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Xie JL, Zhu HY, Dong Y, Sun PP, Qi DD, Luan SX, Zhang Y, Ma HG. Pulsatile gonadotropin-releasing hormone therapy induces spermatogenesis in pituitary stalk interruption syndrome: A case report and review of the literature. World J Clin Cases 2024; 12:4348-4356. [PMID: 39015932 PMCID: PMC11235527 DOI: 10.12998/wjcc.v12.i20.4348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/18/2024] [Accepted: 06/04/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Pituitary stalk interruption syndrome (PSIS) is a rare anatomical defect of the pituitary gland falling under the spectrum of holoprosencephaly phenotypes. It is characterized by a deficiency in anterior pituitary hormones, such as growth hormone, gonadotropins, and thyroid hormones. Due to the syndrome's rarity and nonspecific manifestations, there is a lack of standardized treatment strategies. Consequently, early diagnosis through imaging and on-time intervention are crucial for improving patients' outcomes. CASE SUMMARY A 30-year-old man presented with absent secondary sexual characteristics and azoospermia. Laboratory evaluation revealed a deficiency in gonadotropins, while thyroid function was mostly within normal ranges. Magnetic resonance imaging of the pituitary gland showed pituitary stalk agenesis, hypoplasia of the anterior pituitary, and ectopic posterior pituitary, leading to the diagnosis of PSIS. Initially, the patient underwent 6 mo of gonadotropin therapy without significant changes in hormone levels and secondary sexual characteristics. Pulsatile gonadotropin-releasing hormone therapy was then administered, resulting in the detection of sperm in the semen analysis within 3 mo. After 6 mo, routine semen tests showed normal semen quality. The couple faced challenges in conceiving due to abstinence and underwent three cycles of artificial insemination, which was unsuccessful. They also attempted in vitro fertilization, but unfortunately, the woman experienced a miscarriage 10 wk after the embryo transfer. CONCLUSION Early detection, accurate diagnosis, and timely treatment are crucial in improving the quality of life and fertility of PSIS patients.
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Affiliation(s)
- Jin-Long Xie
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Hai-Ying Zhu
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Yang Dong
- Department of Radiology, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Ping-Ping Sun
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Dan-Dan Qi
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Su-Xian Luan
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Yan Zhang
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, China
| | - Hua-Gang Ma
- The Reproductive Medicine Centre, Weifang People's Hospital, Weifang 261000, Shandong Province, 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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Diwaker C, Thadani P, Memon SS, Sarathi V, Lila AR, Arya S, Krishnappa B, Karlekar M, Patil VA, Shah N, Bandgar T. Pituitary stalk interruption syndrome: phenotype, predictors, and pathophysiology of perinatal events. Pituitary 2022; 25:645-652. [PMID: 35749012 DOI: 10.1007/s11102-022-01243-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/13/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE There is limited data regarding Pituitary Stalk Interruption Syndrome (PSIS) from India. Moreover, the pathophysiological link between perinatal events and PSIS is unclear. We aim to elucidate the predictors of PSIS among patients with growth hormone deficiency (GHD) and perinatal events in PSIS by comparing cohorts of PSIS and genetically proven GHD without PSIS. METHODS Among 179 GHD patients, 56 PSIS and 70 genetically positive GHD (52-GHRHR, 15-POU1F1, and 3-PROP1) patients were included. Perinatal events, clinical anomalies, pituitary hormone deficiency, and imaging findings were recorded. We compared PSIS-isolated GHD (PSIS-IGHD) subgroup with GHRHR-IGHD and PSIS-combined pituitary hormone deficiency (PSIS-CPHD) subgroup with POU1F1/PROP1-CPHD. RESULTS PSIS patients (45 males, median age: 12.5 years) most commonly presented with short stature. At last follow-up (median age: 17.35 years), gonadal (during pubertal-age), thyroid and cortisol axes were affected in 81.6%, 62.5%, and 62.5%. 10/13 (77%) of PSIS children with initial IGHD diagnosis manifested hypogonadism during pubertal age. Male predominance, sporadic presentation, and clinical anomalies were significantly higher in both PSIS subgroups than in the respective genetic subgroups. Breech presentation was higher in PSIS-CPHD than POU1F1/PROP1-CPHD (44.4% vs 5.5%, p = 0.004). Neonatal hypoglycemia (22% vs. 0%, p = 0.05) and jaundice (42 vs. 5%, p = 0.004) were higher in PSIS-CPHD than PSIS-IGHD. CONCLUSION Later age at presentation and frequent hypogonadism were observed in our PSIS cohort. Male sex, sporadic presentation, clinical anomalies, and breech presentation predicted PSIS at presentation. Breech presentation in PSIS is likely due to stalk interruption rather than hormonal deficiency.
