scholarly journals Pituitary stalk interruption syndrome is characterized by genetic heterogeneity

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0242358
Author(s):  
Raja Brauner ◽  
Joelle Bignon-Topalovic ◽  
Anu Bashamboo ◽  
Ken McElreavey
Keyword(s):  
Genetic Heterogeneity ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Pituitary Stalk ◽  
Specific Gene ◽  
Genetic Syndromes ◽  
Pituitary Development ◽  
Pediatric Endocrinologist ◽  
Novel Variants ◽  
Pituitary Hypoplasia

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.

scholarly journals Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes

2013 ◽  
Vol 98 (4) ◽  
pp. E779-E784 ◽  
Author(s):  
Christina Tatsi ◽  
Amalia Sertedaki ◽  
Antonis Voutetakis ◽  
Eleni Valavani ◽  
Maria-Alexandra Magiakou ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Gene Mutations ◽  
Pituitary Stalk ◽  
Hormone Deficiency ◽  
Molecular Defect ◽  
Pituitary Hormone ◽  
Developmental Defect ◽  
Central Incisor ◽  
Related Gene ◽  
Pituitary Hypoplasia

Context: Holoprosencephaly (HPE) is a developmental defect characterized by wide phenotypic variability, ranging from minor midline malformations (eg, single central incisor) to severe deformities. In 10–15% of HPE patients, mutations in specific genes have been identified (eg, SHH, TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a distinct abnormality of unknown pathogenesis, whereas isolated pituitary hypoplasia (IPH) has been linked to various developmental genes. Objective: Three of our patients with PSIS had a single central incisor, a malformation encountered in some HPE cases. Based on this observation, we initiated a search for mutations in HPE-associated genes in 30 patients with PSIS or IPH. Design and Participants: The entire coding region of the TGIF, SHH, and SIX3 genes was sequenced in patients with combined pituitary hormone deficiency associated with either PSIS or IPH and in healthy controls. Results: Two novel mutations in the HPE-related genes were detected (ie, c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH gene) in 2 of our patients. The overall incidence of HPE-related gene mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No molecular defect in the SIX3 gene was detected in our cohort. Conclusions: The data suggest that HPE-related gene mutations are implicated in the etiology of isolated pituitary defects (PSIS or IPH). Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE spectrum.

Familial ROBO1 deletion associated with ectopic posterior pituitary, duplication of the pituitary stalk and anterior pituitary hypoplasia

2019 ◽  
Vol 32 (1) ◽  
pp. 95-99
Author(s):  
Marcello Scala ◽  
Andrea Accogli ◽  
Anna Maria Elsa Allegri ◽  
Elisa Tassano ◽  
Mariasavina Severino ◽  
...  
Keyword(s):  
Anterior Pituitary ◽  
Pituitary Stalk ◽  
Comparative Genomic ◽  
Posterior Pituitary ◽  
Loss Of Function ◽  
Human Pituitary ◽  
Developmental Abnormalities ◽  
Pituitary Development ◽  
Pituitary Hypoplasia ◽  
Ectopic Posterior Pituitary

Abstract Background The genetic causes of abnormal pituitary development have been extensively studied in the last few years. ROBO1 is involved in neurogenesis and axon guidance. Loss-of-function variants in ROBO1 have been associated with pituitary stalk interruption syndrome (PSIS), suggesting that its haploinsufficiency could impair the guidance of hypothalamic axons to the pituitary gland leading to developmental abnormalities. Case presentation We report a 4.5-year-old girl with anterior pituitary hypoplasia and pituitary stalk duplication in the ventral-dorsal direction. Her father had a similar pituitary phenotype, characterized by anterior pituitary hypoplasia combined with ectopic posterior pituitary. Comparative genomic hybridization (CGH) microarray analysis identified a 343.7 kb deletion of 3p12.3 encompassing ROBO1 in both individuals. Conclusions We report the first familial ROBO1 deletion in two individuals with peculiar pituitary anomalies, including the rare pituitary stalk duplication in the ventral-dorsal direction. These findings widen the spectrum of the phenotypes associated with ROBO1 haploinsufficiency and support its role in human pituitary development.

