Identification of two compound heterozygous GNRHR mutations in two siblings with congenital hypogonadotropic hypogonadism

Dear Editor, Congenital hypogonadotropic hypogonadism(CHH)is a rare genetic disease characterized by gonadotropin-releasing hormone(GnRH)deficiency or insufficiency and normal hypothalamic-pituitary structures,resulting in defective sexual maturation or/and infertility.1 CHH presents as a variety of nonreproductive phenotypes,such as renal hypoplasia,dental hypoplasia,or oculomotor abnormalities.Most pubertal patients exhibit delayed puberty and the underdevelopment of secondary sexual characteristics.2 GnRH therapy is widely used for the treatment of male CHH patients.2 However,a small proportion of these patients show an atypical response to GnRH treatment,with abnormal hormone levels,a lack of spermatogenic activity,or persistently small testicular volume.Insensitivity to GnRH treatment may be attributed to GnRH receptor gene(GNRHR)mutations that negatively affect the response to GnRH therapy.3 However,this hypothesis has not been fully verified in clinical samples.In this study,we identified compound heterozygous mutations of GNRHR in a Chinese family featuring two CHH patients.Subsequently,we enrolled three male CHH patients who did not carry variants of GNRHR or DSS-AHC critical region on the X chromosome 1,gene 1(DAX1),and performed GnRH stimulation tests to investigate whether GNRHR mutations affect the sensitivity of male CHH patients to GnRH treatment.