitary pathology (see Table  4.2). If initial blood sampling was stressful or was performed at night, in the postprandial period, or following nipple stimulation, repeat sampling may be advisable (see “Considerations in Prolactin Measurement” below). Hypothyroidism may cause hyperprolactinemia through thyrotropin-releasing hormone (TRH) stimulation of prolactin, and we recommend assessment of TSH and free T4 to exclude this possibility. Of note, longstanding primary hypothyroidism can also cause pituitary hyperplasia through stimulation of thyrotrophs and lactotrophs, potentially mimicking the appearance of pituitary adenoma [9]. Renal insufficiency is also associated with increased prolactin levels, due to both increased secretion and reduced renal clearance, and patients with renal failure can have levels as high as 200 ng/mL [9–11]. Pregnancy and lactation cause prolactin elevation up to 300–400 ng/mL [12, 13]. Numerous medications may cause prolactin elevation, as shown in Table 4.2. In general, when medication is the suspected cause of hyperprolactinemia, this should be confirmed by documenting Table 4.2  Non-pituitary factors causing elevation of serum prolactin Typical range of serum prolactin elevation Physiologic Pregnancy or breastfeeding Stress (including surgery, critical illness) Nipple stimulation, chest trauma, chest wall lesions Exercise Sleep Medical conditions Hypothyroidism Renal failure Medications Estrogen

Antipsychotics (typical and atypical; see text for more detail regarding atypical antipsychotics) Antidepressants (including serotonin selective reuptake inhibitors [SSRIs], monoamine oxidase inhibitors, and tricyclics) Metoclopramide Domperidone Cocaine Opiates Verapamil

50% total prolactin is considered confirmatory for macroprolactinemia [26]. We do not recommend routine testing for macroprolactinemia in patients with symptoms of hyperprolactinemia, but testing should be considered in asymptomatic patients, particularly those with a normal pituitary MRI [9].

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Pituitary MRI Patients with confirmed hyperprolactinemia for which non-pituitary causes are excluded (as best as possible) should undergo a brain MRI with pituitary protocol, using thin slices through the pituitary region and imaging before and after the injection of contrast. Approximately 10% of normal adults have incidental pituitary adenomas on MRI [30], and autopsy studies have shown a similar prevalence [31], such that a very small adenoma in the presence of mild prolactin elevation does not necessarily indicate a prolactinoma. Generally, however, a pituitary adenoma along with persistent hyperprolactinemia is highly suggestive of prolactinoma. Microprolactinomas, which are 250 ng/mL and often in the several 1000s. A prolactin level of >500 ng/ml is usually diagnostic of a macroprolactinoma. Figure 4.3 shows

Fig. 4.3  Borderline macroprolactinoma A left-sided borderline macroprolactinoma is shown in this T1-weighted coronal image obtained after the administration of gadolinium

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a T1-weighted post-contrast coronal image of a 9-mm left-sided prolactinoma (borderline macroadenoma) in a 15-year-old who presented with initial prolactin concentrations around 350 ng/mL. A minority of prolactinomas are “aggressive,” invading surrounding sellar and suprasellar structures but contiguous with the sellar lesion. Pituitary carcinoma, defined as a pituitary adenoma that is non-contiguous with the sellar lesion or has metastasized to other parts of the body, is incredibly rare [32] . When a sizeable (≥10 mm) lesion is found on MRI without the expected degree of elevation in prolactin (i.e., prolactin  1 cm) were recorded in more than 85% of the cases before 1996 [2, 5–8]. Interestingly, the prevalence of microadenomas is progressively increasing as confirmed by data collected by Malchiodi et al. showing that the percentage of microadenomas ranges between 30 and 35% of all TSHomas [9]. However, most TSHomas are diagnosed at the stage of invasive macroadenomas [2, 5–9], extra- and parasellar extension being present in most of cases.

Pathology and Etiopathogenesis TSHomas are benign tumors that arise from adenomatous transformation of thyrotropes. Up to now TSH-secreting carcinomas with multiple metastases have been described in three patients [10–12], loss of pituitary glycoprotein hormone alpha-­ subunit (α-GSU) secretion being considered as a marker of malignant transformation [10]. Though the majority of TSHomas secretes TSH alone, about one fourth of them are mixed adenomas that cosecrete TSH and other anterior pituitary hormones. Hypersecretion of TSH and GH is the most frequent association (15–20%), followed by cosecretion of TSH and PRL (8–10%), while no TSHomas cosecreting ACTH have been so far identified. Occasionally pituitary adenomas cosecreting TSH and gonadotropins have been described [2, 13, 14] leading to precocious puberty during childhood or to ovarian hyperstimulation in adult female. The notion that GH and PRL share with TSH common transcription factors (e.g., PROP-1,

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Pit-1, and HESX-1) justifies why GH and PRL are frequently cosecreted in TSHomas [15]. However, it is important to remember that a positive immunohistochemistry for pituitary hormones other than TSH does not necessarily correlate with their hypersecretion in vivo [16, 17]. As mentioned before, most TSHomas are macroadenomas that are characterized by high local invasiveness at morphologic and histopathologic analysis. Interestingly, previous thyroid ablation negatively affects clinical behavior. In fact, invasive macroadenomas are found in 49% of patients who had undergone thyroid ablation (i.e., radioiodine or thyroidectomy) versus 27% in those who were untreated thus suggesting that a reduction in T3 and T4 circulating levels might stimulate neoplastic thyrotrope cells growth through an altered feedback mechanism, a situation like that observed in some patients after bilateral adrenalectomy for Cushing’s disease (Nelson’s syndrome) [2]. TSHomas are frequently very fibrous and sometimes are so hard that they are defined “pituitary stones” [18]. It this respect, overexpression of basic fibroblast growth factor by some TSHomas suggests that it may play a role in the development of fibrosis of this pituitary neoplasm [19]. In patients with confirmed biochemical findings of TSHoma and neuroradiological imaging negative for the presence of a pituitary adenoma, an ectopic TSH secretion should be taken into consideration [20]. TSHoma ectopically occurring in the nasopharyngeal pituitary residue has been reported [21–23]. The molecular pathogenetic mechanisms leading to TSHomas formation are presently unknown. As demonstrated in other secreting and nonsecreting pituitary adenomas, TSHomas originate from the clonal expansion of a single transformed cell [24]. Therefore, a transforming event leading to an increased cell proliferation and secondary mutations or alterations favoring tumor progression is needed to induce TSHoma formation. However, no mutations in oncogenes commonly activated in human neoplasia have been so far reported in TSHomas. Moreover, none of the screened TSHomas has been shown to express activating mutations of genes encoding for stimulatory or inhibitory G protein subunits (i.e., αs, αq, α11, or αi2) or TRH receptor [25]. Since Pit-1 is a transcription factor involved in TSH gene expression, it has been studied and shown to be overexpressed but not mutated in a series of TSHomas [26]. As for oncogenes, no mutations affecting common antioncogenes (i.e., p53, Rb, Menin) have been so far identified. Though the presence of a TSHoma has been reported in five cases within a familial setting of MEN1, a screening study carried out on sporadic TSHomas found LOH on 11q13, where menin is located, but none of these tumors had a menin mutation [27]. Finally, a mutation of aryl hydrocarbon receptor-interacting protein (AIP) was found in a single patient with TSHoma [28]. A recently published whole-exome sequencing study of 12 TSHomas identified several candidate somatic mutations (e.g., SMOX and SYTL3) and changes in copy numbers [29]. However, the low number of mutations, as well as the absence of recurrence of mutations in the tumors studied, seems to further confirm the benign nature of these tumors. TSHomas are characterized by an extreme refractoriness to the negative feedback mechanism exerted by thyroid hormones, this observation leading to search for alterations in thyroid hormone receptor (TR) expression and function [30, 31].

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While the absence of TRα1, TRα2, and TRβ1 expression was reported in one TSHoma, aberrant alternative splicing of TRβ2 mRNA encoding TRβ variant lacking T3-binding activity was recently shown as a mechanism responsible for impaired T3-dependent negative regulation of both TSHβ and α-GSU in tumoral tissue [32]. Recently it has been suggested that somatic mutations of TRβ may be responsible for the defective negative feedback mechanism at least in some TSHomas [33]. Finally, knock-in mutant mice harboring a mutation in the TRβ gene spontaneously develop TSHomas via phosphatidylinositol 3-kinase signaling activation [34]. Tumorous thyrotropes express somatostatin receptor type 2 and 5 (SST2 and SST5), this expression explaining the antisecretory and antiproliferative effects exerted by somatostatin analogs in patients with TSHoma [35]. Though no mutations affecting somatostatin receptor genes have been identified, LOH and polymorphisms at the somatostatin receptor type 5 gene locus seem to be associated with an aggressive phenotype and resistance to medical treatment [36].

Clinical Features Patients with TSHomas present signs and symptoms of hyperthyroidism frequently associated with the consequences of tumor compression on the surrounding anatomical structures (i.e., visual field defects, loss of vision, headache, and partial or complete hypopituitarism) (Table 8.1). In this respect, while the occurrence of bilateral exophthalmos may be the consequence of a coexistent autoimmune thyroiditis, unilateral exophthalmos may represent the consequence of orbital invasion by pituitary tumor [2, 37, 38]. In many cases, patients are diagnosed after a long history of thyroid dysfunction (diagnosed as Graves’ disease or toxic multinodular goiter), and about 30% of them underwent inappropriate surgical or radiometabolic thyroid ablation [2, 39, 40] that may negatively affect tumor behavior, invasive macroadenomas being found in half of patients who had undergone thyroid ablation [2]. Interestingly, Macchia et  al. observed a mean estimated latency of 39  months Table 8.1  Clinical features in patients with TSHoma

Clinical features Female/male ratio Previous thyroidectomy Severe thyrotoxicosis Goiter Thyroid nodule(s) Macroadenomas Visual field defects Headache Menstrual disorders Galactorrhea Acromegaly