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Affiliation(s)
- Chakra Diwaker
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Puja Thadani
- University Hospitals Coventry and Warwickshire (UHCW) NHS Trust, Coventry, England, UK
| | - Saba Samad Memon
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Vijaya Sarathi
- Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, Karnataka, India
| | - Anurag Ranjan Lila
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Sneha Arya
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Brijesh Krishnappa
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Manjiri Karlekar
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Virendra A Patil
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Nalini Shah
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India
| | - Tushar Bandgar
- Department of Endocrinology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, 400012, India.
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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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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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Diversity of Pathological Conditions Affecting Pituitary Stalk. J Clin Med 2021; 10:jcm10081692. [PMID: 33920036 PMCID: PMC8071026 DOI: 10.3390/jcm10081692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/31/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Pituitary stalk lesions (PSL) are a very rare pathology. The majority of conditions affecting the infundibulum do not present with clinically apparent symptoms, what makes the diagnosis difficult. The recognition might be also complicated by the non-specific and transient characteristics of hormonal insufficiencies. In our study, we retrospectively analysed demographic, biochemical, and clinical long-term data of 60 consecutive, unselected adult patients (34 women and 26 men) with PSL diagnosed in the Department of Endocrinology, Jagiellonian University in Krakow. The diagnosis of PSL were categorized as confirmed, probable, or undetermined in 26, 26 and 8 patients, accordingly. Given the possible aetiology congenital, inflammatory, and neoplastic stalk lesions were diagnosed in 17, 15 and 20 patients, accordingly. In eight cases the underlying pathology remained undetermined. The most common pituitary abnormality was gonadal insufficiency diagnosed in 50.8% of cases. Diabetes insipidus was detected in 23.3% of cases. In 5% of patients the pituitary function recovered partially over time. Stalk lesions were extensively discussed in the context of the current literature. Based on the published data and our own experience a diagnostic algorithm has been proposed to help physicians with the management of patients with this challenging condition.
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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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10
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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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11
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Matsumoto R, Suga H, Aoi T, Bando H, Fukuoka H, Iguchi G, Narumi S, Hasegawa T, Muguruma K, Ogawa W, Takahashi Y. Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells. J Clin Invest 2020; 130:641-654. [PMID: 31845906 DOI: 10.1172/jci127378] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 10/15/2019] [Indexed: 12/15/2022] Open
Abstract
Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.
