Loss-of-function mutations in FGF8 in humans have been associated with Kallmann syndrome (KS), which is characterised by the combination of hypogonadotrophic hypogonadism with anosmia, suggesting that FGF8 is critical for GnRH neuronal development. Interestingly, hypomorphic Fgf8 mutant mice demonstrate poor telencephalic development with deletions of midbrain tissue, absence of olfactory bulbs and optic chiasm, and holoprosencephaly (HPE) with an abnormal corpus callosum; thus it appears that FGF8 is important for forebrain development, but its role in hypothalamo-pituitary (HP) development remains to be determined. We aimed to investigate the role of FGF8 in the formation of midline forebrain, HP and craniofacial development in mouse and human.
Patients with congenital hypopituitarism and midline forebrain/craniofacial defects (n=421) were screened for FGF8 mutations. Two novel missense mutations were identified: i) homozygous p.R189H and ii) heterozygous p.Q216E. The p.R189H mutation was identified in a female patient with semi-lobar HPE, diabetes insipidus and ACTH insufficiency born to consanguineous parents. The p.Q216E mutation was identified in a female patient with an absent corpus callosum, hypoplastic optic nerves and Moebius syndrome. In situ hybridization revealed FGF8 expression in human embryonic ventral diencephalon and anterior forebrain but not in Rathkes pouch, which parallels known patterning in mice. Additionally, hypomorphic mice showed a reduction in vasopressin and oxytocin, with small/hyperplastic anterior pituitary glands and absent posterior pituitary glands in the most severely affected mice.
To conclude, we demonstrate the first recessive case of HPE associated with a mutation in FGF8, a condition previously associated with heterozygous mutations in SIX3, TGIF and the Sonic Hedgehog signalling pathway. We have shown that Fgf8/FGF8 appears to be important for forebrain and HP development in mouse and human, with overlapping phenotypes between KS and complex midline defects with hypopituitarism. Furthermore, this is the first report to implicate FGF8 mutations in Moebius syndrome.