1.4 30% 15% 90% 58% 70% 30% 18% 35% 25% 17%

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between first symptom appearance and diagnosis of TSHoma, this latency being significantly shorter in the case of macroadenomas (mean, 24 vs 50 months) [41]. In general, clinical features of hyperthyroidism are milder than expected on the basis of circulating thyroid hormone levels [42, 43]. Though severe thyrotoxic features (e.g., atrial fibrillation, cardiac failure) are observed in 25% of cases, some patients with untreated TSHoma may be clinically asymptomatic, thus suggesting that tumorous thyrotropes may secrete TSH molecules with a reduced biological activity [44]. The presence of these clinically “silent” TSHomas makes mandatory the systematic measurement of both TSH and FT4  in all patients with pituitary tumor, this approach being useful also to rule out the presence of a central hypothyroidism in non-TSH-secreting pituitary tumors. It is worth noting that in patients bearing pituitary tumors cosecreting TSH and other pituitary hormones, hyperthyroidism may be missed. This is the case of GH cosecretion that leads to the appearance of acromegaly symptoms that overshadow those related to TSH hypersecretion [2, 40]. Disorders of the gonadal axis are frequently seen not only in patients with mixed TSH/PRL or mixed TSH/FSH adenomas but also in 30% of patients with pure TSHoma [2]. Goiter is observed in more than 90% of patients, and the presence of multinodular goiter has been reported in several patients. Progression toward functional autonomy seems to be infrequent [45], and circulating antithyroid autoantibodies are found in 8% of patients, this figure being similar to that found in the general population. However, Graves’ hyperthyroidism may coexist with TSHoma in some patients [46]. The presence of differentiated thyroid carcinoma (DTC) has been reported [2, 47, 48]. In a recently published series of 62 TSHomas, DTC incidence of 4.8% has been reported as possibly related to the chronic TSH hypersecretion [48]. However, it has been demonstrated that the outcome of patients with the coexistence of TSHoma and DTC is in general favorable despite the presence of non-suppressible TSH [47]. Finally, though all these data suggest the opportunity to perform a high-­resolution ultrasound of the thyroid in all patients with TSHoma [48], no consensus regarding the management of patients with DTC and TSHoma has been so far agreed. It remains to be demonstrated that an aggressive management of these patients might result in a more favorable outcome (i.e., the complete removal of the tumor followed by radioablation and attempts to reduce serum TSH to the lowest tolerable level). The diagnosis of TSHoma may be delayed in patients in whom hypothyroidism is coexistent with the pituitary tumor [2, 48–50]. In these patients, an autonomous TSH hypersecretion should be suspected when TSH does not adequately normalize/ suppress during LT4 replacement therapy.

Diagnostic Work-Up Elevated levels of circulating thyroid hormones in the presence of detectable TSH concentrations are the biochemical characteristics of central hyperthyroidism. Diagnosis of central hyperthyroidism should be suspected in patients who have

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undergone thyroid ablation in whom high/normal TSH levels are found in the presence of high FT4 and FT3 levels during L-T4 treatment [2]. It is necessary to exclude all those factors (i.e., abnormalities in the pituitary-­ thyroid axis, laboratory artifacts, or drugs) that may lead to wrongly diagnose a condition of central hyperthyroidism. In this respect, inhibition of T4 to T3 conversion induced by iodine-containing drugs (e.g., povidone, amiodarone, iodinated contrast media) or nonthyroidal illness may induce the presence of high FT4 levels with detectable TSH that are, however, associated with normal or low-normal T3. Some laboratory artifacts can give spuriously high hormone levels and possibly simulate the biochemical characteristics of central hyperthyroidism. This is the case of heterophilic antibodies directed against mouse gamma globulins or anti-TSH antibodies. The presence of anti-T4 or anti-T3 autoantibodies or both as well as the familial dysalbuminemic hyperthyroxinemia (a condition characterized by abnormal circulating albumin with increased T4 affinity) may cause FT4 and/or FT3 overestimation, particularly when “one-step” analog methods are used [2, 51]. In TSHomas, extremely variable levels of serum TSH and thyroid hormones have been reported, and no difference in basal values of TSH and free thyroid hormone levels was seen between patients with TSHoma and those with RTH [1, 2]. Interestingly, any significant correlation between immunoreactive TSH and free thyroid hormone levels has been observed in patients with TSHoma, as demonstrated by the observation that in 30% of them, high levels of free thyroid hormones are associated with immunoreactive TSH levels within the normal range. In this respect, it has hypothesized that adenomatous thyrotropes secrete TSH molecules with peculiar glycosylation and biologic properties [44, 52, 53]. An unbalanced excess of circulating free α-GSU levels and elevated α-GSU/ TSH molar ratio are detected in patients with TSHoma [2, 54], a ratio greater than 1.0 being possibly indicative of the presence of TSHoma provided that appropriate control groups matched for TSH and gonadotropin levels are considered. Interestingly, normal α-GSU levels and α-GSU/TSH molar ratio are observed in the majority of microadenomas [6], this finding demonstrating a possible relationship between the size of the tumor and its secretory activity. Furthermore, it has been suggested that a spontaneous and marked decrease in both TSH and α subunit might indicate that the tumor is becoming less differentiated and might correlate with invasive and metastatic behavior [10]. The degree of tissue hyperthyroidism may be evaluated by measuring several parameters of peripheral thyroid hormone action [2]. Sex hormone-binding globulin (SHBG) , cholesterol, angiotensin-converting enzyme, osteocalcin, red blood cell sodium content, and carboxyterminal cross-linked telopeptide of type I collagen (ICTP) have been proposed, SHBG and ICTP being those more frequently used in differentiating patients with TSHoma from those with RTH [55, 56]. In fact, as it occurs in all forms of hyperthyroidism, patients with TSHoma have high ICTP and SHBG levels, while they are into the normal range in patients with central hyperthyroidism due to RTH [1, 2]. Though several stimulatory and inhibitory tests have been proposed to confirm the diagnosis of TSHoma, none of them has a clear-cut diagnostic value. Recently,

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the guideline for the diagnosis of TSHoma endorsed by the European Thyroid Association suggests that both stimulatory and inhibitory tests (i.e., TSH stimulation test and T3 suppression test) should be used in the differential diagnosis of central hyperthyroidism [54]. Patients with TSHoma are characterized by a blunted/ absent TSH increase after TRH stimulation test (200 μg bolus intravenously, sampling at 0, 20, 60, 90, and 120 min) and fail to completely suppress TSH following T3 suppression test (80–100 μg/day divided in three administrations for 10 days, sampling at 0, 5 and, 10 days). T3 suppression is considered as the most specific and sensitive test to be used when a TSHoma is suspected in previously thyroidectomized patients [2, 6]. High-resolution computed tomography (CT) and nuclear magnetic resonance imaging (MRI) are used to visualize a TSHoma. Though microadenomas are now reported with increasing frequency (up to 30%), 70% of TSHomas are diagnosed with frequent suprasellar extension or sphenoidal sinus invasion [2]. However, ectopic tumors in the pharyngeal region have been reported [21, 23]. In these cases, pituitary scintigraphy with radiolabeled octreotide (octreoscan) has been shown to successfully localize TSHomas [2, 58]. The coexistence of high thyroid hormones levels and measurable circulating TSH is sufficient to rule out the diagnosis of Graves’ disease, uni- or multinodular toxic goiter or activating mutations of TSH receptor. Once the presence of methodological interferences is excluded [2, 51, 57], it is mandatory to exclude a possible RTH (Table  8.2). The presence of neurological signs and symptoms (e.g., visual defects and headache) or clinical features of concomitant hyper- or hyposecretion of other pituitary hormones are characteristically seen in patients with TSHoma. Furthermore, an alteration of the pituitary gland at MRI or CT scan strongly supTable 8.2  Parameters useful in differentiating patients with TSH-secreting pituitary adenomas (TSHomas) from those with resistance to thyroid hormones (RTH) [3] Parameter Serum TSH mU/L High α-GSU levels High α-GSU/TSH m.r. Serum FT4 pmol/L Serum FT3 pmol/L Serum SHBG nmol/L Serum ICTP μg/L Abnormal TSH response to T3 suppressiona,b Blunted TSH response to TRH test

Significant differences No Yes Yes No No Yes Yes No Yes

(in TSHomas) (in TSHomas)

(in TSHomas) (in TSHomas)

(in TSHomas)

α-GSU, pituitary glycoprotein hormone alpha-subunit; SHBG, sex hormone-binding globulin; ICTP, carboxyterminal cross-linked telopeptide of type I collagen a T3 suppression test, i.e., Werner’s test (80–100 μg T3 for 8–10 days). Complete inhibition of both basal and TRH-stimulated TSH levels has never been recorded in either group of patients b Although abnormal in quantitative terms, TSH response to T3 suppression test was qualitatively normal in the majority of RTH patients

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ports the diagnosis of TSHoma. In this respect, it is worth noting that a nonfunctioning pituitary incidentaloma may be found in a patient with RTH, thus suggesting that pituitary imaging should be performed only when all clinical and biochemical finding point to the presence of TSHomas [57]. Elevated α-GSU concentrations or high α-GSU/TSH molar ratio, high circulating levels of parameters of peripheral thyroid hormone action (SHBG, ICTP), and TSH unresponsiveness to TRH stimulation or to T3 suppression tests are characteristically associated with the presence of a TSHoma [1, 2, 57]. Since familial cases of TSHomas have not been documented, the finding of a similar biochemical profile in relatives points to the presence of RTH. Finally, an apparent association between TSHoma and RTH has been recently reported, and somatic mutations in the thyroid hormone receptor have been found in some tumors [32, 33], thus the occurrence of TSHoma in patients with RTH should be carefully considered [59–61].

Treatment and Follow-Up As recently stated by the European Thyroid Association guideline for the diagnosis and treatment of TSHomas, surgical removal of the adenoma remains the firstline therapy [57]. Though methimazole (or propylthiouracil) or somatostatin analogs (i.e., octreotide and lanreotide) along with propranolol could be administered to restore euthyroidism before surgery, it has been demonstrated that presurgical medical treatment seems not to significantly improve surgical outcome (63% vs 57%) [9]. Complete removal of the tumor is achieved in up to 80% of patients with microadenoma, whereas no more than 50–60% of patients with macroadenoma may be considered as cured after the surgical procedure [9, 40]. The reasons of surgical failure are the marked fibrosis frequently seen in TSHomas and the frequent extra- and parasellar extension of the tumor [5–9, 40, 62]. If surgery is contraindicated or declined, pituitary fractionated stereotaxic radiotherapy or radiosurgery might be considered. The therapeutic dose is suggested to be between 45 and 55 Gy administered by conventional fractionated radiotherapy or 10–25 Gy if radiosurgery is used. Available studies do not show any significant difference between conventional fractionated radiotherapy and radiosurgery [9]. Recently, Malchiodi et al. demonstrated that radiotherapy was effective in controlling hormone hypersecretion in 37% of patients within 2  years, 32% of patients developing new pituitary deficiencies from 18 to 96 months from treatment [9]. In summary, while thyroid hormone level normalization and apparent complete removal of tumor mass are achieved by surgery alone or combined with radiotherapy in one third of patients, thyroid hormone normalization without complete removal of the adenoma is demonstrated in a third of patients, thus indicating that about 60–70% of TSHomas are controlled with surgery, irradiation, or both. Tumorous thyrotropes express somatostatin receptor subtypes 1, 2A, 3, and 5, and it has been demonstrated that long-acting somatostatin analogs (i.e., octreotide