scholarly journals The identification of novel gene mutations for degenerative lumbar spinal stenosis using whole-exome sequencing in a Chinese cohort

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xin Jiang ◽  
Dong Chen
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Spinal Stenosis ◽  
Lumbar Spinal Stenosis ◽  
Gene Mutations ◽  
Specific Gene ◽  
Single Nucleotide ◽  
Degenerative Lumbar Spinal Stenosis ◽  
Whole Exome ◽  
Lumbar Spinal

Abstract Background Degenerative lumbar spinal stenosis (DLSS) is a common lumbar disease that requires surgery. Previous studies have indicated that genetic mutations are implicated in DLSS. However, studies on specific gene mutations are scarce. Whole-exome sequencing (WES) is a valuable research tool that identifies disease-causing genes and could become an effective strategy to investigate DLSS pathogenesis. Methods From January 2016 to December 2017, we recruited 50 unrelated patients with symptoms consistent with DLSS and 25 unrelated healthy controls. We conducted WES and exome data analysis to identify susceptible genes. Allele mutations firstly identified potential DLSS variants in controls to the patients’ group. We conducted a site-based association analysis to identify pathogenic variants using PolyPhen2, SIFT, Mutation Taster, Combined Annotation Dependent Depletion, and Phenolyzer algorithms. Potential variants were further confirmed using manual curation and validated using Sanger sequencing. Results In this cohort, the major classification variant was missense_mutation, the major variant type was single nucleotide polymorphism (SNP), and the major single nucleotide variation was C > T. Multiple SNPs in 34 genes were identified when filtered allele mutations in controls to retain only patient mutations. Pathway enrichment analyses revealed that mutated genes were mainly enriched for immune response-related signaling pathways. Using the Novegene database, site-based associations revealed several novel variants, including HLA-DRB1, PARK2, ACTR8, AOAH, BCORL1, MKRN2, NRG4, NUP205 genes, etc., were DLSS related. Conclusions Our study revealed that deleterious mutations in several genes might contribute to DLSS etiology. By screening and confirming susceptibility genes using WES, we provided more information on disease pathogenesis. Further WES studies incorporating larger DLSS patient cohorts are required to comprehend the genetic landscape of DLSS pathophysiology fully.

scholarly journals NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Satoshi Tamaoka ◽  
Erina Suzuki ◽  
Atsushi Hattori ◽  
Tsutomu Ogata ◽  
Maki Fukami ◽  
...  
Keyword(s):  
Splice Site ◽  
Genetic Heterogeneity ◽  
Hypogonadotropic Hypogonadism ◽  
Causative Gene ◽  
Synonymous Substitutions ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Site Recognition

AbstractAlthough NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.

scholarly journals Occult Langerhans Cell Histiocytosis Presenting with Papillary Thyroid Carcinoma, a Thickened Pituitary Stalk and Diabetes Insipidus

2016 ◽  
Vol 2016 ◽  
pp. 1-3 ◽  
Author(s):  
Michael S. Gordon ◽  
Murray B. Gordon
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Diabetes Insipidus ◽  
Langerhans Cell Histiocytosis ◽  
Hypogonadotropic Hypogonadism ◽  
Langerhans Cell ◽  
Pituitary Stalk ◽  
Bright Spot ◽  
Molecular Testing ◽  
Papillary Thyroid

Etiologies of a thickened stalk include inflammatory, neoplastic, and idiopathic origins, and the underlying diagnosis may remain occult. We report a patient with a thickened pituitary stalk (TPS) and papillary thyroid carcinoma (PTC) whose diagnosis remained obscure until a skin lesion appeared. The patient presented with PTC, status postthyroidectomy, and I131therapy. PTC molecular testing revealed BRAF mutant (V600E, GTC>GAG). She had a 5-year history of polyuria/polydipsia. Overnight dehydration study confirmed diabetes insipidus (DI). MRI revealed TPS with loss of the posterior pituitary bright spot. Evaluation showed hypogonadotropic hypogonadism and low IGF-1. Chest X-ray and ACE levels were normal. Radiographs to evaluate for extrapituitary sites of Langerhans Cell Histiocytosis (LCH) were unremarkable. Germinoma studies were negative: normal serum and CSF beta-hCG, alpha-fetoprotein, and CEA. Three years later, the patient developed vulvar labial lesions followed by inguinal region skin lesions, biopsy of which revealed LCH. Reanalysis of thyroid pathology was consistent with concurrent LCH, PTC, and Hashimoto’s thyroiditis within the thyroid. This case illustrates that one must be vigilant for extrapituitary manifestations of systemic diseases to diagnose the etiology of TPS. An activating mutation of the protooncogene BRAF is a potential unifying etiology of both PTC and LCH.

