大样本低促性腺激素性腺功能减退患者的临床及分子特点

Objective: To characterize the phenotype,modes of inheritance, karyotype, and molecular basis of patients with idiopathic hypogonadotropic hypogonadism(IHH).Design: Review of medical records, karyotyping, and collation of gene mutation analysis. Setting: University 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 hypogonadismis 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.

促性腺激素功能减退性性腺功能低下患者中促性腺激素释放激素受体基因突变率的大规模队列研究

Objective: To determine the prevalence of GNRH receptor (GNRHR) gene mutations in a large cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH). Design: Molecular analysis and genotype/phenotype correlations. Setting: University molecular reproductive endocrinology laboratory. Patient(s): North American and Turkish patients with IHH. Intervention(s): DNA from 185 IHH patients were subjected to denaturing gradient gel electrophoresis for exons and splice junctions of the GNRHR gene. Variant fragments were sequenced. Main Outcome Measure(s): GNRHR mutations were characterized and compared with the phenotype. The prevalence of GNRHR mutations was also determined. Result(s): Three of 185 (1.6%; confidence interval [CI] 0.3%-4.7%) total IHH patients demonstrated compound heterozygous GNRHR mutations. All three were identified from a cohort of 85 normosmic patients (3.5%, CI 0.73%-7.5%), and none were demonstrated in hyposmic or anosmic IHH patients. GNRHR mutations were identified in 1 of 15 (6.7%; CI 0.2%-32.0%)-families with at least two affected siblings, and in 2 of 18 (11.1%; CI 1.4%-34.7%) normosmic females. None were found in presumably autosomal dominant families. Conclusion(s): GNRHR mutations account for approximately 3.5%of all normosmic and 7%-11%of presumed autosomal recessive IHH, suggesting that additional genes play an important role in normal puberty. We believe this to be the largest GNRHR gene mutation analysis performed to date in a population of IHH patients.