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LAR® or lanreotide SR® or lanreotide Autogel®) are highly effective in reducing TSH secretion in patients with TSHomas [57]. Interestingly, FT4 and FT3 circulating level normalization is observed in up to 90% of cases, goiter size being significantly reduced in 30% of them [5–9, 54]. As demonstrated in patients with acromegaly, somatostatin analog treatment induces a significant tumor mass shrinkage in about 40% of patients [57]. Resistance to somatostatin analog treatment, tachyphylaxis (i.e., escape of TSH secretion from the inhibitory effects of the drug), or discontinuation of treatment due to side effects (e.g., nausea, abdominal discomfort, bloating, diarrhea, glucose intolerance, and cholelithiasis) was documented in a minority of cases. If somatostatin analogs are not tolerated, dopamine agonists (bromocriptine, cabergoline) can be used even though only partial TSH suppression is seen in most of cases [57]. Thyroidectomy is reserved to patients with goiter in whom pharmacotherapy or surgery of the pituitary lesion has failed; in these patients thyroid hormone replacement should be initiated at a dose which maintains the serum-free T4 concentration in the upper 50 percent of the normal range; in fact serum TSH cannot be used to monitor therapy, since it is not suppressible [57]. There are no well-established criteria to define as cured a TSHoma after transsphenoidal surgery [57]. However, some parameters can help to assess the efficacy of the treatment. Clinical remission of hyperthyroidism, disappearance of neurological symptoms, resolution of neuroradiological alterations, and normalization of thyroid hormones, TSH, or α-GSU/TSH molar ratio may reflect the cure of a TSHoma [57]. Interestingly, the presence of undetectable TSH levels 1 week after surgery seems to be a sign of a complete adenomectomy, provided that presurgical treatment with antithyroid drugs or daily somatostatin analog injections were stopped at least 10 days before surgery [63]. Since only patients in whom T3 administration completely inhibits basal and TRH-stimulated TSH secretion may be considered as cured, T3 suppression test remains the most sensitive and specific test to document the complete removal of the adenoma [57, 63]. The recurrence of the TSHomas does not appear to be a frequent event, at least in the first years after successful surgery [2, 9]. In general, the evaluation of the patient should include the measurement of TSH and circulating free thyroid hormones two or three times the first year and then every year. Pituitary imaging should be performed 4 months postoperatively and then every 2 or 3 years. In patients with persistent macroadenoma, a close follow-up of visual fields is required. TSHoma patients should be evaluated clinically and biochemically two or three times the first year postoperatively and then every year. TSH and circulating free thyroid hormones should be measured. Pituitary imaging (MRI) should be performed 3–4 months after surgery, and then every 2 or 3 years, but should be promptly done in the presence of a sudden rise in THS and FT4/FT3 levels. In the case of persistent macroadenoma, a close follow-up of visual fields is required to ensure that visual function is not threatened [57]. Data on the recurrence rate of TSHoma in patients who are judged to be cured after surgery or radiotherapy are area scarce. In this respect, Malchiodi et al. recently observed a tumor or hormonal recurrence within the first 2 years after surgery [9].

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TSHomas in Children and Adolescents Only eight cases (four boys and four girls) of TSHomas in patients aged 15 and under (range 8–15 years) have been so far reported [61, 64–70]; presenting symptoms were mainly related to T4 and T3 excess (Table 8.3). Tumors were reported to be microadenomas in two cases and macroadenomas in five cases. All patients underwent surgical treatment and in one case patient was pre-treated with octreotide without any significant effect on TSH secretion. Interestingly, in one of these cases, the coexistence of TSHoma and RTH was demonstrated [61]. Finally, TSHoma was considered as cured in three patients only.

Summary Patients with TSHoma present with high levels of circulating free thyroid hormones in the presence of normal/high concentrations of TSH. It is mandatory to check the results using different methods of measurement and to establish a close collaboration with the Institution laboratory to exclude any methodological interference in the measurement technique of both TSH and free thyroid hormones that may mimic the biochemical picture of TSHomas. The clinical appearance of hyperthyroidism may be mild, sometimes overshadowed by signs and symptoms of concomitant acromegaly or by neurological symptoms (headache, visual field defect). It is mandatory to differentiate between a TSHoma and syndromes of thyroid hormone resistance by performing both TRH stimulation test and T3 suppression test to avoid unnecessary treatments. Since the restoration of euthyroidism and the prevention of neurological symptoms due to the mass effect exerted by the tumor on surrounding structures are the

Table 8.3  Clinical presentation and outcome of pediatric patients with TSHoma Tumor Sex Age size M 11 Macro M M

15 13

Macro Macro

F F F M

11 13 15 8

Macro Micro NA Macro

F

12

Micro

Presenting symptoms Hyperthyroidism; intrachranial hypertension NA School performance deterioration, behavioral changes and secondary enuresis Hyperthyroidism; goiter Poor weight gain and pubertal delay NA Emaciation and muscle weakness of the legs Goiter, sinus tachycardia, and tremors

Medical treatment No

Surgery Cure Refs. Yes No [63]

NA Yes

NA Yes

NA No

[64] [65]

No No NA No

Yes Yes NA Yes

No Yes NA Yes

[66] [67] [68] [69]

No

Yes

Yes

[70]

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main objective of the treatment, the first-line approach to TSHomas remains the surgical removal of the adenoma. If surgery is contraindicated or declined, as well as in the case of surgical failure, long-acting somatostatin analog administration is indicated, octreotide or lanreotide being successful in most patients with TSHoma.

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17. Azzalin A, Appin CL, Schniederjan MJ, Constantin T, Ritchie JC, Veledar E, et  al. Comprehensive evaluation of thyrotropinomas: single-center 20-year experience. Pituitary. 2016;19:183–93. 18. Webster J, Peters JR, John R, Smith J, Chan V, Hall R, Scanlon MF.  Pituitary stone: two cases of densely calcified thyrotropin-secreting pituitary adenomas. Clin Endocrinol. 1994;40: 137–43. 19. Ezzat S, Horvath E, Kovacs K, Smyth HS, Singer W, Asa SL. Basic fibroblast growth factor expression by two prolactin and thyrotropin-producing pituitary adenomas. Endocr Pathol. 1995;6:125–34. 20. Thompson LD, Seethala RR, Muller S. Ectopic sphenoid sinus pituitary adenoma (ESSPA) with normal anterior pituitary gland: a clinicopathologic and immuno-phenotypic study of 32 cases with a comprehensive review of the english literature. Head Neck Pathol. 2012;6: 75–100. 21. Collie RB, Collie MJ.  Extracranial thyroid-stimulating hormone-secreting ectopic pituitary adenoma of the nasopharynx. Otolaryngol Head Neck Surg. 2005;133:453–4. 22. Song M, Wang H, Song L, Tian H, Ge Q, Li J, et al. Ectopic TSH-secreting pituitary tumor: a case report and review of prior cases. BMC Cancer. 2014;14:544–7. 23. Wang Q, Lu XJ, Sun J, Wang J, Huang CY, Wu ZF. Ectopic suprasellar thyrotropin-secreting pituitary adenoma: case report and literature review. World Neurosurg. 2016;95:617.e13–8. 24. Ma W, Ikeda H, Watabe N, Kanno M, Yoshimoto T. A plurihormonal TSH-producing pituitary tumor of monoclonal origin in a patient with hypothyroidism. Horm Res. 2003;59:257–61. 25. Dong Q, Brucker-Davis F, Weintraub BD, Smallridge RC, Carr FE, Battey J, et al. Screening of candidate oncogenes in human thyrotroph tumors: absence of activating mutations of the Gαq, Gα11, Gαs, or thyrotropin-releasing hormone receptor genes. J Clin Endocrinol Metab. 1996;81:1134–40. 26. Pellegrini-Bouiller I, Morange-Ramos I, Barlier A, Gunz G, Enjalbert A, Jaquet P. Pit-1 gene expression in human pituitary adenomas. Horm Res. 1997;47(4–6):251–8. 27. Asteria C, Anagni M, Persani L, Beck-Peccoz P. Loss of heterozigosity of the MEN1 gene in a large series of TSH-secreting pituitary adenomas. J Endocrinol Investig. 2001;24:796–801. 28. Daly AF, Tichomirowa MA, Petrossians P, Heliövaara E, Jaffrain-Rea ML, Barlier A, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab. 2010;95:E373–83. 29. Sapkota S, Horiguchi K, Tosaka M, Yamada S, Yamada M.  Whole-Exome Sequencing Study of Thyrotropin-Secreting Pituitary Adenomas. J Clin Endocrinol Metab. 2017;102(2): 566–75. 30. Gittoes NJ, McCabe CJ, Verhaeg J, Sheppard MC, Franklyn JA. An abnormality of thyroid hormone receptor expression may explain abnormal thyrotropin production in thyrotropin-­ secreting pituitary tumors. Thyroid. 1998;8:9–14. 31. Tagami T, Usui T, Shimatsu A, Beniko M, Yamamoto H, Moriyama K, Naruse M. Aberrant expression of thyroid hormone receptor beta isoform may cause inappropriate secretion of TSH in a TSH-secreting pituitary adenoma. J Clin Endocrinol Metab. 2011;96:E948–52. 32. Ando S, Sarlis NJ, Oldfield EH, Yen PM.  Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab. 2001;86:5572–6. 33. Ando S, Sarlis NJ, Krishnan J, Feng X, Refetoff S, Zhang MQ, et  al. Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance. Mol Endocrinol. 2001;15:1529–38. 34. Lu C, Willingham MC, Furuya F, Cheng SY. Activation of phosphatidylinositol 3-kinase signaling promotes aberrant pituitary growth in a mouse model of thyrois-stimulating hormone-­ secreting pituitary tumors. Endocrinology. 2008;149:3339–45. 35. Horiguchi K, Yamada M, Umezawa R, Satoh T, Hashimoto K, Tosaka M, et al. Somatostatin receptor subtypes mRNA in TSH-secreting pituitary adenomas: a case showing a dramatic reduction in tumor size during short octreotide treatment. Endocr J. 2007;54:371–8.

