Kallmann syndrome is an inherited disorder characterized by the association of hypogonadotropic hypogonadism, due to gonadotropin-releasing hormone (GnRH) deficiency, with inability to smell (anosmia). These symptoms are the result of a defect in migration and targeting of two specific neuronal subpopulations, the GnRH producing neurons and the olfactory neurons.
Autosomal dominant (MIM 147950), autosomal recessive (MIM 244200), and X-linked recessive inheritance patterns have been described in Kallmann syndrome, indicating the presence of genetic heterogeneity. Deletion mapping and positional cloning efforts in the distal short arm of the X chromosome (Xp22.3) led to the isolation of the gene involved in the X-linked type of Kallmann syndrome (Kallmann syndrome protein or gene symbol, respectively (KAL)) (MIM 308700). Patients with Kallmann syndrome who carry deletions in the Xp22.3 region may have contiguous gene syndromes and may, therefore, display the phenotype of several X-linked disorders associated with Kallmann syndrome.
In addition to deletions, several point mutations in the KAL gene have been identified in patients with isolated Kallmann syndrome.
The KAL gene encodes a secreted protein of 680 amino acids that shares significant similarities with protease inhibitors and neural-cell adhesion molecules (cDNA GenBank M97252).
The characterization of KAL spatiotemporal expression pattern in human and chick embryos has provided important clues to the understanding of Kallmann syndrome pathogenesis. Within the olfactory system, the gene is expressed by the olfactory bulb, which represents the target of the olfactory axons.
It appears likely that the primary defect in Kallmann syndrome is an abnormality of olfactory system development affecting axonal targeting and/or synaptogenesis.