Molecular Genetic Analysis and Endocriological Evaluation of Isolated Hypogonadotropic Hypogonadism Presented with Delayed Puberty / 대한소아내분비학회지

ABSTRACT

PURPOSE: Isolated hypogonadotropic hypogonadism (HH) is a disorder of the hypothalamic-pituitary axis causing gonadotrophin releasing hormone or gonadotrophin deficiency. Kallman syndrome has a constellation of features, characterized by HH, hyposomia, deafness and congenital heart defects, whereas a normal sense of smell indicates idiopathic HH. Defects in some genes such as KAL-1, FGFR1, GNRHR and GPR54, have been described. The study was undertaken to identify the molecular defects of aforementioned genes and to evaluate clinical profiles in patients with HH. METHODS: Among the patients who visited the hospital due to delayed puberty from March 1995 to March 2006, seven male patients were suspected of having HH and included in this study. Clinical characteristics at diagnosis and endocrinological data including gonadotropin-releasing hormone (GnRH) agonist stimulation test were investigated. For molecular genetic evaluation, routine karyotyping in all patients and mutation analyses of the KAL, FGFR-1, GNRHR and GPR54 genes in six patients were performed. RESULTS: The study included 7 patients diagnosed as HH by GnRH stimulation; 4 with Kallman syndrome and 3 with idiopathic HH. No mutation was identified by DNA sequence analysis of KAL-1, FGFR1, GNRHR and GPR54 genes in 7 patients with HH. At diagnosis, chronologic age was 16.88+/-.90 years; height SDS, -0.36+/-.43; mean volume of the testis, 1.79+/-.76 mL. Of the patients with Kallman syndrome, 3 had sensory neural hearing loss, 2 congenital heart disease and 1 bilateral cryptorchidism. The olfactory bulb or sulci hypoplasia was found in all Kallman syndrome patients on the brain MRI. No abnormal finding was found in the brain MRI of the patients with idiopathic HH. Peak LH and FSH levels were 1.27+/-.60 IU/L and 1.15+/-.65 IU/L after GnRH stimulation. Baseline total testosterone level was 0.41+/-.24 ng/mL. The patients were treated with testosterone enanthate every 3-4 weeks for the mean duration of 40.60+/-8.61 months. During the follow-up period, 5 patients reached the final adult height with the mean height of 175.00+/-.47 cm (0.28+/-.14 SDS). CONCLUSION: For differential diagnosis of delayed puberty, physical, radiological, hormonal evaluations are all necessary. Many genes associated with Isolated HH were founded until now. But, mutations in these genes account for small proportion of Isolated HH yet. Further study of genes that regulate secondary sexual development and function will give important information regarding the development of normal puberty in humans.