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36. Filopanti M, Ballaré E, Lania AG, Bondioni S, Verga U, Locatelli M, et al. Loss of heterozygosity at the SS receptor type 5 locus in human GH- and TSH-secreting pituitary adenomas. J Endocrinol Investig. 2004;27:937–42. 37. Kourides IA, Pekonen F, Weintraub BD.  Absence of thyroid-binding immunoglobulins in patients with thyrotropin-mediated hyperthyroidism. J Clin Endocrinol Metab. 1980;51: 272–4. 38. Yovos JG, Falko JM, O’Dorisio TM, Malarkey WB, Cataland S, Capen CC. Thyrotoxicosis and a thyrotropin-secreting pituitary tumor causing unilateral exophthalmos. J Clin Endocrinol Metab. 1981;53:338–43. 39. Varsseveld NC, Bisschop PH, Biermasz NR, Pereira AM, Fliers E, Drent ML. A long-term follow-up study of eighteen patients with thyrotrophin-secreting pituitary adenomas. Clin Endocrinol. 2014;80:395–402. 40. Yamada S, Fukuhara N, Horiguchi K, Yamaguchi-Okada M, Nishioka H, Takeshita A, et al. Clinicopathological characteristics and therapeutic outcomes in thyrotropin-secreting pituitary adenomas: a single-center study of 90 cases. J Neurosurg. 2014;121:1462–73. 41. Macchia E, Gasperi M, Lombardi M, et  al. Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience. J Endocrinol Investig. 2009;32(9):773–9. 42. Lim EM, Bhagat CI, Walsh J. Asymptomatic thyrotropin-secreting pituitary microadenoma. Intern Med J. 2001;31:428–9. 43. Rabbiosi S, Peroni E, Tronconi GM, Chiumello G, Losa M, Weber G.  Asymptomatic thyrotropin-­secreting pituitary macroadenoma in a 13-year-old girl: successful first-line treatment with somatostatin analogs. Thyroid. 2012;22:1076–9. 44. Beck-Peccoz P, Persani L. Variable biological activity of thyroid-stimulating hormone. Eur J Endocrinol. 1994;131:331–40. 45. Abs R, Stevenaert A, Beckers A. Autonomously functioning thyroid nodules in a patient with a thyrotropin-secreting pituitary adenoma: possible cause-effect relationship. Eur J Endocrinol. 1994;131:355–8. 46. Kamoun M, d’Herbomez M, Lemaire C, Fayard A, Desailloud R, Huglo D, Wemeau JL.  Coexistence of thyroid-stimulating hormone-secreting pituitary adenoma and Graves’ hyperthyroidism. Eur Thyroid J. 2014;3:60–4. 47. Ünlütürk U, Sriphrapradang C, Erdoğan MF, Emral R, Güldiken S, Refetoff S, Güllü S. Management of differentiated thyroid cancer in the presence of resistance to thyroid hormone and TSH-secreting adenomas: a report of four cases and review of the literature. J Clin Endocrinol Metab. 2013;98:2210–7. 48. Perticone F, Pigliaru F, Mariotti S, Deiana L, Furlani L, Mortini P, Losa M. Is the incidence of differentiated thyroid cancer increased in patients with thyrotropin-secreting adenomas? Report of three cases from a large consecutive series. Thyroid. 2015;25(4):417–24. 49. Idiculla JM, Beckett G, Statham PF, Ironside JW, Atkin SL, Patrick AW. Autoimmune hypothyroidism coexisting with a pituitary adenoma secreting thyroid-stimulating hormone, prolactin and a-subunit. Ann Clin Biochem. 2001;38:566–71. 50. Losa M, Mortini P, Minelli R, Giovanelli M. Coexistence of TSH-secreting pituitary adenoma and autoimmune hypothyroidism. J Endocrinol Investig. 2006;29:555–9. 51. Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab. 2013;27: 745–62. 52. Gesundheit N, Petrick P, Nissim M, et al. Thyrotropin-secreting pituitary adenomas: Clinical and biochemical heterogeneity. Ann Intern Med. 1989;111:827. 53. Magner JA, Kane J.  Binding of thyrotropin to lentil lectin is unchanged by thyrotropin-­ releasing hormone administration in three patients with thyrotropin-producing pituitary adenomas. Endocr Res. 1992;8:163. 54. Terzolo M, Orlandi F, Bassetti M, et al. Hyperthyroidism due to a pituitary adenoma composed of two different cell types, one secreting alpha-subunit alone and another cosecreting alpha-­ subunit and thyrotropin. J Clin Endocrinol Metab. 1991;72:415–21.

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55. Beck-Peccoz P, Roncoroni R, Mariotti S, et al. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab. 1990;71:19–25. 56. Persani L, Preziati D, Matthews CH, Sartorio A, Chatterjee VK, Beck-Peccoz P. Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndromes of inappropriate secretion of TSH. Clin Endocrinol. 1997;47:207–14. 57. Beck-Peccoz P, Lania A, Beckers A, Chatterjee K, Wemeau JL.  European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. Eur Thyroid J. 2013;2:76–82. 58. Losa M, Magnani P, Mortini P, Persani L, Acerno S, Giugni E, et al. Indium-111 pentetreotide single-photon emission tomography in patients with TSH-secreting pituitary adenomas: correlation with the effect of a single administration of octreotide on serum TSH levels. Eur J Nucl Med. 1997;24:728–31. 59. Watanabe K, Kameya T, Yamauchi A, et al. Thyrotropin-producing microadenoma associated with pituitary resistance to thyroid hormone. J Clin Endocrinol Metab. 1993;76:1025–30. 60. Safer JD, Colan SD, Fraser LM, Wondisford FE. A pituitary tumor in a patient with thyroid hormone resistance: a diagnostic dilemma. Thyroid. 2001;11:281–91. 61. Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z.  A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab. 2015;100:2511–4. 62. Elston MS, Conaglen JV.  Clinical and biochemical characteristics of patients with thyroid-­ stimulating hormone-secreting pituitary adenomas from one New Zealand centre. Intern Med J. 2010;40(3):214–9. 63. Losa M, Giovanelli M, Persani L, Mortini P, Faglia G, Beck-Peccoz P. Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas. J Clin Endocrinol Metab. 1996;81:3086–90. 64. Suntornlohanakul S, Vasiknanont P, Mo-Suwan L, Phuenpathom N, Chongchitnant N. TSH secreting pituitary adenoma in children: a case report. J Med Assoc Thail. 1990;73(3):175–8. 65. Stanley JM, Najjar SS. Hyperthyroidism secondary to a TSH-secreting pituitary adenoma in a 15-year-old male. Clin Pediatr (Phila). 1991;30(2):109–11. 66. Phillip M, Hershkovitz E, Kornmehl P, Cohen A, Leiberman E. Thyrotropin secreting pituitary adenoma associated with hypopituitarism and diabetes insipidus in an adolescent boy. J Pediatr Endocrinol Metab. 1995;8(1):47–50. 67. Avramides A, Karapiperis A, Triantafyllidou E, Vayas S, Moshidou A, Vyzantiadis A. TSH-­ secreting pituitary macroadenoma in an 11-year-old girl. Acta Paediatr. 1992;81(12):1058–60. 68. Korn EA, Gaich G, Brines M, Carpenter TO. Thyrotropin-secreting adenoma in an adolescent girl without increased serum thyrotropin-alpha. Horm Res. 1994;42(3):120–3. 69. Gannage MH, Maacaron C, Okais N, Halaby G. Thyroid-stimulating hormone hypophyseal adenoma. A case report. J Med Liban. 1997;45(2):97–101. 70. Nakayama Y, Jinguji S, Kumakura S, et al. Thyroid-stimulating hormone (thyrotropin)-secretion pituitary adenoma in an 8-year-old boy: case report. Pituitary. 2012;15(1):110–5.

Chapter 9

Molecular Predictors of Clinical Behavior in Pituitary Adenohypophysial Tumors Shereen Ezzat and Sylvia L. Asa

Defining Aggressive Pituitary Tumors The increased use of imaging modalities including CT and MRI in investigating complaints ranging from headaches to growth disorders has led to an increase of potentially incidental pituitary findings [1]. The rising incidence of pituitary tumors is attributed to detection of a spectrum of lesions including small “microadenomas” and large tumors that cause significant morbidity and mortality [2, 3]. In view of the fact that pituitary tumors can exhibit a wide range of clinical behaviors, it has been suggested that the term “adenoma” is inappropriate and instead these lesions should be classified in a manner analogous to other tumors of neuroendocrine cells that can be indolent or aggressive, and the term “pituitary neuroendocrine tumor” or PitNET has been proposed [4]. From the clinical perspective, it is imperative to make every effort to distinguish those that are likely to remain dormant from the potentially more serious ones [5]. The terminology “aggressive” has been adopted to imply “invasive” when evaluating pituitary neoplasms. However, it is also important to note that aggressive lesions include those at high risk of recurrence or that exhibit reduced therapeutic responsiveness. Previous studies suggested that invasive pituitary tumors have higher mitotic activity, with a Ki67 labeling index >3%, and p53 immunoreactivity; these features were used to define “atypical adenomas” by the WHO in 2004 [6]. The reproducibility of these criteria became the subject of concern and in 2017 the WHO removed this category [5, 7, 8]. Recently, some groups have chosen to stratify pituitary tumors into three pathological categories, noninvasive, invasive, and aggressive-invasive tumors, based principally on imaging features [9]. According to S. Ezzat Medicine, University Health Network, University of Toronto, Toronto, ON, Canada S. L. Asa (*) Pathology, University Health Network, University of Toronto, Toronto, ON, Canada © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_9

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this approach, aggressive-invasive tumors exhibit a Ki-67 index >1%, mitotic activity >2 per 10 high-power fields, and positive p53 immunoreactivity [9]; however, as with the previous WHO classification of “atypical adenoma”, the reproducibility of these criteria remains to be proven.

Germline Genetic Abnormalities A growing list of molecular alterations have been identified as responsible for familial endocrine neoplasias including those that involve the pituitary gland [10]. The onset of pituitary neoplasia in childhood should raise the possibility of a hereditary syndrome.

Multiple Endocrine Neoplasias (MEN) Multiple endocrine neoplasia (MEN) type 1 and the more recently recognized MEN type 4 that is phenotypically similar are characterized by frequent development of pituitary neuroendocrine tumors [11, 12]. These syndromes are due to mutations in known genes, specifically MEN1 that encodes menin [13, 14] and CDKN1B that encodes p27 [15, 16] or possibly p18 [17]. At least one paper suggests that patients with MEN1 syndrome have larger and more aggressive tumors [18].

Carney Complex Patients with Carney complex develop pituitary somatotroph proliferations. The majority of patients with this syndrome harbor mutations of the PRKAR1A gene that encodes the type 1A regulatory subunit of protein kinase A [19]. The genetic abnormalities causing disease in the remainder of these patients remain to be clarified.

Familial Isolated Pituitary Adenomas (FIPA) Familial predisposition to pituitary adenohypophysial neoplasia is associated with germline mutations of the AIP gene that encodes the aryl hydrocarbon receptor-­ interacting protein (AIP) [20–24], also known as immunophilin homolog ARA9, or HBV X-associated protein 2 (XAP-2). AIP has proven to represent a chaperone protein with multifunctional properties including transcriptional control of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects. Recent studies have shown that AIP regulates cAMP concentrations through

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Gαi-2 and Gαi-3 proteins that inhibit cyclic adenosine monophosphate (cAMP) synthesis [24]. Germline mutations in AIP have been identified in some families with the isolated familial somatotropinoma (IFS) syndrome where acromegaly and gigantism predominate and in those with familial isolated pituitary adenoma (FIPA) syndrome, with various types of pituitary tumors but usually including some GHand PRL-secreting tumors [24]. Loss of heterozygosity (LOH) of the AIP gene in the tumors suggests that it acts as a tumor suppressor, consistent with its role in cAMP modulation. There is a high incidence of germline AIP mutations in children and young adults with gigantism and acromegaly [25]. While reduced AIP protein expression has been reported in sporadic sparsely granulated somatotroph tumors, [26] this is not due to AIP mutation. The aggressive behavior of sparsely granulated somatotroph tumors raises the possibility that AIP may be implicated in such behavior, but not all patients with AIP mutations harbor this subtype of tumor [27, 28].

