Clinical and molecular characterization of a large sample of patients with hypogonadotropic hypogonadism

ObjectiveTo characterize the phenotype, modes of inheritance, karyotype, and molecular basis of patients with idiopathic hypogonadotropic hypogonadism (IHH).DesignReview of medical records, karyotyping, and collation of gene mutation analysis.SettingUniversity molecular reproductive endocrinology laboratory.Patient(s)Patients with IHH.Intervention(s)Review of medical records, laboratory studies, and molecular studies.Main Outcome Measure(s)Sense of smell, severity of IHH (complete vs. incomplete), associated anomalies, karyotype, mutation analysis, and genotype/phenotype correlations were studied.Result(s)Of 315 patients with IHH, 6.3% had one or more affected relatives. Autosomal recessive inheritance was likely in most of these familial cases, but autosomal-dominant and X-linked recessive inheritance patterns were likely in some families. Complete IHH was more commonly found in males (62%), whereas incomplete IHH was more commonly observed in females (54.3%). Anosmia was present in 31.3% of males and 27.9% of females. The karyotype was normal in all 19 females tested, but was abnormal in 3 of 57 (5.3%) of males tested. Although cryptorchidism did not differ among those who were anosmic vs. normosmic, it was approximately four times more common in patients with complete IHH than incomplete IHH (15.3% vs. 3.9%). Approximately 10% of the IHH patients tested had mutations in either the GNRHR or KAL1 gene.Conclusion(s)Idiopathic hypogonadotropic hypogonadism is a heterogeneous disorder affecting fertility, in which the number of familial cases is probably underestimated. Further study of genes that regulate hypothalamic-pituitary development and function will likely reveal important information regarding the development of normal puberty in humans.