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Affiliation(s)
- Ryusaku Matsumoto
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and.,Department of iPS cell Applications, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.,Department of Advanced Medical Science, Kobe University Graduate School of Science, Technology, and Innovation, Kobe, Hyogo, Japan
| | - Hidetaka Suga
- Department of Diabetes and Endocrinology, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Takashi Aoi
- Department of iPS cell Applications, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.,Department of Advanced Medical Science, Kobe University Graduate School of Science, Technology, and Innovation, Kobe, Hyogo, Japan
| | - Hironori Bando
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Hidenori Fukuoka
- Department of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Hyogo, Japan
| | - Genzo Iguchi
- Department of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Hyogo, Japan.,Medical Center for Student Health, Kobe University, Kobe, Hyogo, Japan.,Department of Biosignal Pathophysiology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Satoshi Narumi
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.,Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Tomonobu Hasegawa
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Keiko Muguruma
- Laboratory for Cell Asymmetry, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan.,Department of iPS Cell Applied Medicine, Graduate School of Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Yutaka Takahashi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
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12
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Hamdi-Rozé H, Ware M, Guyodo H, Rizzo A, Ratié L, Rupin M, Carré W, Kim A, Odent S, Dubourg C, David V, de Tayrac M, Dupé V. Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency. J Clin Endocrinol Metab 2020; 105:5836893. [PMID: 32403133 DOI: 10.1210/clinem/dgaa249] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 05/10/2020] [Indexed: 12/16/2022]
Abstract
CONTEXT In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown. OBJECTIVE The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain. DESIGN In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients. RESULTS We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways. CONCLUSIONS These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.
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Affiliation(s)
- Houda Hamdi-Rozé
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
- Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
| | - Michelle Ware
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Hélène Guyodo
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Aurélie Rizzo
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Leslie Ratié
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Maïlys Rupin
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Wilfrid Carré
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
- Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
| | - Artem Kim
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Sylvie Odent
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
- Service de Génétique Clinique, CHU, Rennes, France
| | - Christèle Dubourg
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
- Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
| | - Véronique David
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
| | - Marie de Tayrac
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
- Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
| | - Valérie Dupé
- Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France
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13
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Fang X, Zhang Y, Cai J, Lu T, Hu J, Yuan F, Chen P. Identification of novel candidate pathogenic genes in pituitary stalk interruption syndrome by whole-exome sequencing. J Cell Mol Med 2020; 24:11703-11717. [PMID: 32864857 PMCID: PMC7579688 DOI: 10.1111/jcmm.15781] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 06/25/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a type of congenital malformation of the anterior pituitary, which leads to isolated growth hormone deficiency or multiple hypothalamic-pituitary deficiencies. Many genetic factors have been explored, but they only account for a minority of the genetic aetiology. To identify novel PSIS pathogenic genes, we conducted whole-exome sequencing with 59 sporadic PSIS patients, followed by filtering gene panels involved in pituitary development, holoprosencephaly and midline abnormality. A total of 81 heterozygous variants, distributed among 59 genes, were identified in 50 patients, with 31 patients carrying polygenic variants. Fourteen of the 59 pathogenic genes clustered to the Hedgehog pathway. Of them, PTCH1 and PTCH2, inhibitors of Hedgehog signalling, showed the most frequent heterozygous mutations (22%, seven missense and one frameshift mutations were identified in 13 patients). Moreover, five novel heterozygous null variants in genes including PTCH2 (p.S391fs, combined with p.L104P), Hedgehog acyltransferase (p.R280X, de novo), MAPK3 (p.H50fs), EGR4 (p.G22fs, combined with LHX4 p.S263N) and SPG11 (p.Q1624X), which lead to truncated proteins, were identified. In conclusion, genetic mutations in the Hedgehog signalling pathway might underlie the complex polygenic background of PSIS, and the findings of our study could extend the understanding of PSIS pathogenic genes.