Paraganglioma-Associated Pituitary Tumor Syndromes (3PA) A novel multiple endocrine neoplasia syndrome, “3PA syndrome,” is characterized by pituitary tumor with paraganglioma and/or pheochromocytoma. This entity has been attributed to SDH complex mutations [29]. While these are rare [30], there has been one pituitary carcinoma reported in a patient with germline SDHB mutation [31].

X-Linked Acrogigantism Rare patients with early childhood gigantism have been shown to have Xq26 microduplications and GPR101 mutation. This syndrome has been labeled “X-linked acrogigantism” (X-LAG) [32]. These patients have aggressive disease from a functional perspective; the pituitary pathology has ranged from hyperplasia to neoplasia.

The Role of Histopathology Histopathological morphology represents an integrated reflection of genetic and epigenetic regulation of cells. In the pituitary, histology and immunohistochemistry have identified biomarkers of cell differentiation, including transcription factors, hormones, and keratins. Detailed morphologic studies can identify histological subtypes of pituitary adenohypophysial tumors that are much more complex than originally or commonly appreciated [33–35]. Although continuing to evolve, histopathologic classification systems can provide robust prediction of aggressive behavior of pituitary tumors [5, 7] (Table 9.1). For example, pituitary tumors that frequently behave

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Table 9.1  Relative aggressiveness of histological subtypes of pituitary adenohypophysial tumors Clinical hormone hypersecretion Tpit lineage ACTH Pit-1 lineage GH PRL

Less aggressive tumor type

More aggressive tumor type

Densely granulated corticotroph

Sparsely granulated corticotroph Crooke cell

Densely granulated somatotroph Sparsely granulated lactotroph Mammosomatotroph Thyrotroph Plurihormonal Pit-1 lineage

Sparsely granulated somatotroph

GH and PRL TSH GH± PRL±TSH SF-1 lineage FSH, LH Gonadotroph Various or unknown lineages None Gonadotroph

Multiple unusual

Densely granulated lactotroph Acidophil stem cell Acidophil stem cell Poorly differentiated Pit-1 lineagea

Silent corticotroph Poorly differentiated Pit-1 lineagea Null cell Unusual plurihormonal tumor of multiple lineages

Formerly known as “silent subtype 3” tumor

a

aggressively include the sparsely granulated somatotroph tumors that present with growth hormone excess, the acidophil stem cell tumors that frequently present with dopamine-resistant hyperprolactinemia and progressive growth, and the sparsely granulated corticotroph tumors that cause subtle Cushing’s disease which can be difficult to diagnose and manage [33, 34, 36]. These aggressive tumors are typically associated with parasellar invasion into the optic chiasm superiorly and/or the cavernous sinuses laterally. Acidophil stem cell tumors and the poorly differentiated Pit1lineage tumors that may be clinically silent or may be associated with acromegaly, hyperthyroidism, and/or hyperprolactinemia [37] characteristically invade downward into the bone rather than following the suprasellar path of expansion that characterizes the more common gonadotroph tumors [33]. These lesions have been reported in children and young adults [37–39]. Indeed, such atypical growth patterns should raise the clinical suspicion of these potentially more aggressive tumor types. Occasionally, the growth can be entirely or predominantly situated within the sphenoid sinus, rendering some confusion regarding the nature of the lesion [33, 40, 41].

Tissue Biomarkers of Aggressive Pituitary Neoplasms An ever-increasing number of tissue biomarkers has been examined for their ability to predict aggressive pituitary tumor behavior [34, 42]. These have ranged from chromosomal aberrations or duplications to expression of microRNAs, proliferation

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markers, oncogenes, tumor suppressor genes, growth factors, and their receptors. Unfortunately, thus far there has been no single biomarker or group of markers that can stand alone to provide independent prediction of aggressive behavior in pituitary lesions [34, 42–52]. In the next sections, we will review groups of biomarkers for their rationale and the extent to which they meet their intended applications in predicting aggressive behavior of pituitary neuroendocrine tumors.

Proliferation Biomarkers The most classic of tissue biomarkers in endocrine tumors, including those of the pituitary, is the nuclear Ki-67 antigen, a marker of cell cycle progression. The Ki-67 labeling index (LI) , usually detected by the MIB-1 antibody and therefore also referred to as the MIB-1 LI, is of prognostic significance in the assessment of proliferative capacity of many tumors, including neuroendocrine tumors of the gastroenteropancreatic system [53]. Ki-67 LIs in adenohypophysial tumors have been reported to range from less than 1% to as high as 23% (Fig. 9.1) with the majority being 90%) [105–108]. Germinomas arise from primordial germ cells and account for 50–70% of germ cell tumors [102, 109]. The remaining one- third are NGGCTs which originate from cells at various stages of embryonal development [102, 109, 110] and include embryonal carcinomas, yolk sac tumors, choriocarcinomas and mixed malignant germ cell tumors (MMGCTs) [43, 102]. Intracranial germ cell tumors may present with endocrine abnormalities, signs of increased intracranial pressure, and/or visual changes, depending on tumor location and size [30, 102]. Suprasellar germ cell tumors most often present with CDI which may antecede other clinical symptoms by months to years [30, 108, 111]. Eventually, hypothalamic- pituitary deficiencies emerge such as pubertal delay or precocious puberty, growth hormone deficiency, hypothyroidism, adrenal insufficiency, or panhypopituitarism [30, 102, 111]. Patients may present with visual disturbances if there is impingement or infiltration of the chiasm or optic nerves; and if they enlarge sufficiently dorsally, may fill the third ventricle and rarely present with signs of increased intracranial pressure [102, 108, 109]. CDI (85–100%) is the most frequent endocrine disturbance in GCTs along with GHD (75–100%) [97, 111–114]. TSH, ACTH and gonadotropin deficiency may be present at the time of diagnosis [111, 113] or seen later on long- term follow up along with hyperprolactinemia [97, 111, 112, 115]. Pineal region tumors often present with signs of increased intracranial pressure such as obstructive or non-communicating hydrocephalus [108, 116]. Approximately 50% of patients with pineal germ cell tumors present with Parinaud syndrome due

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to compression of the adjacent midbrain structure and is characterized by vertical gaze palsy, nystagmus on convergence, and pupillary dilation with poor reactiveness to light [30, 102, 108]. Ophthalmologic abnormalities and somnolence is seen in approximately 25–50% of patients; another 25% of patients present with ataxia, seizures and behavioral changes. If there are concurrent endocrine deficiencies such as CDI, there is likely an occult suprasellar lesion involving the infundibulum. This is a critical observation, since this syndrome requires special radiation therapy modifications [102]. CDI typically presents early, at the time of diagnosis, in GCTs [112]. Long- term follow up has shown occasional improvement of CDI in patients with a CNS germinoma following medical therapy [112], especially if tumor size is greater than 2 cm at diagnosis as compared with smaller tumors [117]. On MR imaging, a well-marginated, homogeneous round solid mass with gray matter signal intensity is seen that invades the infundibular stalk and the floor of the third ventricle. GCTs are isointense to hypointense on T1 signal intensity and isointense to slightly hyperintense on T2 signal intensity, with marked homogeneous or heterogeneous enhancement [69, 116]. Neuroimaging studies cannot differentiate germinomas from other NGGCTs [102]. A tumor biopsy is required for diagnosis, except in cases where characteristic serum and/or CSF tumor markers such as alpha-­fetoprotein (AFP) and/ or β-hCG are elevated [102, 118]. Pure germinomas and teratomas usually present with negative markers or low levels of β-hCG in the lumbar CSF ( + 3 SDS) may be present at diagnosis or later [173]. Hyperphagia, due to anatomic damage to the hypothalamic satiety center and functional dysregulation of anorexigenic and orexigenic hormones contribute [174]. Other hypothalamic symptoms include somnolence, sleep-wake cycle disturbances, adipsia, temperature dysregulation; and cognitive and behavioral disorders.

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133. Donadieu J, et al. Incidence of growth hormone deficiency in pediatric-onset Langerhans cell histiocytosis: efficacy and safety of growth hormone treatment. J Clin Endocrinol Metab. 2004;89(2):604–9. 134. Nanduri VR, et al. Growth and endocrine disorders in multisystem Langerhans’ cell histiocytosis. Clin Endocrinol. 2000;53(4):509–15. 135. Abla O, Egeler RM, Weitzman S. Langerhans cell histiocytosis: current concepts and treatments. Cancer Treat Rev. 2010;36(4):354–9. 136. Aquilina K, Boop FA.  Nonneoplastic enlargement of the pituitary gland in children. J Neurosurg Pediatr. 2011;7(5):510–5. 137. Kocova M, et  al. Diagnostic approach in children with unusual symptoms of acquired hypothyroidism. When to look for pituitary hyperplasia? J Pediatr Endocrinol Metab. 2016;29(3):297–303. 138. Satyarthee GD, Sharma BS.  Repeated headache as presentation of pituitary apoplexy in the adolescent population: unusual entity with review of literature. J Neurosci Rural Pract. 2017;8(Suppl 1):S143–s146. 139. Chao CC, Lin CJ.  Pituitary apoplexy in a teenager--case report. Pediatr Neurol. 2014;50(6):648–51. 140. Spampinato MV, Castillo M.  Congenital pathology of the pituitary gland and parasellar region. Top Magn Reson Imaging. 2005;16(4):269–76. 141. Tominaga JY, Higano S, Takahashi S. Characteristics of Rathke’s cleft cyst in MR imaging. Magn Reson Med Sci. 2003;2(1):1–8. 142. Teramoto A, et  al. Incidental pituitary lesions in 1000 unselected autopsy specimens. Radiology. 1994;193(1):161–4. 143. Han SJ, et al. Rathke’s cleft cysts: review of natural history and surgical outcomes. J Neuro-­ Oncol. 2014;117(2):197–203. 144. Evliyaoglu O, Evliyaoglu C, Ayva S.  Rathke cleft cyst in seven-year-old girl presenting with central diabetes insipidus and review of literature. J Pediatr Endocrinol Metab. 2010;23(5):525–9. 145. Al-Holou WN, et al. Prevalence and natural history of arachnoid cysts in children. J Neurosurg Pediatr. 2010;5(6):578–85. 146. Rao G, et al. Expansion of arachnoid cysts in children: report of two cases and review of the literature. J Neurosurg. 2005;102(3 Suppl):314–7. 147. Pradilla G, Jallo G.  Arachnoid cysts: case series and review of the literature. Neurosurg Focus. 2007;22(2):E7. 148. Guzel A, Trippel M, Ostertage CB.  Suprasellar arachnoid cyst: a 20- year follow-up after stereotactic internal drainage: case report and review of the literature. Turk Neurosurg. 2007;17(3):211–8. 149. Invergo D, Tomita T. De novo suprasellar arachnoid cyst: case report and review of the literature. Pediatr Neurosurg. 2012;48(3):199–203. 150. Lee JY, et  al. Long-term endocrine outcome of suprasellar arachnoid cysts. J Neurosurg Pediatr. 2017;19(6):696–702. 151. Caldarelli M, et  al. Intracranial midline dermoid and epidermoid cysts in children. J Neurosurg. 2004;100(5 Suppl Pediatrics):473–80. 152. Amelot A, et  al. Child dermoid cyst mimicking a craniopharyngioma: the benefit of MRI T2-weighted diffusion sequence. Childs Nerv Syst. 2018;34(2):359–62. 153. Zada G, Lopes MBS, Mukundan S, Laws E. Sellar region epidermoid and dermoid cysts. In: Zada G, Lopes M, Mukundan Jr S, Laws Jr E, editors. Atlas of sellar and parasellar lesions. Cham: Springer; 2016. 154. Gasparini S, et al. The journey of a floating fat: from suprasellar dermoid cyst to lateral ventricles. Neurol Sci. 2018;39(2):381–2. 155. Osborn AG, Preece MT.  Intracranial cysts: radiologic-pathologic correlation and imaging approach. Radiology. 2006;239(3):650–64.

