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Zhang Z, Wang J, Shi Y, Zhao Y, Hu Y, Wang W, Chen Z. Progress in investigating pituitary stalk lesions: A review. Medicine (Baltimore) 2025; 104:e41232. [PMID: 39792770 PMCID: PMC11729155 DOI: 10.1097/md.0000000000041232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/07/2024] [Indexed: 01/12/2025] Open
Abstract
Pituitary stalk lesions are uncommon and are typically identified through pituitary magnetic resonance imaging and screening for causes of diabetes insipidus. Recent literature indicates that pituitary stalk lesions primarily manifest as pituitary stalk interruption syndrome and thickening of the pituitary stalk. The etiology of these lesions is complex and can be divided into major categories: congenital disorders, inflammatory or infectious diseases, and tumors. Therefore, achieving accurate diagnosis, differential diagnosis, and treatment for pituitary stalk lesions is crucial. This article aims to classify pituitary stalk lesions and delve into the latest research on their etiology, pathological mechanisms, clinical manifestations, diagnosis, and treatment of associated diseases.
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Affiliation(s)
- Zaidong Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong, P.R. China
| | - Jinlin Wang
- Department of Clinical Medicine, Jining Medical University, Jining, Shandong, P.R. China
| | - Yaru Shi
- Department of Clinical Medicine, Jining Medical University, Jining, Shandong, P.R. China
| | - Yahui Zhao
- Department of Clinical Medicine, Jining Medical University, Jining, Shandong, P.R. China
| | - Yanli Hu
- Department of Emergency Medicine, Linyi People’s Hospital, Linyi, Shandong, P.R. China
| | - Wentao Wang
- Department of Geriatrics, Taian Central Hospital, Taian, Shandong, P.R. China
| | - Zonglan Chen
- Department of Endocrinology and Metabolism, Affiliated Hospital of Jining Medical University, Jining, Shandong, P.R. China
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Terray A, Baussart B, Zins M, Goldberg M, Kab S, Cazabat L, Brière M, Brue T, Barraud S, Reznik Y, Christin-Maitre S, Illouz F, Raverot G, Young J, Raffin-Sanson ML, Hage M. Gonadotropic status in adult women with pituitary stalk interruption syndrome. Eur J Endocrinol 2024; 190:501-508. [PMID: 38857190 DOI: 10.1093/ejendo/lvae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/06/2024] [Accepted: 06/08/2024] [Indexed: 06/12/2024]
Abstract
OBJECTIVE Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN A retrospective multicentric French study. METHODS We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.
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Affiliation(s)
- Aglaé Terray
- Department of Endocrinology, Diabetology and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, F-92100 Boulogne Billancourt, France
- EA4340, Université de Versailles Saint-Quentin-en-Yvelines, UFR des Sciences de la Santé Simone Veil, F-78423 Montigny-le-Bretonneux, France
| | - Bertrand Baussart
- Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière University Hospital, F-75013 Paris, France
- Université Paris Cité, CNRS, INSERM, Institut Cochin, F-75014 Paris, France
| | - Marie Zins
- UMS 011, Population-based Cohorts Unit, Université Paris Cité, Paris Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, INSERM, F-94800 Villejuif, France
| | - Marcel Goldberg
- UMS 011, Population-based Cohorts Unit, Université Paris Cité, Paris Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, INSERM, F-94800 Villejuif, France
| | - Sofiane Kab
- UMS 011, Population-based Cohorts Unit, Université Paris Cité, Paris Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, INSERM, F-94800 Villejuif, France
| | - Laure Cazabat
- UMR 1198 BREED, équipe RHuMA, UFR Simone Veil Santé, Université Versailles Saint Quentin en Yvelines, F-78423 Montigny-le-Bretonneux, France
- Service de Neurochirurgie, Hôpital Foch, F-92150 Suresnes, France
| | - Mathilde Brière
- Department of Endocrinology, Diabetology and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, F-92100 Boulogne Billancourt, France
| | - Thierry Brue
- Aix Marseille Université, APHM, INSERM, MMG, MarMaRa, F-13305 Marseille, France
- Department of Endocrinology, Reference Center for Rare Pituitary Diseases HYPO, La Conception University Hospital, AP-HM, F-13305 Marseille, France
| | - Sara Barraud
- Department of Endocrinology Diabetes Nutrition, University of Reims Champagne-Ardenne, Reims University Hospital, CRESTIC, F-51092 Reims, France
| | - Yves Reznik
- Department of Endocrinology, Côte de Nacre University Hospital, F 14033 Caen, France
| | - Sophie Christin-Maitre
- Department of Endocrinology, Saint-Antoine Hospital, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris, ER9 University Pierre et Marie Curie, F-75005 Paris, France
| | - Frédéric Illouz
- Department of Endocrinology, Reference Center for Rare Pituitary Diseases HYPO, Angers University Hospital, F-49000 Angers, France
| | - Gérald Raverot
- Department of Endocrinology, "Groupement Hospitalier Est" Hospices Civils de Lyon, Reference Center for Rare Pituitary Diseases HYPO, F-69500 Bron, France
| | - Jacques Young
- Department of Endocrinology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Pituitary Diseases HYPO, F-94270 Le Kremlin-Bicêtre, France
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, F-94270 Le Kremlin-Bicêtre, France
| | - Marie-Laure Raffin-Sanson
- Department of Endocrinology, Diabetology and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, F-92100 Boulogne Billancourt, France
- EA4340, Université de Versailles Saint-Quentin-en-Yvelines, UFR des Sciences de la Santé Simone Veil, F-78423 Montigny-le-Bretonneux, France
| | - Mirella Hage
- Department of Endocrinology, Diabetology and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, F-92100 Boulogne Billancourt, France
- EA4340, Université de Versailles Saint-Quentin-en-Yvelines, UFR des Sciences de la Santé Simone Veil, F-78423 Montigny-le-Bretonneux, France
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Wang S, Qin Q, Jiang D, Xiao Y, Ye L, Jiang X, Guo Q. Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology. Front Endocrinol (Lausanne) 2024; 15:1338781. [PMID: 38464967 PMCID: PMC10920343 DOI: 10.3389/fendo.2024.1338781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/09/2024] [Indexed: 03/12/2024] Open
Abstract
Background Pituitary stalk interruption syndrome (PSIS) is a complex clinical syndrome characterized by varied pituitary hormone deficiencies, leading to severe manifestations across multiple systems. These include lifelong infertility, short stature, mental retardation, and potentially life-threatening pituitary crises if not promptly diagnosed and treated. Despite extensive research, the precise pathogenesis of PSIS remains unclear. Currently, there are two proposed theories regarding the pathogenic mechanisms: the genetic defect theory and the perinatal injury theory. Methods We systematically searched English databases (PubMed, Web of Science, Embase) and Chinese databases (CNKI, WanFang Med Online, Sinomed) up to February 24, 2023, to summarize studies on gene sequencing in PSIS patients. Enrichment analyses of reported mutated genes were subsequently performed using the Metascape platform. Results Our study included 37 articles. KEGG enrichment analysis revealed mutated genes were enriched in the Notch signaling pathway, Wnt signaling pathway, and Hedgehog signaling pathway. GO enrichment analysis demonstrated mutated genes were enriched in biological processes such as embryonic development, brain development, axon development and guidance, and development of other organs. Conclusion Based on our summary and analyses, we propose a new hypothesis: disruptions in normal embryonic development, partially stemming from the genetic background and/or specific gene mutations in individuals, may increase the likelihood of abnormal fetal deliveries, where different degrees of traction during delivery may lead to different levels of pituitary stalk interruption and posterior lobe ectopia. The clinical diversity observed in PSIS patients may result from a combination of genetic background, specific mutations, and variable degrees of traction during delivery.