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Affiliation(s)
- Xuqian Fang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuwen Zhang
- Department of Endocrinology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jialin Cai
- Clinical Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Tingwei Lu
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junjie Hu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peizhan Chen
- Clinical Research Center, Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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14
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Budny B, Karmelita-Katulska K, Stajgis M, Żemojtel T, Ruchała M, Ziemnicka K. Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency. Int J Mol Sci 2020; 21:ijms21165757. [PMID: 32796691 PMCID: PMC7461210 DOI: 10.3390/ijms21165757] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/07/2020] [Accepted: 08/08/2020] [Indexed: 12/25/2022] Open
Abstract
Combined pituitary hormone deficiency represents a disorder with complex etiology. For many patients, causes of the disease remain unexplained, despite usage of advanced genetic testing. Although major and common transcription factors were identified two decades ago, we still struggle with identification of rare inborn factors contributing to pituitary function. In this report, we follow up genomic screening of CPHD patient cohort that were previously tested for changes in a coding sequences of genes with the use of the whole exome. We aimed to find contribution of rare copy number variations (CNVs). As a result, we identified genomic imbalances in 7 regions among 12 CPHD patients. Five out of seven regions showed copy gains whereas two presented losses of genomic fragment. Three regions with detected gains encompassed known CPHD genes namely LHX4, HESX1, and OTX2. Among new CPHD loci, the most interesting seem to be the region covering SIX3 gene, that is abundantly expressed in developing brain, and together with HESX1 contributes to pituitary organogenesis as it was evidenced before in functional studies. In conclusion, with the use of broadened genomic approach we identified copy number imbalances for 12 CPHD patients. Although further functional studies are required in order to estimate its true impact on expression pattern during pituitary organogenesis and CPHD etiology.
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Affiliation(s)
- Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
- Correspondence: ; Tel.: +48-691-814-330
| | - Katarzyna Karmelita-Katulska
- Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (K.K.-K.); (M.S.)
| | - Marek Stajgis
- Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (K.K.-K.); (M.S.)
| | - Tomasz Żemojtel
- Genomics Platform, Berlin Institute of Health, 10117 Berlin, Germany;
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 60-569 Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
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15
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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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16
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Two Cases of Pituitary Stalk Interruption Syndrome in Syrian Children. Case Rep Endocrinol 2020; 2020:2039649. [PMID: 32231812 PMCID: PMC7091520 DOI: 10.1155/2020/2039649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/09/2020] [Accepted: 02/22/2020] [Indexed: 12/27/2022] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is an extremely rare cause of growth failure and delayed puberty. It can be diagnosed by magnetic resonance imaging (MRI) of the hypothalamus and pituitary gland, showing an ectopic or absent posterior pituitary, an absent or interrupted pituitary stalk, or small anterior pituitary, in combination with growth hormone or other pituitary hormone deficiencies. The exact etiology of PSIS is unknown. In this article, we describe two cases of PSIS in Syria which are, as far as we know, the first published cases.
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17
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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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18
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Budny B, Zemojtel T, Kaluzna M, Gut P, Niedziela M, Obara-Moszynska M, Rabska-Pietrzak B, Karmelita-Katulska K, Stajgis M, Ambroziak U, Bednarczuk T, Wrotkowska E, Bukowska-Olech E, Jamsheer A, Ruchala M, Ziemnicka K. SEMA3A and IGSF10 Are Novel Contributors to Combined Pituitary Hormone Deficiency (CPHD). Front Endocrinol (Lausanne) 2020; 11:368. [PMID: 32612575 PMCID: PMC7308526 DOI: 10.3389/fendo.2020.00368] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 05/11/2020] [Indexed: 12/13/2022] Open
Abstract
Background: The mutation frequencies of pituitary transcription factors genes in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. However, apart from PROP1 the mutation rate of other genes is low and for almost half of the patients with CPHD the routine sequencing of known genes is unsuccessful in the identification of genetic causes. Methods: A cohort of 66 sporadic and nine familial CPHD cases (80 patients in total) were subjected to initial testing of the genes PROP1, POU1F1, LHX3, LHX4, and HESX1 using a targeted gene panel and MLPA. In patients who tested negative, a whole exome sequencing approach was employed. Results: In nine of the familial cases and 32 of the sporadic patients mutations in the PROP1 gene were found (the common pathogenic variants included c.301_302delAG and c.150delA). Mutations were also found in genes so far not related directly to CPHD. A unique homozygous and clinically relevant variant was identified in the SEMA3A gene, which may contribute to neural development and his phenotypic spectrum including short stature and isolated hypogonadotropic hypogonadism (IHH). Another pathogenic variant p.A1672T was found in the IGSF10 gene reported to be responsible for delayed puberty and neuronal migration during embryogenesis. Several suspected novel but predicted benign variants were also identified for the CHD7, WDR11 and FGF17 genes. Conclusion: Although PROP1 defects account for a majority of CPHD patients, identification of rare, less frequent variants constitutes a big challenge. Multiple genetic factors responsible for CPHD are still awaiting discovery and therefore the usage of efficient genomic tools (i.e., whole exome sequencing) will further broaden our knowledge regarding pituitary development and function.