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156. Kalra AA, Riel-Romero RM, Gonzalez-Toledo E. Lymphocytic hypophysitis in children: a novel presentation and literature review. J Child Neurol. 2011;26(1):87–94. 157. Gellner V, et  al. Lymphocytic hypophysitis in the pediatric population. Childs Nerv Syst. 2008;24(7):785–92. 158. Molitch ME, Gillam MP. Lymphocytic hypophysitis. Horm Res. 2007;68(Suppl 5):145–50. 159. Caturegli P.  Autoimmune hypophysitis: an underestimated disease in search of its autoantigen(s). J Clin Endocrinol Metab. 2007;92(6):2038–40. 160. Rivera JA. Lymphocytic hypophysitis: disease spectrum and approach to diagnosis and therapy. Pituitary. 2006;9(1):35–45. 161. Sato N, Sze G, Endo K. Hypophysitis: endocrinologic and dynamic MR findings. AJNR Am J Neuroradiol. 1998;19(3):439–44. 162. Maghnie M, et al. Evolution of childhood central diabetes insipidus into panhypopituitarism with a large hypothalamic mass: is ‘lymphocytic infundibuloneurohypophysitis’ in children a different entity? Eur J Endocrinol. 1998;139(6):635–40. 163. Corsello SM, et al. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361–75. 164. Yang JC, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825–30. 165. Torino F, et al. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17(4):525–35. 166. Torino F, et al. Endocrine side-effects of anti-cancer drugs: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses. Eur J Endocrinol. 2013;169(6):R153–64. 167. Blansfield JA, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28(6):593–8. 168. Chodakiewitz Y, et al. Ipilimumab treatment associated pituitary hypophysitis: clinical presentation and imaging diagnosis. Clin Neurol Neurosurg. 2014;125:125–30. 169. Ryder M, et  al. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014;21(2):371–81. 170. Downey SG, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13(22 Pt 1):6681–8. 171. Roessmann U, Kaufman B, Friede RL. Metastatic lesions in the sella turcica and pituitary gland. Cancer. 1970;25(2):478–80. 172. Nagashima H, et  al. Medulloblastoma with suprasellar solitary massive metastasis: case report. Neurol Neurochir Pol. 2016;50(3):211–4. 173. Muller HL, et al. Post-operative hypothalamic lesions and obesity in childhood craniopharyngioma: results of the multinational prospective trial KRANIOPHARYNGEOM 2000 after 3-year follow-up. Eur J Endocrinol. 2011;165(1):17–24. 174. Muller HL, et al. Functional capacity, obesity and hypothalamic involvement: cross-sectional study on 212 patients with childhood craniopharyngioma. Klin Padiatr. 2003;215(6):310–4.

Part III

Posterior Pituitary Disorders

Chapter 11

Posterior Pituitary Disorders: Anatomy and Physiology, Central Diabetes Insipidus (CDI), and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Colin Patrick Hawkes, Adriana Herrera, Brenda Kohn, Shana E. McCormack, and Craig A. Alter

Introduction Arginine vasopressin (AVP) is vital in the maintenance of the body’s osmolality and water balance. In this chapter, we review the physiology of water regulation and AVP secretion and action. We describe how to evaluate the child who presents with excessive thirst and urination and how to confirm the diagnosis of central diabetes insipidus (CDI) and define etiology. We discuss treatment options for infants and children with CDI, including children with thirst insensitivity and children undergoing pituitary-hypothalamic surgery. We also review the syndrome of inappropriate antidiuretic hormone (SIADH) and cerebral salt wasting (CSW), two disorders characterized by low serum osmolality.

Anatomy and Physiology of AVP Neurons The hypothalamic-pituitary AVP system is comprised of a network of vasopressinergic neurons; the physiologic control of water balance is dependent on the integrity of these neurons. In response to neural signaling, AVP release and de novo synthesis are stimulated at the level of the AVP neuronal cell bodies situated within two hypothalamic nuclei, the supraoptic nucleus (SON) and paraventricular nucleus (PVN). C. P. Hawkes · A. Herrera · S. E. McCormack · C. A. Alter (*) Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA e-mail: [email protected] B. Kohn Division of Pediatric Endocrinology and Diabetes, New York University – Langone Medical Center, Hassenfeld Children’s Hospital, New York, NY, USA © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_11

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Neurotransmitter signaling converges on the cell bodies of these hypothalamic AVP magnocellular neurons. When present, the neural stimulus induces an axon potential that propagates along the axons of the neurohypophyseal tract to the posterior pituitary and, via a calcium channel-dependent pathway, results in degranulation of stored AVP and release of AVP from the posterior pituitary into the circulation, bypassing the blood-brain barrier. At the same time, de novo transcription of AVP prohormone is stimulated. AVP is transported via the neurohypophyseal tract to the posterior pituitary gland, to be stored as neurosecretory granules until needed. These are the neurosecretory AVP granules that appear as the “posterior pituitary bright spot” on T1-weighted MRI images. AVP stores in the posterior pituitary are sufficient to support 4–6 weeks of basal AVP requirement, equivalent to 5–10 days of maximal AVP release. Absence of the “posterior bright spot” on MRI T1 images is consistent with central diabetes insipidus (CDI) or nephrogenic diabetes insipidus (NDI) (in NDI, the absent pituitary “bright spot” results from depletion of AVP stores).

Action of AVP AVP enters the circulation through the blood-brain barrier, binds to AVP V2 receptors in the collecting duct of the renal tubule and via a cyclic AMP signal transduction pathway, and results in activation, transport, and insertion of aquaporin-2 water channels into the apical membrane of the collecting duct. As a result, permeability of the collecting duct to water increases, leading to reabsorption of water along osmotic gradients, i.e., from the collecting duct into the hypertonic inner medulla and, ultimately, antidiuresis. AVP V1 alpha receptors on blood vessels play an ancillary role in the vascular control of fluid balance. (V2 receptors are involved in von Willebrand factor production and factor VIII production.) Typically, plasma osmolality and intravascular fluid homeostasis are preserved by an organized collaboration between thirst, AVP, and the renal reabsorption of water. AVP, also referred to as antidiuretic hormone (ADH), is secreted in a linear fashion in response to as little as a 1% increase in osmolality or a 10% or greater decrease in intravascular volume or pressure. The renin-angiotensin-aldosterone system, whose physiology is beyond the scope of this chapter, also plays an integral role in the regulation of blood pressure and intravascular volume [1].

Physiologic Regulation of AVP Release and Synthesis Regulation of AVP release and synthesis is controlled by hypothalamic osmoreceptors located within the area of the OVLT and anterior hypothalamus and by pressure and volume baroreceptors. These include high-pressure arterial baroreceptors

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responsible for AVP release that are located in the carotid sinus and aortic arch and low-pressure volume receptors that are located in the atria and pulmonary venous system. The baroreceptors transmit afferent signals from the cardiovascular system to the brainstem via cranial nerves IX and X in response to fluctuations in intravascular volume or pressure [2–6]. A 10–15% decrease in circulating volume or change in arterial pressure results in a substantial compensatory rise in AVP release. The osmoreceptors are situated outside the blood-brain barrier. They respond to minute (as noted previously, as low as 1%) changes in the serum osmolality. Neural signals from the osmoreceptors are transmitted to the cell bodies of the SON and PVN AVP neurons to stimulate AVP release and de novo mRNA transcription and synthesis of AVP. There is a physiologic threshold for AVP release. Basal plasma AVP concentrations typically range between 0.5 and 2 pg/ml, with a half-life in the circulation of approximately 15  minutes. An increase in serum osmolality above 282–285 mOsm/kg (corresponding to a serum sodium of approximately 142 mEq/l) induces a linear increase in AVP secretion. Minimal variation in serum osmolality will stimulate changes in AVP release within the physiologic range of approximately 0.5–6 pg/ml. These changes in AVP will in turn produce changes in urine osmolality that can cause urine to transition from dilute to a maximally concentrated urine of 800–1200 mOsm/kg. Increases in AVP concentrations above 6 pg/ml do not produce a further rise in urine osmolality [7–11]. Thus, although a linear increase in AVP release to greater than 20 pg/mL occurs in response to an acute rise in serum osmolality of 320 mOsm/kg [7, 12, 13], no further antidiuresis is achieved. The capacity of the inner renal medulla to maintain hypertonicity defines the maximal urine osmolality. In the mature kidney, the maximal urine osmolality is 800–1200 mOsm/kg H2O. Although plasma vasopressin levels may increase beyond the physiologic range of approximately 6 pg/ml, in response to osmotic or baroreceptive cues, no further antidiuresis occurs. Conversely, basal plasma vasopressin levels of approximately 0.5–2 pg/ml are sufficient to avoid massive diuresis beyond 4 liters daily. Plasma AVP levels below 0.5 pg/ml are associated with a dramatic increase in urine volume to greater than 10–15 liters per day. This physiology of AVP regulation of urine osmolality explains how a partial deficit in AVP reserve can go unrecognized. In contrast, even a small excess of AVP release from damaged AVP neurons can result in antidiuresis and hyponatremia.

Thirst and Control of Water Intake The thirst center is located within the hypothalamus in close proximity to the SON and PVN, although its precise location is uncertain. It is known that while destruction of the SON and PVN eliminates the capacity to synthesize or release AVP, the sensation of thirst that drives the desire to drink remains intact [14, 15].