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Affiliation(s)
- Shengjie Wang
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qiaozhen Qin
- Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Deyue Jiang
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yan Xiao
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lingtong Ye
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoxia Jiang
- Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Qinghua Guo
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K. Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study. PLoS One 2023; 18:e0292664. [PMID: 38096238 PMCID: PMC10721018 DOI: 10.1371/journal.pone.0292664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/26/2023] [Indexed: 12/17/2023] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.
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Affiliation(s)
- Raja Brauner
- Pediatric Endocrinology Unit, Hôpital Fondation Adolphe de Rothschild and Université Paris Cité, Paris, France
| | | | - Anu Bashamboo
- Human Developmental Genetic Unit, Institut Pasteur, Paris, France
| | - Ken McElreavey
- Human Developmental Genetic Unit, Institut Pasteur, Paris, France
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Bian Y, Hahn H, Uhmann A. The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis. Front Endocrinol (Lausanne) 2023; 14:1219018. [PMID: 37476499 PMCID: PMC10355329 DOI: 10.3389/fendo.2023.1219018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Hedgehog signaling plays pivotal roles in embryonic development, adult homeostasis and tumorigenesis. However, its engagement in the pituitary gland has been long underestimated although Hedgehog signaling and pituitary embryogenic development are closely linked. Thus, deregulation of this signaling pathway during pituitary development results in malformation of the gland. Research of the last years further implicates a regulatory role of Hedgehog signaling in the function of the adult pituitary, because its activity is also interlinked with homeostasis, hormone production, and most likely also formation of neoplasms of the gland. The fact that this pathway can be efficiently targeted by validated therapeutic strategies makes it a promising candidate for treating pituitary diseases. We here summarize the current knowledge about the importance of Hedgehog signaling during pituitary development and review recent data that highlight the impact of Hedgehog signaling in the healthy and the diseased adult pituitary gland.
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Dou X, Wang Z, Lu W, Miao L, Zhao Y. METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way. BMC Pulm Med 2022; 22:324. [PMID: 36008805 PMCID: PMC9413890 DOI: 10.1186/s12890-022-02119-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 08/08/2022] [Indexed: 11/25/2022] Open
Abstract
Background N6-methyladenosine (m6A) is the most common RNA modification, which plays a pivotal role in tumor development and progression. In this study, we assessed the role of m6A methyltransferase METTL3 in FRAS1-involved cell proliferation and colony formation of non-small cell lung cancer (NSCLC) cell lines. Methods Cell viability was analyzed by Cell Counting Kit (CCK-8) and colony formation. M6A RNA immunoprecipitation (IP), Ribosomal immunoprecipitation, RNA immunoprecipitation (RIP) were performed to verify the relationship between METTL3, FRAS1 and YTHDF1. Rescue experiments to confirm the regulatory mechanism of METTL3-FRAS1 promoted NSCLC cell proliferation through CDON by cooperating YTHDF1. Results We found that FRAS1 was correlated with poor prognosis in NSCLC patients, of which the transcript undergoes m6A modification regulated by METTL3. METTL3 silence reduced cell viability of NSCLC cells HCC827 and NCI-H1975, which could be restored by FRAS1 overexpression. The m6A modification of FRAS1 could be recognized by YTHDF1. FRAS1 silence or YTHDF1 silence could rescue the elevated NSCLC cell proliferation, colony formation, and tumor growth induced by METTL3 overexpression in vitro and in vivo. Conclusions Our study reveals that METTL3-FRAS1 plays a crucial role in NSCLC cell proliferation, colony formation, and tumor growth through the regulation of CDON by cooperating YTHDF1. Supplementary Information The online version contains supplementary material available at 10.1186/s12890-022-02119-3.
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Affiliation(s)
- Xuejun Dou
- Department of Thoracic Surgery, Space Central Hospital, Beijing, China.
| | - Zhiyuan Wang
- Department of Thoracic Surgery, Space Central Hospital, Beijing, China
| | - Weiqiang Lu
- Department of Thoracic Surgery, Space Central Hospital, Beijing, China
| | - Libin Miao
- Department of Thoracic Surgery, Space Central Hospital, Beijing, China
| | - Yuefeng Zhao
- Department of Thoracic Surgery, Space Central Hospital, Beijing, China
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Hage C, Gan HW, Ibba A, Patti G, Dattani M, Loche S, Maghnie M, Salvatori R. Advances in differential diagnosis and management of growth hormone deficiency in children. Nat Rev Endocrinol 2021; 17:608-624. [PMID: 34417587 DOI: 10.1038/s41574-021-00539-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2021] [Indexed: 02/07/2023]
Abstract
Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000-10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.
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Affiliation(s)
- Camille Hage
- Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hoong-Wei Gan
- Genetics & Genomic Medicine Research and Teaching Department, University College London Great Ormond Street Hospital Institute of Child Health, London, UK
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Anastasia Ibba
- Paediatric Endocrine Unit, Paediatric Hospital Microcitemico "A. Cao", AO Brotzu, Cagliari, Italy
| | - Giuseppa Patti
- Department of Paediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Genova, Italy
| | - Mehul Dattani
- Genetics & Genomic Medicine Research and Teaching Department, University College London Great Ormond Street Hospital Institute of Child Health, London, UK
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Sandro Loche
- Paediatric Endocrine Unit, Paediatric Hospital Microcitemico "A. Cao", AO Brotzu, Cagliari, Italy
| | - Mohamad Maghnie
- Department of Paediatrics, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genova, Genova, Italy
| | - Roberto Salvatori
- Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Jee YH, Gangat M, Yeliosof O, Temnycky AG, Vanapruks S, Whalen P, Gourgari E, Bleach C, Yu CH, Marshall I, Yanovski JA, Link K, Ten S, Baron J, Radovick S. Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic. Front Genet 2021; 12:697549. [PMID: 34456972 PMCID: PMC8386283 DOI: 10.3389/fgene.2021.697549] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/12/2021] [Indexed: 01/31/2023] Open
Abstract
Purpose Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. Methods We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. Results First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). Conclusion Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.
