Novel Mutations in FGFR1 Causing Idiopathic Hypogonadotropic Hypogonadism: A Cohort Study in Eastern Indian Population

Introduction: IHH is a clinically and genetically heterogeneous condition with more than 80 different mutations described in literature, some of the important being KAL-1 (anosmin), fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor-8 (FGF8). Objective: To characterize the clinical findings and molecular analysis of FGFR1 (KAL2) genes in 10 unrelated patients of idiopathic hypogonadotropic hypogonadism with and without hyposmia/anosmia. Methods: After confirming the diagnosis of IHH from detailed history, clinical and biochemical examination the patients were subjected to MRI of pituitary hypothalamic area and olfactory bulb and tract. For genetic analysis PCR of 18 exons was performed on the genomic DNA. The PCR products were purified, sequenced and analysed using BLAST search from NCBI GenBank. Results: We diagnosed ten unrelated sporadic cases of IHH (9 male and 1 female). Out of 10 cases 6 (60%) had anosmia (KS) 4 had normosmia. A variable degree of pubertal development was observed, including various clinical abnormalities, such as micropenis, dental agenesis, skeletal deformity, seizure disorder and bimanual synkinesis. All the patients who had anosmia (KS) had either hypoplasia or aplasia of olfactory bulb and tract on MRI. Two KS patients had novel sporadic FGFR1 mutation, one had a mutation n.2370 C>A detected at exon 10 of FGFR1 gene and another had a mutation n.1875 GA>CA at exon 8C of FGFR1 gene. Discussion: Loss-of-function sequence variants in FGFR1, encoding the fibroblast growth factor receptor-1, account for one autosomal dominant form of KS. Pathogenic changes in KAL1 or FGFR1 have been detected in approximately 20% of the KS patients, which indicates that other responsible genes are still to be discovered. FGFR1 comprises an extracellular region consisting of three immunoglobulin-like domains (D1-D3), a single transmembrane helix, and an intracellular region containing the tyrosine kinase domain. D2, D3 and the short linker between them house all the determinants of ligand (FGF) binding and specificity. In addition, alternative splicing of exon 8, encoding the D3 C-terminal half, leads to two FGFR1 isoforms, FGFR1b (exon 8A) and FGFR1c (exon 8B), with different specificities towards FGF ligands. All the pathogenic changes in FGFR1 that have been reported in KS so far disrupt both isoforms of FGFR1 i.e. FGF1b and FGF1c, therefore leaving open the question of which isoform(s) is (are) required in the olfactory bulb morphogenetic process. We identified a new mutation in exon 8C (patient no 2). Conclusions: IHH and KS patients present with broad spectrum of clinical manifestations. We identified two novel mutations in FGFR1 gene in two unrelated sporadic cases of KS in the Indian population.