Kallmann syndrome (KS) is a heterogeneous genetic disorder that associates variable gonadotropin-releasing hormone (GnRH) deficiency with anosmia and, sometimes, other non-reproductive clinical features. X-linked recessive, as well as autosomal recessive and dominant modes of transmission have been described. The first KS-related gene to be described (KAL1) was in the X-linked form. The second gene (KAL2) was initially unexpected, as it was known to encode the fibroblast growth receptor 1 (FGFR1). Its consideration as a candidate gene arose as a result of cases with contiguous gene syndrome and, initially, mutations were mostly described in familial cases with autosomal dominant transmission of KS. Since its initial discovery, numerous mutations of FGFR1 have been described in several functional domains of the receptor. Genotype-phenotype correlations have shown that some clinical features associated with KS, such as loss of nasal cartilage, hearing impairment, and anomalies of the limbs seem to be mainly associated with KAL2 mutations. The role of FGFR1 in the normal development of the olfactory bulb explains the association of anosmia with GnRH deficiency in FGFR1-mutated patients. Phenotype analysis indicates that FGFR1 is involved in normal migration of GnRH fetal neurons, but this is clearly not the whole story as a substantial proportion of KAL2-mutated individuals have normosmic GnRH deficiency. Finally, recent additional observations, notably using animal models, but also the description of human mutations in a specific ligand of FGFR1, FGF8, are beginning to shed light on the pathogenesis of GnRH deficiency in general, not just KS.
Copyright 2010 S. Karger AG, Basel.