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Affiliation(s)
- Youn Hee Jee
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Mariam Gangat
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Olga Yeliosof
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Adrian G Temnycky
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Selena Vanapruks
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Philip Whalen
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Evgenia Gourgari
- Division of Pediatric Endocrinology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Cortney Bleach
- Division of Pediatric Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, United States
| | - Christine H Yu
- Section of Adult and Pediatric Endocrinology and Metabolism, University of Chicago, Chicago, IL, United States
| | - Ian Marshall
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
| | - Jack A Yanovski
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Kathleen Link
- Division of Pediatric Endocrinology, Pediatric Subspecialists of Virginia, Fairfax, VA, United States
| | - Svetlana Ten
- Pediatric Endocrinology, Richmond University Medical Center, Staten Island, NY, United States
| | - Jeffrey Baron
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Sally Radovick
- Division of Pediatric Endocrinology Rutgers Robert Wood Johnson Medical School Child Health Institute of New Jersey, New Brunswick, NJ, United States
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Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum. Genes (Basel) 2021; 12:genes12081128. [PMID: 34440302 PMCID: PMC8394260 DOI: 10.3390/genes12081128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/06/2021] [Accepted: 07/15/2021] [Indexed: 11/17/2022] Open
Abstract
We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.
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Obara-Moszyńska M, Budny B, Kałużna M, Zawadzka K, Jamsheer A, Rohde A, Ruchała M, Ziemnicka K, Niedziela M. CDON gene contributes to pituitary stalk interruption syndrome associated with unilateral facial and abducens nerve palsy. J Appl Genet 2021; 62:621-629. [PMID: 34235642 PMCID: PMC8571149 DOI: 10.1007/s13353-021-00649-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 11/06/2022]
Abstract
The relationship between congenital defects of the brain and facial anomalies was proven. The Hedgehog signaling pathway plays a fundamental role in normal craniofacial development in humans. Mutations in the sonic hedgehog (SHH) signaling gene CDON have been recently reported in patients with holoprosencephaly and with pituitary stalk interruption syndrome (PSIS). This study’s aim was an elucidation of an 18-year-old patient presenting PSIS, multiple pituitary hormone deficiency, and congenital unilateral facial and abducens nerve palsy. Additionally, bilateral sensorineural hearing loss, dominating at the right site, was diagnosed. From the second year of life, growth deceleration was observed, and from the age of eight, anterior pituitary hormone deficiencies were gradually confirmed and substituted. At the MRI, characteristic triad for PSIS (anterior pituitary hypoplasia, interrupted pituitary stalk and ectopic posterior lobe) was diagnosed. We performed a comprehensive genomic screening, including microarrays for structural rearrangements and whole-exome sequencing for a monogenic defect. A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.
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Affiliation(s)
- Monika Obara-Moszyńska
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland.
| | - Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Małgorzata Kałużna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Katarzyna Zawadzka
- MNM Diagnostics Sp. z o.o., 64 Macieja Rataja Str., 61-695, Poznan, Poland
| | - Aleksander Jamsheer
- Department of Medical Genetics, Poznan University of Medical Sciences, 8 Rokietnicka Str, 60-806, Poznan, Poland
| | - Anna Rohde
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Marek Niedziela
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland
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11
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Wang Q, Meng X, Sun Y, Liu F, Xu C, Qiao Y, Yang J, Li G, Wang Y. Hypoglycemia and jaundice in newborns with pituitary stalk interruption syndrome. Medicine (Baltimore) 2021; 100:e25843. [PMID: 34106625 PMCID: PMC8133236 DOI: 10.1097/md.0000000000025843] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 04/17/2021] [Indexed: 11/26/2022] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare disease associated with either isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD). In older children and adults, most patients experience short stature or hypogonadism. Neonatal PSIS is extremely rare and is difficult to recognize due to absence of dwarfism. However, when this condition occurs in newborns, it is often life-threatening. Here, we collected patients with neonatal PSIS to clarify its characteristics to improve its early diagnosis.The patients included in this study were treated at the pediatric endocrine department of Shandong Provincial Hospital from January 2017 to July 2020. We obtained the clinical characteristics, endocrine hormone levels, pituitary magnetic resonance imaging (MRI) and further genetic data for all the patients. Hormone therapy was first given at the time of diagnosis, and the patients received regular follow-up.Three neonatal patients were identified in our clinic. The characteristics of these patients included hypoglycemia and jaundice, as well as CPHD, which included features such as micropenis and hypothyroidism. Genetic etiology was still hard to discover. All the patients responded well to alternative therapy, and the longest follow-up period was 3 years. Regular replacement ensures good prognosis.Sustained hypoglycemia and jaundice in newborns, indicate the presentation of PSIS. Early recognition is of great importance to avoid a life-threatening crisis.
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Affiliation(s)
- Qi Wang
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Xiangji Meng
- Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences
| | - Yan Sun
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Fan Liu
- Department of Paediatrics, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yu Qiao
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Jianmei Yang
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Guimei Li
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
| | - Yulin Wang
- Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan
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12
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Zhang J, Tang SY, Zhu XB, Li P, Lu JQ, Cong JS, Wang LB, Zhang F, Li Z. Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism. Asian J Androl 2021; 23:288-293. [PMID: 33208564 PMCID: PMC8152424 DOI: 10.4103/aja.aja_65_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided thefirst evidence that women are probably more tolerant to variants of IHH-related genes than men.
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Affiliation(s)
- Jian Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Shu-Yan Tang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Xiao-Bin Zhu
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Peng Li
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Jian-Qi Lu
- Department of Research Institute, Reproduction Medical Center, The first Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jiang-Shan Cong
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Ling-Bo Wang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Zheng Li
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
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13
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Lauffer P, Zwaveling-Soonawala N, Naafs JC, Boelen A, van Trotsenburg ASP. Diagnosis and Management of Central Congenital Hypothyroidism. Front Endocrinol (Lausanne) 2021; 12:686317. [PMID: 34566885 PMCID: PMC8458656 DOI: 10.3389/fendo.2021.686317] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/13/2021] [Indexed: 11/21/2022] Open
Abstract
Central congenital hypothyroidism (CH) is defined as thyroid hormone (TH) deficiency at birth due to insufficient stimulation by the pituitary of the thyroid gland. The incidence of central CH is currently estimated at around 1:13,000. Central CH may occur in isolation, but in the majority of cases (60%) it is part of combined pituitary hormone deficiencies (CPHD). In recent years several novel genetic causes of isolated central CH have been discovered (IGSF1, TBL1X, IRS4), and up to 90% of isolated central CH cases can be genetically explained. For CPHD the etiology usually remains unknown, although pituitary stalk interruption syndrome does seem to be the most common anatomic pituitary malformation associated with CPHD. Recent studies have shown that central CH is a more severe condition than previously thought, and that early detection and treatment leads to good neurodevelopmental outcome. However, in the neonatal period the clinical diagnosis is often missed despite hospital admission because of feeding problems, hypoglycemia and prolonged jaundice. This review provides an update on the etiology and prognosis of central CH, and a practical approach to diagnosis and management of this intriguing condition.
