FGF8 – Kallmann syndrome

Heterozygous loss-of-function variants in FGF8 have been implicated in autosomal dominant Kallmann syndrome, characterized by hypogonadotropic hypogonadism and anosmia. Initial case reports described two unrelated IHH probands with nonsense mutations (c.379C>T (p.Arg127Ter) and c.385C>T (p.Arg129Ter)) absent from controls, confirming FGF8 as a novel GnRH deficiency locus (PMID:20463092).

In the p.Arg127Ter kindred, the index 18-year-old female with anosmia and delayed puberty carried the variant along with four affected siblings presenting variable normosmic IHH or delayed puberty, demonstrating segregation in five individuals across one family ([PMID:20463092]). These data, together with six additional heterozygous missense mutations identified in six sporadic probands with variable olfactory phenotypes, establish a mutation spectrum of nonsense and missense alleles in FGF8.

Functional assays of mutant FGF8 isoforms revealed significantly reduced ligand activity in vitro, while mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons and heterozygotes showed a 50–80% reduction in GnRH neuronal number and peptide levels, directly modeling the human phenotype (PMID:18596921). These concordant in vitro and in vivo findings support haploinsufficiency as the primary pathogenic mechanism.

No studies have refuted the association, and variant penetrance is incomplete, reflecting variable expressivity. While additional digenic interactions have been reported for other FGFR pathway genes, FGF8 variants alone are sufficient to cause Kallmann syndrome.

In summary, FGF8 haploinsufficiency causes human GnRH deficiency with or without anosmia, supported by segregation, multiple unrelated probands, and robust animal and biochemical models. FGF8 should be included in diagnostic gene panels for Kallmann syndrome to guide genetic counseling and management.

References

• The Journal of clinical endocrinology and metabolism • 2010 • Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. PMID:20463092
• The Journal of clinical investigation • 2008 • Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. PMID:18596921

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