Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

Purpose:CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants.Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed.Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms.Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.

Congenital hypogonadotropic hypogonadism: from clinical characteristics to genetic aspects

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by a deficiency in gonadotropin-releasing hormone (GnRH). CHH is characterized by delayed puberty and/or infertility; this is because GnRH is the main component of the hypothalamic-pituitary-gonadal (HPG) axis, which is a key factor in pubertal development and reproductive function completion. However, since the development of sexual characteristics and reproduction begins in the prenatal period and is very complex and delicate, the clinical characteristics and involved genes are very diverse. In particular, the HPG axis is activated three times in a lifetime, and the symptoms and biochemical findings of CHH vary by period. In addition, related genes also vary according to the formation and activation process of the HPG axis. In this review, the clinical characteristics and treatment of CHH according to HPG axis activation and different developmental periods are reviewed, and the related genes are summarized according to their pathological mechanisms.

The Clinical and Genetic Characteristics of Chinese Male Pediatric Patients with Congenital Hypogonadotropic Hypogonadism

Purpose：Congenital hypogonadotropic hypogonadism (CHH) are invided into Kallmann Syndrome (KS) and normosmic HH(nHH). The clinical and genetic characteristics of CHH are more studied in adults, but less in pre-adults. Methods: Medical records of 126 patients with CHH at our hospital during 2008−2020 were evaluated. Results: Totally, seven patients (5.6%) had hypospadias. Among 49 patients with positive family history, delayed puberty, KS/nHH and olfactory abnormalities accounted for 44.9%, 16.3%, and 12.2%, respectively. Sixty-five patients completed the hCG prolongation test, and T levels of 24 patients were lower than 100 ng/dl. 25 CHH-related genes were found in 78 patients, digenic mutations in 23 patients, and trigenic mutations in 3 patients. The most common pathogenic genes were FGFR1 (21.1%), PROKR2 (17.9%), ANOS1 (12.6%) and CHD7 (12.6%). The oligogenicity rate of common autosomal dominant heredity genes accounted for 50.0% (FGFR1, 10/20) and 33.3% (CHD7, 4/12), of autosomal recessive heredity gene PROKR2 accounted for 47.1% (8/17). And W178S accounted for 58.8% of all mutations in PROKRR2.Conclusion: Micropenis and cryptorchidism are important cues for CHH in pre-adulthood; hypospadias is a rare phenotype of CHH. At least 22.9% of patients tested had testicular Leydig cell dysfunction (dual CHH). Oligogenic mutations were found in 27.4% of all patients with CHH. W178S in PROKRR2 maybe a founder mutation in Chinese CHH crowds.