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Affiliation(s)
- Peter Lauffer
- Emma Children’s Hospital, Amsterdam University Medical Centers (UMC), Department of Pediatric Endocrinology, University of Amsterdam, Amsterdam, Netherlands
| | - Nitash Zwaveling-Soonawala
- Emma Children’s Hospital, Amsterdam University Medical Centers (UMC), Department of Pediatric Endocrinology, University of Amsterdam, Amsterdam, Netherlands
| | - Jolanda C. Naafs
- Emma Children’s Hospital, Amsterdam University Medical Centers (UMC), Department of Pediatric Endocrinology, University of Amsterdam, Amsterdam, Netherlands
| | - Anita Boelen
- Endocrine Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - A. S. Paul van Trotsenburg
- Emma Children’s Hospital, Amsterdam University Medical Centers (UMC), Department of Pediatric Endocrinology, University of Amsterdam, Amsterdam, Netherlands
- *Correspondence: A. S. Paul van Trotsenburg,
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14
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Abstract
Pituitary stalk interruption syndrome (PSIS) is a distinct developmental defect of the pituitary gland identified by magnetic resonance imaging and characterized by a thin, interrupted, attenuated or absent pituitary stalk, hypoplasia or aplasia of the adenohypophysis, and an ectopic posterior pituitary. The precise etiology of PSIS still remains elusive or incompletely confirmed in most cases. Adverse perinatal events, including breech delivery and hypoxia, were initially proposed as the underlying mechanism affecting the hypothalamic-pituitary axis. Nevertheless, recent findings have uncovered a wide variety of PSIS-associated molecular defects in genes involved in pituitary development, holoprosencephaly (HPE), neural development, and other important cellular processes such as cilia function. The application of whole exome sequencing (WES) in relatively large cohorts has identified an expanded pool of potential candidate genes, mostly related to the Wnt, Notch, and sonic hedgehog signaling pathways that regulate pituitary growth and development during embryogenesis. Importantly, WES has revealed coexisting pathogenic variants in a significant number of patients; therefore, pointing to a multigenic origin and inheritance pattern of PSIS. The disorder is characterized by inter- and intrafamilial variability and incomplete or variable penetrance. Overall, PSIS is currently viewed as a mild form of an expanded HPE spectrum. The wide and complex clinical manifestations include evolving pituitary hormone deficiencies (with variable timing of onset and progression) and extrapituitary malformations. Severe and life-threatening symptomatology is observed in a subset of patients with complete pituitary hormone deficiency during the neonatal period. Nevertheless, most patients are referred later in childhood for growth retardation. Prompt and appropriate hormone substitution therapy constitutes the cornerstone of treatment. Further studies are needed to uncover the etiopathogenesis of PSIS.
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Affiliation(s)
- Antonis Voutetakis
- Department of Pediatrics, School of Medicine, Democritus University of Thrace, Alexandroupolis, Thrace, Greece.
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15
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Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K. Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism. Front Pediatr 2021; 9:641397. [PMID: 34055685 PMCID: PMC8149944 DOI: 10.3389/fped.2021.641397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/16/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown. Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility. Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them. Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.
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Affiliation(s)
- Raja Brauner
- Hôpital Fondation Adolphe de Rothschild and Université Paris Descartes, Paris, France
| | | | - Anu Bashamboo
- Human Developmental Genetics Unit, Institut Pasteur, Paris, France
| | - Ken McElreavey
- Human Developmental Genetics Unit, Institut Pasteur, Paris, France
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16
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Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K. Pituitary stalk interruption syndrome is characterized by genetic heterogeneity. PLoS One 2020; 15:e0242358. [PMID: 33270637 PMCID: PMC7714207 DOI: 10.1371/journal.pone.0242358] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 10/30/2020] [Indexed: 12/11/2022] Open
Abstract
Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following-midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.
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Affiliation(s)
- Raja Brauner
- Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, Paris, France
| | | | - Anu Bashamboo
- Human Developmental Genetics Unit, Institute Pasteur, Paris, France
| | - Ken McElreavey
- Human Developmental Genetics Unit, Institute Pasteur, Paris, France
- * E-mail:
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17
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Wu ZY, Li YL, Chang B. Pituitary stalk interruption syndrome and liver changes: From clinical features to mechanisms. World J Gastroenterol 2020; 26:6909-6922. [PMID: 33311939 PMCID: PMC7701950 DOI: 10.3748/wjg.v26.i44.6909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/14/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. Although the etiology of PSIS is still unclear, gene changes and perinatal adverse events such as breech delivery may play important roles in the pathogenesis of PSIS. PSIS can cause multiple hormone deficiencies, such as growth hormone, which then cause a series of changes in the human body. On the one hand, hormone changes affect growth and development, and on the other hand, they could affect human metabolism and subsequently the liver resulting in nonalcoholic fatty liver disease (NAFLD). Under the synergistic effect of multiple mechanisms, the progression of NAFLD caused by PSIS is faster than that due to other causes. Therefore, in addition to early identification of PSIS, timely hormone replacement therapy and monitoring of relevant hormone levels, clinicians should routinely assess the liver function while managing PSIS.
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Affiliation(s)
- Ze-Yu Wu
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yi-Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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18
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Reis LM, Basel D, McCarrier J, Weinberg DV, Semina EV. Compound heterozygous splicing CDON variants result in isolated ocular coloboma. Clin Genet 2020; 98:486-492. [PMID: 32729136 PMCID: PMC8341436 DOI: 10.1111/cge.13824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/25/2020] [Indexed: 12/20/2022]
Abstract
Ocular coloboma is caused by failure of optic fissure closure during development and recognized as part of the microphthalmia, anophthalmia, and coloboma (MAC) spectrum. While many genes are known to cause colobomatous microphthalmia, relatively few have been reported in coloboma with normal eye size. Genetic analysis including trio exome sequencing and Sanger sequencing was undertaken in a family with two siblings affected with bilateral coloboma of the iris, retina, and choroid. Pathogenic variants in MAC genes were excluded. Trio analysis identified compound heterozygous donor splice site variants in CDON, a cell-surface receptor known to function in the Sonic Hedgehog pathway, c.928 + 1G > A and c.2650 + 1G > T, in both affected individuals. Heterozygous missense and truncating CDON variants are associated with dominant holoprosencephaly (HPE) with incomplete penetrance and Cdon-/- mice display variable HPE and coloboma. A homozygous nonsense allele of uncertain significance was recently identified in a consanguineous patient with coloboma and a second molecular diagnosis. We report the first compound heterozygous variants in CDON as a cause of isolated coloboma. CDON is the first HPE gene identified to cause recessive coloboma. Given the phenotypic overlap, further examination of HPE genes in coloboma is indicated.
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Affiliation(s)
- Linda M Reis
- Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, WI 53226
| | - Donald Basel
- Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, WI 53226
| | - Julie McCarrier
- Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, WI 53226
| | - David V Weinberg
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Elena V Semina
- Department of Pediatrics, Children’s Research Institute, Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, WI 53226
- Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226
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19
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Islam F, Htun S, Lai LW, Krall M, Poranki M, Martin PM, Sobreira N, Wohler ES, Yu J, Moore AT, Slavotinek AM. Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population. Clin Genet 2020; 98:499-506. [PMID: 32799327 DOI: 10.1111/cge.13830] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/08/2020] [Accepted: 08/10/2020] [Indexed: 12/13/2022]
Abstract
Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.
