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

Abstract 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.