scholarly journals Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism

2012 ◽  
Vol 4 (3) ◽  
pp. 121-126 ◽  
Author(s):  
Fatih Gürbüz ◽  
L. Damla Kotan ◽  
Eda Mengen ◽  
Zeynep Şıklar ◽  
Merih Berberoğlu ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Idiopathic Hypogonadotropic Hypogonadism

scholarly journals Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

2017 ◽  
Vol 114 (37) ◽  
pp. E7697-E7706 ◽  
Author(s):  
Kiyotoshi Satoh ◽  
Shinichi Yachida ◽  
Masahiro Sugimoto ◽  
Minoru Oshima ◽  
Toshitaka Nakagawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Gene Mutations ◽  
Metabolic Reprogramming ◽  
Colorectal Carcinogenesis ◽  
Specific Gene ◽  
Control Mechanisms ◽  
Pyrimidine Synthesis ◽  
Expression Of Genes

Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.

scholarly journals Characteristics of the mutation spectrum identified by comprehensive investigation of the CFTR gene in the Russian patients

2019 ◽  
Vol 47 (1) ◽  
pp. 38-46
Author(s):  
N. V. Petrova ◽  
A. Yu. Marakhonov ◽  
T. A. Vasilyeva ◽  
N. Yu. Kashirskaya ◽  
E. I. Kondratyeva ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Hereditary Disease ◽  
Mutation Spectrum ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Sequencing Method ◽  
Novel Variants ◽  
Frequent Mutations ◽  
Large Rearrangements

Rationale: Cystic fibrosis (CF; OMIM 219700) is a  common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11%  alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88  more variants were determined, including 28  missense mutations, 15  nonsense mutations, 18 frameshift mutations (14 deletions, 4  insertions), 14  splicing mutations, 1  in-frame insertion, 1  in-frame deletion, 1  in/del mutation, and 10  large rearrangements (7  deletions, 3  duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, > 99%), to detect a  significant diversity of the CFTR mutation spectrum (88  additional variants, 32  of them novel), a  number of repeated mutations (c.2353C>T, c.1240_1244delCAAAA, c.1766+1G>A and c.3929G>A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene. 

Idiopathic hypogonadotropic hypogonadism: a rare cause of primary amenorrhoea in adolescence—a review and update on diagnosis, management and advances in genetic understanding.

2021 ◽  
Vol 14 (4) ◽  
pp. e239495
Author(s):  
Grace Cham ◽  
Brooke O'Brien ◽  
Rebecca MN Kimble
Keyword(s):  
Genetic Disorders ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Serum Levels ◽  
Breast Development ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Primary Amenorrhoea ◽  
Normal Menstrual Cycle ◽  
Uterine Growth

Idiopathic hypogonadotropic hypogonadism (IHH) refers to a family of genetic disorders that affect the production and/or action of gonadotropic-releasing hormone, resulting in reduced serum levels of sex steroids. This condition has a prevalence of 1–10 cases/100 000 births and is characterised by the absence of spontaneous pubertal development. In women, the condition is characterised by the onset of normal adrenarche, with the absence of thelarche and menarche. Pubertal induction for breast development and uterine growth with oestradiol, and sequential maintenance of a normal menstrual cycle and adequate oestrogen for bone health, with an oestrogen and progesterone, is considered first-line treatment. Pregnancy can be achieved in patients who have received and responded to treatment with ovulation induction with exogenous gonadotrophins. Advances in genetic testing have led to increased research and understanding of the underlying genetics of IHH with gene mutations described in up to 50% of all IHH cases.

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