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Affiliation(s)
- Farrah Islam
- Department of Ophthalmology, Al-Shifa Eye Trust Hospital, Rawalpindi, Pakistan
| | - Stephanie Htun
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Li-Wen Lai
- Department of Pathology, University of Arizona, Tucson, Arizona, USA
| | - Max Krall
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Menitha Poranki
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
| | - Pierre-Marie Martin
- Institute of Human Genetics, University of California San Francisco, San Francisco, California, USA
| | - Nara Sobreira
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Elizabeth S Wohler
- McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jingwei Yu
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
| | - Anthony T Moore
- Dept. Ophthalmology, University of California San Francisco, San Francisco, California, USA
| | - Anne M Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA
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20
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David O, Eskin-Schwartz M, Ling G, Dolgin V, Kristal E, Benkowitz E, Osyntsov L, Gradstein L, Birk OS, Loewenthal N, Yerushalmi B. Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy. Clin Genet 2020; 98:303-307. [PMID: 32617964 DOI: 10.1111/cge.13805] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 06/27/2020] [Accepted: 06/27/2020] [Indexed: 12/11/2022]
Abstract
Ciliopathies are a heterogeneous group of disorders, related to abnormal ciliary function. Severe biliary ciliopathy, caused by bi-allelic mutations in TTC26, has been recently described in the context of a syndrome of polydactyly and severe neonatal cholestasis, with brain, kidney and heart involvement. Pituitary involvement has not been previously reported for patients with this condition. Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings. We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development.
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Affiliation(s)
- Odeya David
- Pediatric Endocrinology Unit, Soroka University Medical Center, Beer-Sheva, Israel.,Saban Pediatric Medical Center for Israel, Soroka University Medical Center, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Marina Eskin-Schwartz
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Galina Ling
- Saban Pediatric Medical Center for Israel, Soroka University Medical Center, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Pediatric Gastroenterology Unit, Soroka University Medical Center, Beer-Sheva, Israel
| | - Vadim Dolgin
- Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Eyal Kristal
- Saban Pediatric Medical Center for Israel, Soroka University Medical Center, Beer-Sheva, Israel
| | - Ela Benkowitz
- Radiology Department, Soroka Medical Center, Beer-Sheva, Israel
| | - Lidia Osyntsov
- Institute of Pathology, Soroka Medical Center, Beer-Sheva, Israel
| | - Libe Gradstein
- Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Ophthalmology Clinic, Southern District, Clalit Health Services, Beer-sheva, Israel
| | - Ohad S Birk
- Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Neta Loewenthal
- Pediatric Endocrinology Unit, Soroka University Medical Center, Beer-Sheva, Israel.,Saban Pediatric Medical Center for Israel, Soroka University Medical Center, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Baruch Yerushalmi
- Saban Pediatric Medical Center for Israel, Soroka University Medical Center, Beer-Sheva, Israel.,Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Pediatric Gastroenterology Unit, Soroka University Medical Center, Beer-Sheva, Israel
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21
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Liu Z, Chen X. A Novel Missense Mutation in Human Receptor Roundabout-1 (ROBO1) Gene Associated with Pituitary Stalk Interruption Syndrome. J Clin Res Pediatr Endocrinol 2020; 12:212-217. [PMID: 31448886 PMCID: PMC7291404 DOI: 10.4274/jcrpe.galenos.2019.2018.0309] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 08/16/2019] [Indexed: 02/08/2023] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is characterized by the association of an absent or thin pituitary stalk, an absent or hypoplastic anterior pituitary lobe and an ectopic posterior pituitary (EPP) lobe. The causes of this anatomical defect include both genetic and environmental factors. Molecular genetic defects have been indentified in a small number of patients with PSIS. A 4-year-old boy presented with hypoglycemia and hyponatremia associated with growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone deficiencies. The patient had right sided strabismus. magnetic resonance imaging images showed pituitary hypoplasia, EPP and absent pituitary stalk. A novel Receptor Roundabout-1 (ROBO1) missense mutation (c.1690C>T, p.Pro564Ser) that may contribute to the disorder was found in this patient and his mother, who also exhibited pituitary abnormalities.
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Affiliation(s)
- Ziqin Liu
- Capital Institute of Pediatrics, Clinic of Endocrinology, Beijing, China
| | - Xiaobo Chen
- Capital Institute of Pediatrics, Clinic of Endocrinology, Beijing, China
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22
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Gregory LC, Dattani MT. The Molecular Basis of Congenital Hypopituitarism and Related Disorders. J Clin Endocrinol Metab 2020; 105:5614788. [PMID: 31702014 DOI: 10.1210/clinem/dgz184] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 11/07/2019] [Indexed: 12/23/2022]
Abstract
CONTEXT Congenital hypopituitarism (CH) is characterized by the presence of deficiencies in one or more of the 6 anterior pituitary (AP) hormones secreted from the 5 different specialized cell types of the AP. During human embryogenesis, hypothalamo-pituitary (HP) development is controlled by a complex spatio-temporal genetic cascade of transcription factors and signaling molecules within the hypothalamus and Rathke's pouch, the primordium of the AP. EVIDENCE ACQUISITION This mini-review discusses the genes and pathways involved in HP development and how mutations of these give rise to CH. This may present in the neonatal period or later on in childhood and may be associated with craniofacial midline structural abnormalities such as cleft lip/palate, visual impairment due to eye abnormalities such as optic nerve hypoplasia (ONH) and microphthalmia or anophthalmia, or midline forebrain neuroradiological defects including agenesis of the septum pellucidum or corpus callosum or the more severe holoprosencephaly. EVIDENCE SYNTHESIS Mutations give rise to an array of highly variable disorders ranging in severity. There are many known causative genes in HP developmental pathways that are routinely screened in CH patients; however, over the last 5 years this list has rapidly increased due to the identification of variants in new genes and pathways of interest by next-generation sequencing. CONCLUSION The majority of patients with these disorders do not have an identified molecular basis, often making management challenging. This mini-review aims to guide clinicians in making a genetic diagnosis based on patient phenotype, which in turn may impact on clinical management.
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Affiliation(s)
- Louise Cheryl Gregory
- Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Mehul Tulsidas Dattani
- Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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23
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Wang CZ, Guo LL, Guo QH, Mu YM. NBPF9 Gene May Be Involved in Congenital Hypopituitarism: A Whole-Genome Study of a Boy with Pituitary Stalk Interruption Syndrome and His Family. Int J Endocrinol 2020; 2020:5401738. [PMID: 32733554 PMCID: PMC7383300 DOI: 10.1155/2020/5401738] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting as various degrees of anterior pituitary hormone deficiency. Scattered familial cases have been found, revealing some genetic variants. However, most of the previous research studies involved an affected sibling, and the gene spectra of the patients' entire family have rarely been reported. We conducted a study of a family consisting of a PSIS patient with his unaffected sibling and healthy parents of Han Chinese background using whole-genome sequencing. Bioinformatic analysis was carried out, and mutations related to PSIS, single-nucleotide variants (SNVs), insertion-deletion (InDELs), and structural variations (SVs) in all the four samples were filtered. After Sanger sequencing, we confirmed the variants obtained and selected three candidate genes for functional verification. The gene variations in this boy with PSIS and his lineal relatives are reported herein; de novo sequencing revealed that the NBPF9 gene may be involved in the pathogenesis of PSIS.