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Even in the absence of AVP, an intact thirst mechanism will assure an adequate (though often substantial) intake of water to maintain a serum sodium and ­osmolality in the normal range and avoid hypernatremia or dehydration. This occurs because an increase in serum sodium or extracellular fluid osmolality or a decrease in intravascular volume will stimulate the thirst mechanism. An increase in plasma osmolality of 2–3% will elicit the drive for thirst, with resultant water intake [16]. The threshold for thirst (293 mOsm/kg) is approximately 10 mOsm/ kg higher than the threshold for AVP release. AVP concentration and thirst will decrease once blood osmolality and volume return to the normal range [15]. Copeptin is a 39-amino acid glycosylated peptide [17] synthesized along with AVP and neurophysin II in the PVN and SON in the hypothalamus. Given the small size and very short half-life of AVP, its measurement is not routinely used in clinical practice [18]. Studies have shown that in response to fluctuations in serum osmolality, copeptin levels are reliable markers of AVP secretion and effect [19, 20]. Copeptin is secreted in equimolar proportions to AVP, and since it is stable in plasma, it is more readily measured via standard techniques as compared to AVP [19]. In fact, copeptin measurement after infusion of hypertonic saline may be an alternative approach to the water deprivation test in diagnosing DI [21], but this approach has not been tested in pediatric patients.

Physiology of Solute Excretion and Water Balance Maintaining water balance requires that the solute and water intake equals the solute and water excreted. In healthy children, physiologic AVP regulation allows the urine osmolality to vary across a wide range to permit variation in the urine volume excreted. As the urine osmolality increases, as occurs when AVP is high, a lower volume is required to excrete the solute load. As renal solute load increases, for a fixed urine osmolality, more urine volume is required to excrete the solute load. For example, for a fixed urine osmolality of 100 mOsm/L, 0.5 L of urine is required to excrete 50 mOsm, but 2 L of urine is required to excrete 200 mOsm. For these reasons, strategies that reduce renal solute load (e.g., low-solute formulas) and/or increase the fixed urine osmolality in DI (e.g., diuretic therapies) are viable approaches for the management of CDI [22, 23]. This consideration will be discussed in greater detail in the context of treatment options for CDI.

Polyuria: Differential Diagnosis Although CDI is considered as a possible diagnosis when children have polyuria, other diagnoses should be considered prior to evaluating for CDI. These etiologies include endocrine and metabolic disorders as well as medications that can lead to increased urine output. Hyperglycemia is a paradigmatic example. Hyperglycemia with a blood glucose well above the renal threshold (145–160  mg/dL) typically leads to an osmotic diuresis that resolves with initiation of antidiabetic therapy [24].

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Other endocrine disorders have also been associated with polyuria. Thyrotoxicosis can produce polyuria due to decreased expression of aquaporin water channel expression, despite adequate amounts of AVP, along with increased solute excretion [25]. In addition, hypercalcemia, regardless of etiology, can produce deficits in the renal concentrating capacity; indeed, polyuria and dehydration can be presenting features of disorders of calcium metabolism [26]. Hypokalemia can lead to defects in renal concentrating capacity via mechanisms that are incompletely understood but may be related to accelerated autophagy-mediated degradation of aquaporin-2 [27]. Hypernatremia can also be caused by partial urinary tract obstruction [28]; it has been posited that the associated pressure transmitted to the collecting duct is responsible for the associated (and reversible) defect in concentrating capacity. Protein malnutrition can also produce increased output of a dilute urine; in contrast to the previous examples, renal concentrating capacity via AVP appears intact, and increased intrarenal angiotensin II has been posited as a candidate mechanism [29]. With respect to medications, diuresis is an intended consequence of diuretic medications, and these can produce abnormalities in serum sodium levels. Osmotic contrast agents are other potential culprits. Another medication, lithium, reduces the renal responsiveness to AVP, leading to defects in urinary concentrating capacity. This effect may be mediated by the effects of lithium on glycogen synthase kinase alpha isoform, leading to decreased AVP-mediated water permeability in the collecting ducts [30].

Hypernatremia Clinically, hypernatremia in the absence of polyuria most often reflects hypernatremic dehydration, as may occur in the setting of febrile illness, excessive losses of free water (e.g., diarrhea, burns), or impaired fluid intake. In some individuals, lack of the normal thirst mechanism contributes to the so-called adipsic hypernatremia. Adipsia, a result of damage to the thirst center, can also occur in the setting of CDI, significantly complicating its management [31]. In some cases, adipsia is associated with partial CDI, reset osmostat, or global hypothalamic dysfunction [32]. In contrast, polydipsia in the absence of hypernatremia is less often related to a central lesion but can occur in the setting of psychiatric disorders. Persistently low or low-­normal serum sodium should raise awareness of this possibility. In some cases, this “psychogenic polydipsia” can produce sequelae, including, for example, hyponatremic seizures [33].

Central Diabetes Insipidus Clinical disorders of AVP secretion are frequently encountered in pediatrics in the setting of intrasellar and suprasellar pituitary tumors and lesions that involve the neurohypophyseal tract. Damage to the hypothalamic-neurohypophyseal tract is associated with impaired AVP secretion and consequent CDI.  This presents

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clinically as hypernatremia with the inability to concentrate urine and is accompanied by a deficit of body water in relation to sodium and solute. Affected individuals excrete large volumes of dilute urine even as they develop progressive hypovolemia. CDI results from a defect in the regulation and/or production of AVP from the posterior pituitary gland. In contrast, in NDI, the kidney is unable to produce concentrated urine despite the appropriate presence of high amounts of AVP. Although the testing discussed here can suggest the diagnosis of NDI, the management of NDI is beyond the scope of this text; the reader is referred to a recent review of this complex condition [34]. A diagnosis of DI is made when serum sodium concentration exceeds 145 mEq/L, urine osmolality is less than 300 mOsm/kg, urine output persistently (greater than 30 minutes) exceeds 4 mL/kg/hour, and other causes of polyuria have been excluded.

Establishing the Etiology of Central Diabetes Insipidus Once the diagnosis of CDI is established, it is vital to determine its etiology. Any infiltrative or destructive process that involves the hypothalamic-pituitary axis can cause CDI as well as anterior pituitary hormone deficiencies. In addition, tumor invasion of the hypothalamus or pineal region can cause CDI by ventricular seeding or through dilation of the third ventricle [35]. Embryologic neurodevelopmental disorders presenting with anterior pituitary hormone deficiencies, such as septo-­ optic dysplasia, can result in CDI, even if not present clinically at birth. CDI may occur in conjunction with multiple anterior pituitary hormone deficiencies (MPHD); hence anterior pituitary testing and surveillance are warranted in children with CDI. Genetic defects of either AVP production or of its complex with neurophysin II can lead to CDI. The principal causes of CDI are summarized in Table 11.1. After establishing a diagnosis of CDI, an MRI of the pituitary gland and hypothalamus is typically the first step in identifying the etiology. An MRI of the whole brain is insufficient to evaluate the pituitary gland. A dedicated MRI of the pituitary should be requested, with and without contrast to optimally visualize the pituitary gland and surrounding structures. MRI of the pituitary without contrast should have a bright appearance of the posterior pituitary, termed the posterior pituitary “bright spot” (PPBS) on T1-weighted imaging (Fig.  11.1). This “bright spot” is often, though not invariably, absent in CDI of any cause. In a study of 79 children with CDI, all but five of the children with CDI had an absent PPBS at the time of diagnosis of CDI; the remaining five had disappearance of the PPBS over time [36]. In a study of 147 children with DI, 13% still had the presence of the PPBS at onset of CDI [37]. In general, it is not advisable to make the diagnosis of DI based on the presence or absence of the PPBS alone. However, in select cases, the absence of the PPBS can be used to provide additional evidence toward the diagnosis of DI, either CDI or NDI. A child who has an ectopic posterior pituitary gland recognized on T1-weighted images as an ectopic PPBS (Fig. 11.2) does not typically have CDI but is at risk of

11  Posterior Pituitary Disorders: Anatomy and Physiology, Central Diabetes Insipidus… 207 Table 11.1  Central diabetes insipidus etiologies

Genetic defects of AVP production or effect  Autosomal dominant defects  Autosomal recessive or X-linked   Wolfram syndrome (diabetes mellitus, optic atrophy, deafness) Congenital pituitary/hypothalamic disorders  Optic nerve hypoplasia (septo-optic dysplasia, De Morsier syndrome)  Midline craniofacial defects  Holoprosencephaly  Pituitary hypoplasia  Rathke’s cleft cyst  Encephalocele  Arachnoid cyst (congenital or acquired) Acquired disorders   Neoplastic   Craniopharyngioma   Germ cell tumors (germinoma, embryonal carcinoma, teratoma)    Langerhans cell histiocytosis   Pinealoma   Lymphoma    Large pituitary adenoma   Inflammatory or infiltrative   Lymphocytic hypophysitis    Langerhans cell histiocytosis   Sarcoidosis    Systemic lupus erythematosus   Granulomatous disease (e.g., sarcoidosis, Wegener’s granulomatosis)   Infectious   Meningitis   Encephalitis    Other CNS infections (e.g., tuberculosis)   Trauma   Head trauma   Postpituitary surgery Idiopathic diabetes insipidus

anterior pituitary hormone deficiencies [38]. These children need to be monitored throughout life, since the development of anterior pituitary hormone deficiencies can occur over time. The position of the “bright spot” in patients with an ectopic posterior pituitary gland is variable but may have prognostic significance. The presence of a superior “bright spot” and absence of the pituitary infundibulum seen on MRI convey a higher risk of MPHD [39].

