Studies on an Italian Series of Idiopathic Central Hypogonadism : Genetic and Clinical Characterization

Idiopathic central hypogonadism (ICH) is a rare and heterogeneous condition due to defects of GnRH secretion or action. Depending on the association with a normal or defective sense of smell, ICH could be respectively identified as normosmic ICH (nICH) or Kallmann’s syndrome (KS). Novel perspectives in the aetiology of the disease have been opened by very recent molecular studies and animal models, in addition to the numerous causative genetic defects already described. We are studying a series of 16 KS (14M,2F) and 18 nICH (14M,4F). All patients showed normal karyotype, low/normal levels of gonadotropins in the presence of low circulating testosterone or estrogens, impaired LH/FSH increase after GnRH stimulation test. Only one case is familiar, while all other appear as sporadic. Bimanual synkinesia was documented in 4 KS males and cleft lip/palate in one. Hypoplastic pituitary gland and an incidental non-secreting pituitary microadenoma were observed at the MRI respectively in 1 nICH and 1 KS. All KS patients presented anosmia at the olfactory test associated with hypoplastic olfactory structures at the MRI. Genetic analyses were performed by directed automatic sequencing of circulating leukocyte DNA. FGFR1, PROK2, PROKR2 genes were examined in all cases whereas GnRHR and GPR54 gene analysis was limited to nICH. The coding sequences of GnRHR and GPR54 showed no abnormalities. Two novel mutations of PROKR2 (V158I, V334M) and one of PROK2 (G62D) gene were found in 1 nICH female, 1 KS male patients and 1 nICH male patient, respectively. The analysis of FGFR1 gene showed results of particular interest. The mutation D200E was found in two unrelated patients discordant for osmic function and bimanual synkynesia. The mutation F210X was instead found in 1 nICH male patient that did not undergo puberty. This patient had a brother also affected with nICH and absent pubertal development that was found to carry the same mutation. This mutation was therefore inherited from one of the parents who had had a normal puberty and was still unaffected at an age beyond 30 years. These variations are present in the heterozygous state in the patients according to the reported mechanism of haplo-insufficiency. The variable neurological phenotype (osmic function and bimanual synkynesia) associated with the same FGFR1 mutation and the highly variable ICH penetrance in our family represents additional arguments in favour of a multiple genetic origin of these defects