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Affiliation(s)
- Cheng-Zhi Wang
- Department of Endocrinology, The First Medical Center of PLA General Hospital, Beijing 100853, China
- Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Ling-Ling Guo
- Department of Endocrinology, The First Medical Center of PLA General Hospital, Beijing 100853, China
- Department of Endocrinology, Beijing Electric Teaching Hospital of Capital Medical University, Beijing, 100073, China
| | - Qing-Hua Guo
- Department of Endocrinology, The First Medical Center of PLA General Hospital, Beijing 100853, China
- Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan 572000, China
| | - Yi-Ming Mu
- Department of Endocrinology, The First Medical Center of PLA General Hospital, Beijing 100853, China
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24
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Vasques GA, Andrade NLM, Correa FA, Jorge AAL. Update on new GH-IGF axis genetic defects. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2019; 63:608-617. [PMID: 31939486 PMCID: PMC10522240 DOI: 10.20945/2359-3997000000191] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/19/2019] [Indexed: 11/23/2022]
Abstract
The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade. The enhancement of large-scale sequencing techniques has expanded the spectrum of known genes and several other candidate genes that could affect the GH-IGF1-bone pathway. To date, defects in more than forty genes were associated with an impairment of the somatotropic axis. These defects can affect from the secretion of GH to the bioavailability and action of IGF-1. Affected patients present a large heterogeneous group of conditions associated with growth retardation. In this review, we focus on the description of the GH-IGF axis genetic defects reported in the last decade. Arch Endocrinol Metab. 2019;63(6):608-17.
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Affiliation(s)
- Gabriela A. Vasques
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular (LIM25), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Nathalia L. M. Andrade
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular (LIM25), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Fernanda A. Correa
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Alexander A. L. Jorge
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular (LIM25), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
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25
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Wang D, Zhang M, Guan H, Wang X. Osteogenesis Imperfecta Due to Combined Heterozygous Mutations in Both COL1A1 and COL1A2, Coexisting With Pituitary Stalk Interruption Syndrome. Front Endocrinol (Lausanne) 2019; 10:193. [PMID: 30984112 PMCID: PMC6447649 DOI: 10.3389/fendo.2019.00193] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 03/07/2019] [Indexed: 12/30/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a hereditary connective tissue disorder, characterized by reduced bone content, fractures and skeletal malformation due to abnormal synthesis or dysfunction of type I collagen protein. Pituitary stalk interruption syndrome (PSIS) is usually associated with environmental and hereditary factors. Here, we report a rare case of OI and PSIS co-occurrence. A 19-year-old male patient sought treatment for growth delay and absent secondary sexual characteristics. Hormone measurements indicated the presence of hypopituitarism (secondary hypothyroidism, growth hormone deficiency, ACTH-cortisol hormone deficiency, hypogonadotropic hypogonadism). Pituitary magnetic resonance imaging indicated reduced morphology of the anterior lobe, absence of the pituitary stalk, and ectopic displacement of the posterior lobe to the infundibulum, supporting a diagnosis of PSIS. In addition, the patient, his monozygotic twin brother (no evidence of PSIS), and their mother all presented blue sclera and susceptibility to bone fractures before adulthood. Next-generation sequencing demonstrated that the family had compound heterozygous mutations in COL1A1 and COL1A2, with no known mutations related to PSIS, pituitary hormone deficiency (PHD), or holoprosencephaly (HPE). The mother experienced breech and natural delivery of the patient and his brother, respectively. Thus, we deduced that the patient's PSIS might have resulted from breech delivery. Although we cannot exclude the possibility that the proband might have an undetected genetic abnormality causing PSIS or increasing his susceptibility to damage to the hypothalamic-pituitary region due to the limitation of exome sequencing, this rare case suggests that breech delivery in the newborn with OI might be related to PSIS.
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Affiliation(s)
- Dongdong Wang
- Obstetrics and Gynecology Department of Shengjing Hospital, China Medical University, Shenyang, China
| | - Mengmeng Zhang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Haixia Guan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
- Haixia Guan
| | - Xiaoli Wang
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Xiaoli Wang
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26
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Gregory LC, Dattani MT. Embryologic and Genetic Disorders of the Pituitary Gland. CONTEMPORARY ENDOCRINOLOGY 2019:3-27. [DOI: 10.1007/978-3-030-11339-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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27
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Patti G, Guzzeti C, Di Iorgi N, Maria Allegri AE, Napoli F, Loche S, Maghnie M. Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab 2018; 32:425-444. [PMID: 30086867 DOI: 10.1016/j.beem.2018.03.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Central adrenal insufficiency (CAI) is a life-threatening condition caused by either pituitary disease (secondary adrenal insufficiency) or impaired hypothalamic function with inadequate CRH production (tertiary adrenal insufficiency). ACTH deficiency may be isolated or, more frequently, occur in conjunction with other pituitary hormone deficiencies and midline defects. Genetic mutations of the TBX19 causing isolated CAI are rare but a number of genes encoding transcription factors involved in hypothalamic-pituitary gland development, as well as other genes including POMC and PC1, are associated with ACTH deficiency. CAI is frequently identified in congenital, malformative, genetic, and epigenetic syndromes as well as in several acquired conditions of different etiologies. The signs and symptoms vary considerably and depend on the age of onset and the number and severity of associated pituitary defects. They may include hypoglycemia, lethargy, apnea, poor feeding, prolonged cholestatic jaundice, jitteriness, seizures, and sepsis in the neonate, or nonspecific signs such as fatigue, hypotension, vomiting and hyponatremia without hyperkalemia in children. The diagnosis of CAI relies on the measurement of morning cortisol concentrations along with dynamic test for cortisol release with different stimulating agents. Early recognition of CAI and its correct management are mandatory in order to avoid both morbidity and mortality in affected neonates, children and adolescents.
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Affiliation(s)
- Giuseppa Patti
- Departments of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Chiara Guzzeti
- SSD Endocrinologia Pediatrica, Ospedale Pediatrico Microcitemico "A. Cao", AO Brotzu, Cagliari, Italy
| | - Natascia Di Iorgi
- Departments of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | | | - Flavia Napoli
- Departments of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Sandro Loche
- SSD Endocrinologia Pediatrica, Ospedale Pediatrico Microcitemico "A. Cao", AO Brotzu, Cagliari, Italy
| | - Mohamad Maghnie
- Departments of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy.
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28
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Martinez AF, Kruszka PS, Muenke M. Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2018; 178:246-257. [PMID: 29761634 DOI: 10.1002/ajmg.c.31616] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 03/29/2018] [Accepted: 04/11/2018] [Indexed: 12/13/2022]
Abstract
Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS-HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS-HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS-HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation-positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families.
