Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism

2015 ◽  
Author(s):  
Sasha Howard ◽  
Ariel Poliandri ◽  
Helen Storr ◽  
Louise Metherell ◽  
Claudia Cabrera ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism

scholarly journals A Shared Genetic Basis for Self-Limited Delayed Puberty and Idiopathic Hypogonadotropic Hypogonadism

2015 ◽  
Vol 100 (4) ◽  
pp. E646-E654 ◽  
Author(s):  
Jia Zhu ◽  
Ruth E.-Y. Choa ◽  
Michael H. Guo ◽  
Lacey Plummer ◽  
Cassandra Buck ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Shared Genetic

scholarly journals Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism

2005 ◽  
Vol 153 (6) ◽  
pp. 845-852 ◽  
Author(s):  
Fabio Lanfranco ◽  
Jörg Gromoll ◽  
Sigrid von Eckardstein ◽  
Eva M Herding ◽  
Eberhard Nieschlag ◽  
...  
Keyword(s):  
G Protein ◽  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Common Snps ◽  
G Protein Coupled Receptor ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Similar Frequency ◽  
Reading Frame ◽  
Exon 1 ◽  
G Protein Coupled

Objective: To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism (IHH). Methods: In a retrospective study we analyzed the GnRHR and the GPR54 genes of 45 IHH patients and 50 controls. Genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon–intron boundaries of the GnRHR and GPR54 genes and analyzed by single-stranded conformation polymorphism gel electrophoresis and/or DNA sequencing. Results: One heterozygous R262Q mutation of the GnRHR gene was identified in one patient with familial IHH. The silent single-nucleotide polymorphism (SNP) 453C > T occurred at the same frequency in patients and controls. One patient with sporadic IHH and consanguineous parents showed a novel homozygous sequence variation of the GPR54 gene (1001_1002insC) resulting in an open reading frame shift and elongation of 43 amino acids with an increased number of proline residues in the intracellular receptor domain. This patient had delayed puberty, low testosterone (3.4 nmol/l), and low-normal LH and FSH levels responsive to GnRH. Pulsatile GnRH administration normalized testosterone levels and induced spermatogenesis sufficiently to induce a pregnancy with assisted reproduction. Two common SNPs in exon 1 and exon 5 of the GPR54 gene showed similar frequency distribution and hormonal profiles in IHH and controls. Conclusions: Mutations of the GnRHR and of the GPR54 gene are rare in IHH and should be investigated especially in cases with autosomal recessive transmission. Common SNPs of the GnRHR and GPR54 genes do not play any role in IHH.

DLG2 mutations in the etiology of pubertal delay and Idiopathic Hypogonadotropic Hypogonadism

2021 ◽  
Author(s):  
Ihsan Turan ◽  
Korcan Demir ◽  
Eda Mengen ◽  
Leman Damla Kotan ◽  
Fatih Gürbüz ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Allele Frequencies ◽  
The Other ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Pubertal Delay ◽  
Uncertain Significance ◽  
Causal Variants ◽  
Independent Families ◽  
Flanking Regions

Introduction: Idiopathic Hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack proper genotype phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patients variants in a large cohort of IHH patients. Methods: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of the DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. Results: We found one homozygous and two heterozygous missense variants in three independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as “uncertain significance” the other one was “likely pathogenic” according to the ACMG criteria. All patients were normosmic, and in two of the three families there were no causal variants in other IHH-related genes. Conclusion: We detected three rare sequencing variants in DLG2 in five patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

scholarly journals Normosmic idiopathic hypogonadotropic hypogonadism due to a novel GNRH1 variant in two siblings

2020 ◽  
Vol 2020 ◽  
Author(s):  
Satyanarayana V Sagi ◽  
Hareesh Joshi ◽  
Emily Whiles ◽  
Mondy Hikmat ◽  
Vijith R Puthi ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Genetic Disorder ◽  
Hypogonadotropic Hypogonadism ◽  
Clinical Manifestations ◽  
Gonadotropin Releasing Hormone ◽  
Delayed Puberty ◽  
List Type ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Releasing Hormone ◽  
Pathogenic Variants

Summary Hypogonadotropic hypogonadism is characterised by insufficient secretion of pituitary gonadotropins resulting in delayed puberty, anovulation and azoospermia. When hypogonadotropic hypogonadism occurs in the absence of structural or functional lesions of the hypothalamic or pituitary gland, the hypogonadism is defined as idiopathic hypogonadotropic hypogonadism (IHH). This is a rare genetic disorder caused by a defect in the secretion of gonadotropin releasing hormone (GNRH) by the hypothalamus or a defect in the action of GNRH on the pituitary gland. Up to 50% of IHH cases have identifiable pathogenic variants in the currently known genes. Pathogenic variants in the GNRHR gene encoding the GNRH receptor are a relatively common cause of normosmic IHH, but reports of pathogenic variants in GNRH1 encoding GNRH are exceedingly rare. We present a case of two siblings born to consanguineous parents who were found to have normosmic idiopathic hypogonadotropic hypogonadism due to homozygosity of a novel loss-of function variant in GNRH1. Case 1 is a male who presented at the age of 17 years with delayed puberty and under-virilised genitalia. Case 2 is a female who presented at the age of 16 years with delayed puberty and primary amenorrhea. Learning points: IHH is a genetically heterogeneous disorder which can be caused by pathogenic variants affecting proteins involved in the pulsatile gonadotropin-releasing hormone release, action, or both. Currently known genetic defects account for up to 50% of all IHH cases. GNRH1 pathogenic variants are a rare cause of normosmic IHH. IHH is associated with a wide spectrum of clinical manifestations. IHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. Early diagnosis and gonadotrophin therapy can prevent negative physical sequelae and mitigate psychological distress with the restoration of puberty and fertility in affected individuals.

scholarly journals Mutations in HS6ST1 cause self-limited delayed puberty (DP) in addition to idiopathic hypogonadotropic hypogonadism (IHH)

2015 ◽  
Author(s):  
Sasha Howard ◽  
Ariel Poliandre ◽  
Helen L Storr ◽  
Louise A Metherell ◽  
Claudia Cabrera ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Delayed Puberty ◽  
Idiopathic Hypogonadotropic Hypogonadism

scholarly journals A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weiwei Xu ◽  
Weibin Zhou ◽  
Haiyang Lin ◽  
Dan Ye ◽  
Guoping Chen ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Hypogonadotropic Hypogonadism ◽  
Kallmann Syndrome ◽  
Delayed Puberty ◽  
Heterozygous Mutation ◽  
Human Menopausal Gonadotropin ◽  
Z Score ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Contrast Enhanced ◽  
Chd7 Gene

Abstract Background Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5–6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. Case presentation A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score − 3.0) and femoral neck (Z-score − 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient’s health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. Conclusion Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.

A case of idiopathic hypogonadotropic hypogonadism which attained remission by LH and FSH treatment

2013 ◽  
Author(s):  
Yui Watanabe ◽  
Takeshi Hayashi ◽  
Hiroyuki Yamazaki ◽  
Katsuyoshi Tojo ◽  
Kazunori Utsunomiya
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Idiopathic Hypogonadotropic Hypogonadism
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