Phenotypic Spectrum of Idiopathic Hypogonadotropic Hypogonadism Patients With CHD7 Variants From a Large Chinese Cohort

2019 ◽  
Vol 105 (5) ◽  
pp. 1515-1526
Author(s):  
Jia-Da Li ◽  
Jiayu Wu ◽  
Yaguang Zhao ◽  
Xinying Wang ◽  
Fang Jiang ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Hypogonadotropic Hypogonadism ◽  
Choanal Atresia ◽  
Charge Syndrome ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Phenotypic Spectrum ◽  
Skeletal Defects ◽  
Chinese Cohort ◽  
Heart Abnormalities ◽  
Extended Charge

Abstract Purpose Idiopathic hypogonadotropic hypogonadism (IHH) and CHARGE (C, coloboma; H, heart abnormalities; A, choanal atresia, R, retardation of growth and/or development; G, gonadal defects; E, ear deformities and deafness) syndrome are 2 distinct developmental disorders sharing features of hypogonadism and/or impaired olfaction. CHD7 variants contribute to >60% CHARGE syndrome and ~10% IHH patients. A variety of extended CHARGE-like features are frequently reported in CHARGE patients harboring CHD7 variants. In this study, we aimed to systematically analyze the diagnostic CHARGE features and the extended CHARGE-like features in patients with IHH with CHD7 variants. Methods Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 177 IHH probands. Detailed phenotyping was performed in the IHH patients harboring CHD7 variants and their available family members. Results CHD7 RSVs were identified in 10.2% (18/177) of the IHH probands. Two diagnostic CHARGE features, hearing loss and ear deformities, were significantly enriched in patients with CHD7 variants. Furthermore, CHD7 variants were significantly associated with a panel of extended CHARGE-like phenotypes, including mild ocular defects, dyspepsia/gastroesophageal reflux disease and skeletal defects. We also developed a predictive model for prioritizing CHD7 genetic testing in IHH patients. Conclusion CHD7 variants rarely cause isolated IHH. Surveillance of symptoms in CHARGE syndrome-affected organs will facilitate the proper treatment for these patients. Certain clinical features can be useful for prioritizing CHD7 genetic screening.

scholarly journals Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

2022 ◽  
Author(s):  
Ja Hye Kim ◽  
Yunha Choi ◽  
Soojin Hwang ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo ◽  
...  
Keyword(s):  
Short Stature ◽  
Hypogonadotropic Hypogonadism ◽  
Charge Syndrome ◽  
Large Deletion ◽  
Hormone Deficiency ◽  
Delayed Puberty ◽  
Unilateral Deafness ◽  
Phenotypic Spectrum ◽  
Ear Anomalies ◽  
Spectrum Of Patients

Objective: Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. Methods: The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. Results: Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining 11 patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and one patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). Conclusions: A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient’s quality of life.

scholarly journals Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

Endocrines ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 1-15
Author(s):  
Ali Kemal Topaloglu ◽  
Ihsan Turan
Keyword(s):  
Developmental Disorders ◽  
Hypogonadotropic Hypogonadism ◽  
Gene Mutations ◽  
Clinical Diagnostics ◽  
Sex Steroid ◽  
Genetic Etiology ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Sex Steroid Hormone ◽  
Sense Of Smell ◽  
The Face

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

scholarly journals Olfactory Phenotypic Spectrum in Idiopathic Hypogonadotropic Hypogonadism: Pathophysiological and Genetic Implications

2012 ◽  
Vol 97 (1) ◽  
pp. E136-E144 ◽  
Author(s):  
Hilana M. Lewkowitz-Shpuntoff ◽  
Virginia A. Hughes ◽  
Lacey Plummer ◽  
Margaret G. Au ◽  
Richard L. Doty ◽  
...  
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Idiopathic Hypogonadotropic Hypogonadism ◽  
Phenotypic Spectrum

scholarly journals Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism

2020 ◽  
Vol 183 (3) ◽  
pp. 245-254
Author(s):  
Qiao Hou ◽  
Jiayu Wu ◽  
Yaguang Zhao ◽  
Xinying Wang ◽  
Fang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Segregation Analysis ◽  
Hypogonadotropic Hypogonadism ◽  
Sex Steroid ◽  
Phenotypic Spectrum ◽  
Congenital Hypogonadotropic Hypogonadism ◽  
Whole Exome ◽  
Chinese Cohort

Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

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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