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Affiliation(s)
- Ariel F Martinez
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Paul S Kruszka
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
| | - Maximilian Muenke
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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29
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Zwaveling-Soonawala N, Alders M, Jongejan A, Kovacic L, Duijkers FA, Maas SM, Fliers E, van Trotsenburg ASP, Hennekam RC. Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients. J Clin Endocrinol Metab 2018; 103:415-428. [PMID: 29165578 DOI: 10.1210/jc.2017-01660] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/15/2017] [Indexed: 12/13/2022]
Abstract
CONTEXT Pituitary stalk interruption syndrome (PSIS) consists of a small/absent anterior pituitary lobe, an interrupted/absent pituitary stalk, and an ectopic posterior pituitary lobe. Mendelian forms of PSIS are detected infrequently (<5%), and a polygenic etiology has been suggested. GLI2 variants have been reported at a relatively high frequency in PSIS. OBJECTIVE To provide further evidence for a non-Mendelian, polygenic etiology of PSIS. METHODS Exome sequencing (trio approach) in 20 patients with isolated PSIS. In addition to searching for (potentially) pathogenic de novo and biallelic variants, a targeted search was performed in a panel of genes associated with midline brain development (223 genes). For GLI2 variants, both (potentially) pathogenic and relatively rare variants (<5% in the general population) were studied. The frequency of GLI2 variants was compared with that of a reference population. RESULTS We found four additional candidate genes for isolated PSIS (DCHS1, ROBO2, CCDC88C, and KIF14) and one for syndromic PSIS (KAT6A). Eleven GLI2 variants were present in six patients. A higher frequency of a combination of two GLI2 variants (M1352V + D1520N) was found in the study group compared with a reference population (10% vs 0.68%). (Potentially) pathogenic variants were identified in genes associated with midline brain anomalies, including holoprosencephaly, hypogonadotropic hypogonadism, and absent corpus callosum and in genes involved in ciliopathies. CONCLUSION Combinations of variants in genes associated with midline brain anomalies are frequently present in PSIS and sustain the hypothesis of a polygenic cause of PSIS.
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Affiliation(s)
- Nitash Zwaveling-Soonawala
- Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Marielle Alders
- Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Department of Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Lidija Kovacic
- Novartis Ireland Ltd, Beech Hill Office Campus, Dublin, Ireland
| | - Floor A Duijkers
- Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Saskia M Maas
- Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Eric Fliers
- Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - A S Paul van Trotsenburg
- Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Raoul C Hennekam
- Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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30
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Guo QH, Wang CZ, Wu ZQ, Qin Y, Han BY, Wang AP, Wang BA, Dou JT, Wu XS, Mu YM. Multi-genic pattern found in rare type of hypopituitarism: a whole-exome sequencing study of Han Chinese with pituitary stalk interruption syndrome. J Cell Mol Med 2017; 21:3626-3632. [PMID: 28707430 PMCID: PMC5706574 DOI: 10.1111/jcmm.13272] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 05/07/2017] [Indexed: 12/17/2022] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare type of hypopituitarism manifesting various degrees of pituitary hormone deficiency. Although mutations have been identified in some familial cases, the underpinning mechanisms of sporadic patients with PSIS who are in a vast majority remain elusive, necessitating a comprehensive study using systemic approaches. We postulate that other genetic mechanisms may be responsible for the sporadic PSIS. To test this hypothesis, we conducted a study in 24 patients with PSIS of Han Chinese with no family history using whole‐exome sequencing (WES) and bioinformatic analysis. We identified a group of heterozygous mutations in 92% (22 of 24) of the patients, and these genes are mostly associated with Notch, Shh, Wnt signalling pathways. Importantly, 83% (20 of 24) of the patients had more than one mutation in those pathways suggesting synergy of compound mutations underpin the pathogenesis of sporadic PSIS.
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Affiliation(s)
- Qing-Hua Guo
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.,Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan, China
| | - Cheng-Zhi Wang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Zhi-Qiang Wu
- Department of Molecular Biology, Institute of Basic Medicine, Chinese PLA General Hospital, Beijing, China
| | - Yan Qin
- Department of Endocrinology, The First Affiliated Hospital of Xinxiang Medical University, Weihui City, Henan, China
| | - Bai-Yu Han
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China.,Department of Endocrinology and Metabolism, The 264 Hospital of PLA, Taiyuan, Shanxi, China
| | - An-Ping Wang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Bao-An Wang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Jing-Tao Dou
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Xiao-Sheng Wu
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.,Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Yi-Ming Mu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
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31
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Abstract
The understanding of hypopituitarism has increased over the last three years. This review provides an overview of the most important recent findings. Most of the recent research in hypopituitarism has focused on genetics. New diagnostic techniques like next-generation sequencing have led to the description of different genetic mutations causative for congenital dysfunction of the pituitary gland while new molecular mechanisms underlying pituitary ontogenesis have also been described. Furthermore, hypopituitarism may occur because of an impairment of the distinctive vascularization of the pituitary gland, especially by disruption of the long vessel connection between the hypothalamus and the pituitary. Controversial findings have been published on post-traumatic hypopituitarism. Moreover, autoimmunity has been discussed in recent years as a possible reason for hypopituitarism. With the use of new drugs such as ipilimumab, hypopituitarism as a side effect of pharmaceuticals has come into focus. Besides new findings on the pathomechanism of hypopituitarism, there are new diagnostic tools in development, such as new growth hormone stimulants that are currently being tested in clinical trials. Moreover, cortisol measurement in scalp hair is a promising tool for monitoring cortisol levels over time.
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Affiliation(s)
- Mareike R Stieg
- Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, Kraepelinstr. 2-10, D-80804 Munich, Germany
| | - Ulrich Renner
- Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, Kraepelinstr. 2-10, D-80804 Munich, Germany
| | - Günter K Stalla
- Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, Kraepelinstr. 2-10, D-80804 Munich, Germany
| | - Anna Kopczak
- Max Planck Institute of Psychiatry, Clinical Neuroendocrinology, Kraepelinstr. 2-10, D-80804 Munich, Germany
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32
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Lichiardopol C, Albulescu D. PITUITARY STALK INTERRUPTION SYNDROME: REPORT OF TWO CASES AND LITERATURE REVIEW. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2017; 13:96-105. [PMID: 31149155 PMCID: PMC6525749 DOI: 10.4183/aeb.2017.96] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Pituitary stalk interruption syndrome (PSIS) consisting of the triad: ectopic posterior pituitary (EPP), thin or absent pituitary stalk and anterior pituitary hypoplasia is a rare pituitary malformation with variable degrees of pituitary insufficiency, from isolated growth hormone deficiency to TSH, gonadotropin and ACTH deficiency which may occur in time, with normo, hyper or hypoprolactinemia and central diabetes insipidus in up to 10% of cases. Also, extrapituitary malformations have been described in some cases. Genetic defects were identified only in 5% of cases. MRI findings are considered predictive for the endocrine phenotype. We aim to describe two cases with PSIS without central diabetes insipidus, anosmia and extrapituitary malformations, except for minor head dysmorphic features. The first case was referred at the age of 4 years for short stature (-4SDS for height, bone age 2 years), diagnosed with severe GH deficiency and developed central hypothyroidism and hypoprolactinemia during five-years follow-up. The second case, a 26 year old male with birth asphyxia, cryptorchidism, poor growth in childhood and adolescence (-3 to -4 height SDS), absent puberty and normal adult height (-1.18 SDS; bone age 15.5 years and active growth plates) had GH, TSH, ACTH deficiency and low normal PRL levels. Increasing medical awareness on PSIS clinical and endocrine heterogeneity may help a more early and accurate diagnosis. Corroboration of neuroimaging and endocrine data will improve our knowledge and understanding and will create premises for molecular diagnosis, genetic counseling and a better patients' management.