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Affiliation(s)
- Bartlomiej Budny
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
- *Correspondence: Bartlomiej Budny
| | - Tomasz Zemojtel
- Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Genomics Platform, Berlin Institute of Health, Berlin, Germany
| | - Malgorzata Kaluzna
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Pawel Gut
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Niedziela
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Monika Obara-Moszynska
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Barbara Rabska-Pietrzak
- Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Marek Stajgis
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, Poznan, Poland
| | - Urszula Ambroziak
- Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Bednarczuk
- Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland
| | - Elzbieta Wrotkowska
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Aleksander Jamsheer
- Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Ruchala
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
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19
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Rodríguez-Contreras FJ, Marbán-Calzón M, Vallespín E, Del Pozo Á, Solís-López M, Lobato-Vidal N, Fernández-Elvira M, Del Valle Rex-Romero M, Heath KE, González-Casado I, Campos-Barros Á. Loss of function BMP4 mutation supports the implication of the BMP/TGF-β pathway in the etiology of combined pituitary hormone deficiency. Am J Med Genet A 2019; 179:1591-1597. [PMID: 31120642 DOI: 10.1002/ajmg.a.61201] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 04/23/2019] [Accepted: 04/27/2019] [Indexed: 12/19/2022]
Abstract
Despite BMP4 signaling being critical to Rathke's pouch induction and maintenance during early stages of pituitary development, its implication in the etiology of combined pituitary hormone deficiency (CPHD) and other clinical presentations of congenital hypopituitarism has not yet been definitely demonstrated. We report here the first CPHD patient with a de novo pathogenic loss-of-function variant in BMP4. A 6-year-old boy, with macrocephaly, myopia/astigmatism, mild psychomotor retardation, anterior pituitary hypoplasia and ectopic posterior pituitary, clinically diagnosed with growth hormone deficiency, and central hypothyroidism, was referred for genetic analysis of CPHD. Targeted NGS analysis with a custom panel (n = 310 genes) identified a novel heterozygous de novo nonsense variant, NM_001202.5:c.794G > A, p.(Trp265*) in BMP4, which introduces a premature stop codon in the BMP4 pro-domain, impairing the transcription of the TGF-β mature peptide domain. Additional relevant variants in other genes implicated in pituitary development signaling pathways such as SMAD4 and E2F4 (BMP/TGF-pathway), ALMS1 (NOTCH-pathway), and TSHZ1 (Prokineticin-pathway), were also identified. Our results support the implication of the BMP/TGF-β signaling pathway in the etiology of CPHD and suggest that oligogenic contribution of additional inherited variants may modify the phenotypic expressivity of BMP4 pathogenic variants.
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Affiliation(s)
- Francisco J Rodríguez-Contreras
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain.,Department of Pediatrics, Centro de Salud Galapagar, Madrid, Spain
| | | | - Elena Vallespín
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; U753), Instituto de Salud Carlos III, Madrid, Spain
| | - Ángela Del Pozo
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; U753), Instituto de Salud Carlos III, Madrid, Spain
| | - Mario Solís-López
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain
| | - Nerea Lobato-Vidal
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain
| | - María Fernández-Elvira
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain
| | - María Del Valle Rex-Romero
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain
| | - Karen E Heath
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; U753), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Ángel Campos-Barros
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autonóma de Madrid, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; U753), Instituto de Salud Carlos III, Madrid, Spain
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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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