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Fig. 11.1  Normal bright spot: 6-year-old female with growth hormone deficiency. Sagittal T1-weighted image without contrast through the midline: anterior pituitary normal in size for age with no focal lesion and normal native posterior pituitary bright spot

Fig. 11.2  Ectopic bright spot: 14-year-old male with delayed growth and puberty. Sagittal T1-weighted image without contrast through the midline shows a 3 mm intrinsically T1 hyperintense nodule along the infundibular recess of the third ventricle (see arrow), which is truncated inferiorly. Overall, the sella appears slightly small without a native posterior bright spot

It is important to note that absence of the PPBS is consistent with CDI but does not provide information as its etiology. When there is a sellar or suprasellar mass on MRI, an important diagnosis to consider is craniopharyngioma. Calcifications strongly suggest a diagnosis of a craniopharyngioma. A CT is more reliable than MRI in detecting calcifications [40]. Other possibilities include arachnoid cyst,

11  Posterior Pituitary Disorders: Anatomy and Physiology, Central Diabetes Insipidus… 209 Table 11.2  Causes of central diabetes insipidus when a pituitary/hypothalamic mass is seen on MRI Diagnosis Craniopharyngioma Rathke’s cleft cyst Langerhans cell Histiocytosis Hypophysitis Germ cell tumor

Arachnoid cyst Meningioma Sarcoidosis Lymphoma Wegener’s granulomatosis

Specific features Expect multiple pituitary hormone deficiencies; calcifications Lack of calcifications May take years for multiple pituitary hormone deficiencies to develop after the presentation of CDI Can mimic a pituitary adenoma [95] A germinoma can be misdiagnosed as hypophysitis [96] Can have mass in pineal region and hypothalamus and pituitary Serum and CSF hCG and alpha-fetoprotein may be elevated

Serum angiotensin converting enzyme inhibitor may be elevated Unusual in children

meningioma, teratoma, or lymphoma. Inflammatory and infiltrative disorders including Langerhans cell histiocytosis (LCH), germ cell tumor, hypophysitis, or sarcoidosis can present with pituitary stalk thickening (these are summarized in Table 11.2). Magnetic resonance imaging in children with CDI will show a thickened stalk (Fig. 11.3) in approximately one-third of cases [41]. Of the children with a thickened stalk, one study showed that 17% were eventually diagnosed with a germ cell tumor and another 17% with LCH [36]. In the absence of bone lesions and a clear diagnosis of LCH, serum and CSF tumor markers for quantitative hCG and alpha-­ fetoprotein should be obtained at initial presentation for the possibility of a CNS germ cell tumor. We recommend measuring tumor markers and anterior pituitary hormone levels initially in children presenting with CDI and a thickened infundibulum. Pituitary MRI scans, serum tumor markers, and anterior pituitary hormone levels should be performed every 3  months for 1–2  years and then yearly for 2  years (Fig. 11.4). Resolution of pituitary stalk thickening is more often associated with lymphocytic hypophysitis and a positive prognosis. In one study, an infundibular stalk of more than 4.5  mm in thickness was correlated with a greater likelihood of developing MPHD [42]. A normal-appearing stalk and normal anterior pituitary hormone levels at the time of diagnosis of CDI are generally reassuring, but they do not always exclude an underlying pathology. For example, the stalk was normal in appearance in one child who was subsequently diagnosed with a germ cell tumor [36]. We suggest that in children presenting with CDI, a normal pituitary stalk on MRI, and no additional CNS risk factors (such as headaches, seizures, or visual complaints), a repeat MRI be obtained initially in 3–6 months and then every 6–12 months for the next 2 years.

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a

b

Fig. 11.3  Pituitary stalk thickening: 8-year-old male with diabetes insipidus and fatigue for 6 months. Sagittal T1-weighted images with (a) and without (b) contrast through the midline demonstrate non-visualization of the normal posterior bright spot as well as mild abnormal thickening of the infundibulum. These findings can be seen in the setting of infiltrative conditions, such as Langerhans cell histiocytosis and germ cell tumor Central diabetes insipidus Pituitary MRI Mass? NO

YES

Calcifications? YES Craniopharyngioma

Stalk thickened NO

YES

Craniopharyngioma RCC LCH Hypophysitis Germ cell tumor Other neoplasia Vascular lesion

NO

↑Serum or CSF HCG, αFP YES

Structural abnormality of posterior pituitary

NO

YES Septo-optic dysplasia Other (e.g. head trauma)

Germ cell tumor

Repeat MRI every 3 months for 2 years (biopsy if concerns)

Repeat MRI every 6-12 months for an additional 2-4 years

Repeat MRI every 6 months for 2 years Stalk becomes thickened*

Germ cell tumor LCH Other neoplasia

↑Thickening NO

NO

YES

No thickened stalk

Congential genetic idiopathic LCH Hypophysitis Rarely germ cell tumor

Germ cell tumor Hypophysitis LCH idiopathic

Fig. 11.4  Suggested diagnostic algorithm for determining the etiology of central diabetes insipidus. Note that germ cell tumor includes germinoma, embryonal carcinoma, and teratoma. *In one study, 3% (1/33) of patients without a thickened stalk initially were noted to become thickened on serial imaging

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While most cases of CDI are acquired, some may be genetic. Genetic cases of CDI typically reveal an autosomal dominant pattern of inheritance [43], though rarely an autosomal recessive or X-linked pattern can occur. The diagnosis of genetic CDI may not be made until the child is several years old, and genetic CDI may even present in adolescence. Typically, on pituitary MRI, the bright spot is absent and the stalk is normal size. More than 55 mutations that cause CDI have been described [43]; most have autosomal dominant inheritance. Mutations have been described in the gene that encodes the AVP peptide, resulting in reduced AVP biological activity. The interested reader is referred to a detailed review of the genetics of CDI [44, 45]. Other cases of CDI result from congenital or acquired anatomic disruption to the posterior pituitary. In one series of 147 children with CDI, 24% had an associated CNS malformation [37]. Congenital malformations include septo-optic dysplasia, holoprosencephaly, vascular malformations, and encephalocele [46]. CDI can occur following traumatic brain injury or following pituitary-hypothalamic surgery. A suggested approach to identifying the etiology of CDI is summarized in Fig. 11.4.

Water Deprivation Testing Plasma osmolality can be calculated by measuring the concentration of sodium (Na+), glucose, and blood urea nitrogen (BUN). Sodium is the major effective plasma solute. When serum glucose and BUN are in the normal range, Na + concentration correlates closely with serum osmolality.



pOsm = 2 éë Na + ùû + ( GLUCOSE ( mg / dL ) / 18 ) + ( BUN ( mg / dL ) / 2.8 )



In the individual with polyuria and polydipsia, a serum osmolality exceeding 300 mOsm/kg, reflecting hyperosmolality, with a simultaneous dilute urine osmolality, less than 300 mOsm/kg, confirms the diagnosis of DI. Additional testing can determine if this DI is central (hence, responsive to exogenous forms of AVP) or nephrogenic (typically nonresponsive to exogenous forms of AVP). In contrast, if a simultaneous serum osmolality is less than 270 mOsm/kg and the urine osmolality is maximally concentrated, the diagnosis of DI is excluded. Proposed thresholds of urine osmolality used to exclude DI range from 600 [47] to 750 mOsm/kg [48]. In our clinical practice, we have cared for patients who were subsequently diagnosed with partial DI whose initial urine osmolality was between these values. Thus, we advise using a urine osmolality threshold of at least 750 mOsm/kg to assess the possibility of DI when there is clinical suspicion for disease. Water deprivation testing carries associated risks (most notably, dehydration) and should be performed in a carefully monitored setting. A proposed protocol is shown in Table 11.3. Water deprivation studies in those with long-standing partial DI may not reveal a classic abnormal water deprivation study. In these patients, the urine may only concentrate partially with the addition of pharmacological AVP due to “washed-out” renal concentrating capacity.

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Table 11.3  Proposed water deprivation test protocol Start test Time = 0 mins Every hour Criteria to continue test Criteria to end test

Desmopressin test (to distinguish nephrogenic from central diabetes insipidus)

Interpretation

After the patient’s longest usual interval without drinking Collect baseline serum sodium, osmolality, and BUN, along with urine sodium, osmolality, and specific gravity Measure vital signs including weight, urine output, serum sodium/ osmolality, and urine osmolality/specific gravity Serum osmolality is 1 year after the TBI.  Multiple pituitary deficiencies were diagnosed in 25 subjects (78%). Among the 97 reported pituitary deficits, 29 subjects had growth hormone deficiency (30%), 22 had hypogonadotropic hypogonadism (23%), 20 had central hypothyroidism (21%), 20 had ACTH deficiency (21%), and 6 had diabetes insipidus (6%) [17]. R. A. Lal (*) Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA Division of Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA, USA e-mail: [email protected] A. R. Hoffman Division of Endocrinology, Department of Medicine, Stanford University, Stanford, CA, USA © Springer Nature Switzerland AG 2019 B. Kohn (ed.), Pituitary Disorders of Childhood, Contemporary Endocrinology, https://doi.org/10.1007/978-3-030-11339-1_18

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Epidemiology of TBI The worldwide incidence of pediatric traumatic brain injury (TBI) ranges from 47 to 280 per 100,000 children. Falls and motor vehicle collisions represent the most common mechanism of injury, followed by non-accidental trauma and sports-­ related injury. Young children, age 0–2  years, and adolescents, age 15–18  years, have higher rates of TBI.  After the age of 3, boys are more affected than girls. Sports-related traumatic brain injuries predominate in the United States and Australia, which have more contact-driven sports [18].

Pathophysiology The precise pathophysiology of hypopituitarism following head injury remains to be elucidated. Ninety percent of the anterior pituitary is vascularized by long hypophyseal portal vessels, passing through the sellar diaphragm. These vessels are susceptible to injury from compression and stalk injury. Somatotropic and gonadotropic cells located peripherally are more prone to ischemic insult. The posterior pituitary is thought to be less commonly injured due to vascular supply by short hypophyseal portal vessels (Fig.  18.1). In addition to primary injury, secondary damage may occur from hypotension, hypoxia, edema, hemorrhage, increased intracranial pressure accompanying skull fracture, persistent neuroinflammation, and autoimmunity [19]. In 2008, Tanriverdi and colleagues demonstrated anti-­ pituitary antibodies in 13 out of 29 TBI patients tested and none in the age- and sex-matched controls. About 46% of subjects with antibodies had pituitary dysfunction, while only 13% of the antibody negative patients demonstrated hypopituitarism [20].

Recent Scientific Inquiry Given the multitude of case reports, efforts have been aimed at more consistent and rigorous scientific trials. In 2006, Casanueva published conclusions from an expert panel held in Spain regarding pediatric TBI and pituitary function. The panel advocated for (1) prospective pediatric studies of pituitary function, (2) multidisciplinary collaboration for the care of children after TBI, (3) a model of interaction among sub-specialists, and (4) the creation of an endocrinologist-led late effects service for monitoring growth and puberty [21]. As with the adult literature, there has been a recent increase in the number of published studies of pediatric TBI.

18  Pituitary Response to Traumatic Brain Injury Fig. 18.1 Hypophyseal portal system. (Adapted with permission from Karaca’s 2016 “Sheehan Syndrome” Nat Rev Dis Primers) Long Portal Vein (LPV) and Short Portal Vein (SPV) Reprinted by permission from Macmillan Publishers Ltd.: Karaca et al. [45]

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Hypophyseal artery L P V

S P V

Anterior pituitary

Posterior pituitary

Acute Pituitary Dysfunction The first study of acute changes in endocrine function after severe TBI in children was performed by Srinivas and colleagues in 2010. They evaluated cortisol, ACTH, TSH, total T3, total T4, free T4, growth hormone, and prolactin levels in 37 children, age 1–17 years, on the day of injury and on post-injury days 3 and 7. Cortisol and ACTH were found to be elevated on the day of TBI, returning to normal or below normal range by day 3. The authors report that 46% of patients had a cortisol level