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Affiliation(s)
- C. Lichiardopol
- University of Medicine and Pharmacy Craiova, Dept. of Endocrinology, Craiova, Romania
- University of Medicine and Pharmacy Craiova, Dept. of Medical Imagery, Craiova, Romania
| | - D.M. Albulescu
- Emergency Clinical Hospital, Dept. of Endocrinology, Craiova, Romania
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Wang CZ, Guo LL, Han BY, Su X, Guo QH, Mu YM. Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis. J Neuroendocrinol 2017; 29. [PMID: 27917547 DOI: 10.1111/jne.12451] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 11/28/2016] [Accepted: 11/28/2016] [Indexed: 12/21/2022]
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting with varying degrees of pituitary hormone deficiency. The signs and symptoms of PSIS during the neonatal period and infancy are often overlooked and therefore diagnosis is delayed. The typical manifestations of PSIS can be detected by magnetic resonance imaging. Several genes in the Wnt, Notch and Shh signalling pathways related to hypothalamic-pituitary development, such as PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, TGIF and HESX1, have been found to be associated with PSIS. Nevertheless, the aetiology in the majority of cases still remains unknown. In the present review, we provide an overview of clinical features of PSIS and summarise our current understanding of the underlying pathogenic mechanisms for this rare syndrome. Furthermore, we propose future research directions that may help our understanding of the aetiology of PSIS.
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Affiliation(s)
- C-Z Wang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - L-L Guo
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
- Department of Endocrinology, Beijing Electric Teaching Hospital of Capital Medical University, Beijing, 100073, China
| | - B-Y Han
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - X Su
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Q-H Guo
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
- Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan, 572000, China
| | - Y-M Mu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
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Di Iorgi N, Morana G, Allegri AEM, Napoli F, Gastaldi R, Calcagno A, Patti G, Loche S, Maghnie M. Classical and non-classical causes of GH deficiency in the paediatric age. Best Pract Res Clin Endocrinol Metab 2016; 30:705-736. [PMID: 27974186 DOI: 10.1016/j.beem.2016.11.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Growth hormone deficiency (GHD) may result from a failure of hypothalamic GHRH production or release, from congenital disorders of pituitary development, or from central nervous system insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases. Idiopathic, isolated GHD is the most common sporadic form of hypopituitarism. GHD may also occur in combination with other pituitary hormone deficiencies, and is often referred to as hypopituitarism, combined pituitary hormone deficiency (CPHD), multiple pituitary hormone deficiency (MPHD) or panhypopituitarism. Children without any identifiable cause of their GHD are commonly labeled as having idiopathic hypopituitarism. MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of GHD and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with normal pituitary anatomy or hypoplastic pituitary alone. Furthermore, the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is generally associated with permanent GHD. T2 DRIVE images aid in the identification of pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes encoding transcription factors - such as HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGSF1, FGF8, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, IFT72, GPR161 and CDON - have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development and management of patients with hypopituitarism, both in terms of possible genetic counseling, and of early diagnosis of evolving anterior pituitary hormone deficiencies.
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Affiliation(s)
- Natascia Di Iorgi
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Giovanni Morana
- Neuroradiology Unit, Istituto Giannina Gaslini, Genova, Italy
| | - Anna Elsa Maria Allegri
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Flavia Napoli
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Roberto Gastaldi
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Annalisa Calcagno
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Giuseppa Patti
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy
| | - Sandro Loche
- SSD Endocrinologia Pediatrica, Ospedale Pediatrico Microcitemico "A. Cao", Cagliari, Italy
| | - Mohamad Maghnie
- Department of Pediatrics, Istituto Giannina Gaslini, University of Genova, Genova, Italy; Department of Endocrine Unit, Istituto Giannina Gaslini, University of Genova, Genova, Italy.
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Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, Kitzman JO, Mills RE, Li JZ, Camper SA. Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. Endocr Rev 2016; 37:636-675. [PMID: 27828722 PMCID: PMC5155665 DOI: 10.1210/er.2016-1101] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023]
Abstract
The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.
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Affiliation(s)
- Qing Fang
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Akima S George
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Michelle L Brinkmeier
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Amanda H Mortensen
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Peter Gergics
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Leonard Y M Cheung
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Alexandre Z Daly
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Adnan Ajmal
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - María Ines Pérez Millán
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - A Bilge Ozel
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jacob O Kitzman
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Ryan E Mills
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jun Z Li
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Sally A Camper
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
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Abstract
PURPOSE OF REVIEW Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absent pituitary stalk, hypoplasia of the adenohypophysis, and ectopic neurohypophysis. PSIS manifestations include a wide spectrum of clinical phenotypes and pituitary hormone deficiencies of variable degree and timing of onset. In this review, recent advances with respect to the cause of PSIS, clinical characteristics leading to earlier diagnosis, and management are outlined. RECENT FINDINGS Diagnosis of PSIS is often delayed probably because clinical findings such as neonatal hypoglycemia, cholestasis, and/or micropenis as well as decreasing growth velocity are not appropriately and timely validated. Recently, molecular defects in various genes have been associated with PSIS albeit in a small number of cases. These findings suggest that PSIS belongs to the spectrum of holoprosencephaly-related defects. Phenotype-genotype discordance and the existence of asymptomatic carriers of a given molecular aberration indicate that penetrance may be modified favorably or unfavorably by the presence of other genetic and/or environmental factors. SUMMARY PSIS constitutes an antenatal anatomical defect. Neonatal hypoglycemia, cholestasis, and/or micropenis with or without growth deficit should raise the possibility of combined pituitary hormone deficiency, a life-threatening condition in cases of coexisting cortisol deficiency. It is important to search for molecular defects in all PSIS cases, as precise identification of the cause is a prerequisite for genetic counseling.
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Castinetti F, Reynaud R, Saveanu A, Jullien N, Quentien MH, Rochette C, Barlier A, Enjalbert A, Brue T. MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency. Eur J Endocrinol 2016; 174:R239-47. [PMID: 26733480 DOI: 10.1530/eje-15-1095] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 01/05/2016] [Indexed: 01/08/2023]
Abstract
Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.
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Affiliation(s)
- Frederic Castinetti
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Rachel Reynaud
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Alexandru Saveanu
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d
| | - Nicolas Jullien
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Marie Helene Quentien
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Claire Rochette
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Anne Barlier
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d
| | - Alain Enjalbert
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
| | - Thierry Brue
- Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France Aix-Marseille UniversitéCNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille CRN2M UMR 7286, 13344 cedex 15 Marseille, FranceDepartment of EndocrinologyAPHM, Hôpital La Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, 13385 cedex 5 Marseille, FranceCentre de Référence des Maladies Rares d'Origine Hypophysaire DEFHY13385 cedex 15 Marseille, FranceAPHMHôpital Timone Enfants, Service de Pédiatrie Multidisciplinaire, 13385 cedex 5 Marseille, FranceAPHMHôpital de la Conception, Laboratoire de Biologie Moléculaire, 13005 Marseille, France
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