Introduction: Hypogonadotrophic hypogonadism (HH) is a genetically heterogeneous disorder. A number of genes have been implicated in its pathogenesis but, to date, in most cases, the cause remains genetically unknown.
Case: A 14-year old male with delayed puberty (G1P2A3, testes two males) and family history of HH was diagnosed with HH following anterior pituitary assessment and an overnight gonadotrophin profile. His baseline gonadotrophins were low (LH, 0.4 IU/l; FSH, 0.2I U/l) with minimal elevation after stimulation with LHRH (LH peak at 60 min, 0.9 IU/l and FSH 0.4 IU/l). His LH on the profile ranged from 0.31.5 IU/l (mean 0.65 IU/l) with only two peaks above 1 IU/l. Pituitary MRI and renal ultrasound scan were unremarkable. After a year of testosterone replacement, his genital and pubic hair development reached stage 3 with testes of six males. He underwent an overnight gonadotrophin profile following stimulation with LHRH. After stimulation, the LH (6.5 IU/l) and FSH (6.4 IU/l) peaks both declined overnight to 0.5 and 2.9 IU/l respectively (mean LH, 3.5 IU/L; mean FSH, 4.65 IU/l), but rose higher after priming to a further LHRH stimulus the following morning (LH, 11.5 and 13.5 IU/l; FSH, 3.5 and 4.9 IU/l at 20 and 60 min respectively), suggesting prolonged hypothalamic LHRH deficiency and intact pituitary gonadotrophins. Screening for mutations in KAL1, FGFR1, FGF8, PROK2, and PROKR2 revealed a maternally inherited mutation in FGFR1 (G687R) previously described in association with both Kallmann syndrome and isolated HH. His mother suffered from HH and had conceived the proband after 10 years of GnRH therapy. No history of anosmia was reported. Our patient continued on testosterone replacement and is now fully masculinised at 16.3 years but with five males testes.
Conclusion: FGFR1 is implicated in GnRH ontogeny and action. This case report illustrates the autosomal dominant hypothalamic GnRH dysfunction potentially ameliorable with GnRH therapy, that is associated with the FGFR1 (G687R) mutation.
09 - 11 Nov 2011
British Society for Paediatric Endocrinology and Diabetes