Kallmann syndrome (KS) is defined by the combination of isolated hypogonadotrophic hypogonadism (IHH) and anosmia, with renal agenesis occurring in 30% of KS cases with KAL1 gene mutations.
Anosmin-1, the KAL-1 gene product underlying X-linked KS, modulates FGFR1 signalling via regulation of FGF2/FGFR1/heparin signalling complex assembly and activity.
A defective anosmin-1 molecule may also play a role in the development of synkinesia and renal agenesis, which are exclusively seen in the X-linked form of KS.
Loss-of-function mutations of the KAL1 gene are a known cause of Kallmann syndrome, a disorder characterized by the coexistence of hypogonadotropic hypogonadism and anosmia/hiposmia.
Although loss-of-function mutations of the KAL1 gene is associated with the X-linked form of KS, the reproductive capacity remains unidentified in patients with KS with KAL1 gene mutations.
The frequency of Kallmann syndrome (hypogonadotropic hypogonadism and anosmia, HHA) was estimated in patients presenting with hypogonadism and patients with anosmia.Of 791 hypogonadal males 19 had HHA.
Two KS-related loci are currently known: KAL1, encoding anosmin-1, responsible for X-linked KS, and KAL2, encoding the fibroblast growth factor receptor 1 (FGFR1), mutated in autosomal dominant KS.
This low prevalence of KAL1 mutations indicates that other genes, such as the fibroblast growth factor receptor 1 (FGFR1) gene or other as yet undiscovered genes, epigenetic events and/or environmental factors might be involved in the aetiology and phenotypic variability of KS.
The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic KS, providing evidence for the X-linked mode of inheritance and offering the opportunity for genetic counseling.
The phenotype of renal agenesis/dysgenesis strongly indicates the existence of KAL1 gene defects in the genotype of patients with sporadic KS, providing evidence for the X-linked mode of inheritance and offering the opportunity for genetic counseling.
Mutations in KAL1 and FGFR1 cause Kallmann syndrome (KS), whereas mutations in the GNRHR and GPR54 genes cause idiopathic hypogonadotropic hypogonadism with normal olfaction (nIHH).
Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.