In 1944 Kallmann et al. reported several families in which men had CHH and anosmia, suggesting an X-linked trait. The discovery that CHH can be due to mutations of the KAL-1 gene, and its localization to the short arm of the X chromosome, provided an explanation for the male predominance of this disorder, and initiated extensive investigation into how GnRH secretion is linked to olfaction, a critical sense for reproductive success among lower animals. KAL-1 encodes a protein, anosmin, which shares homology with other proteins involved in axon path-finding and neuron migration. It is now known that GnRH neurons, uniquely among hypophysiotropic neurons, originate with olfactory epithelium outside of the brain, and migrate to arrive to their hypothalamic location during fetal development, and that this process fails to occur normally in Kalmann syndrome patients. Anosmin is thought to play a role in neuronal migration and in the development of the olfactory structures; hence the connection between anosmia and CHH. Many mutations of KALl-1 have been identified, with most mutations in exons 5–14 which encode four fibronectin III domains. These regions of the molecule have heparin sulfate (HS)-binding affinity and are present in a number of adhesion proteins that are involved in cell–cell or cell–matrix interaction. KAL-1 transcripts are found not only in the developing olfactory bulb together with GnRH mRNA but also in the retina, spinal column, and developing kidney. The latter location may explain the renal agenesis and horseshoe kidney that sometimes occur in affected patients, while involuntary movements, known as mirror movements, in some patients, are thought to result from disorganization of the pyramidal tracts of the spinal column. Men with KAL-1 mutation present with the most severe form of CHH with lack of LH pulsatile secretion, prepubertal testosterone levels, and sometimes with microphallus and/or cryptorchidism. Eight to ten percent of males with CHH have mutations in KAL-1 in most series.

Genetic studies in individuals with contiguous gene syndromes lead to the finding of FGFR-1 (fibroblast growth factor receptor) mutations in males and females with sporadic or autosomal dominant familial CHH [3]. In addition to hypogonadism, some CHH patients have cleft lip, cleft palate, dental agenesis, and other skeletal anomalies, as well as anosmia, and the disorder is therefore designated KAL-2. There are four functional FGF-receptors, and more than 20 FGFs that are paracrine stimulators of these receptors. At least 22 different mutations have been reported accounting for about 10 % of patients with CHH. FGF receptors are transmembrane receptor tyrosine kinases that activate phosphatidyl inositol and other signaling pathways by forming a dimer when stimulated by FGF and require a heparan sulfate glycosaminoglycans. FGF signaling is involved in the development and growth of a variety of tissues. Mutation of FGFR-1 in mice causes early embryonic death. Facial clefting and hypogonadotropic hypogonadism are also associated with mutation of FGF8. KAL-2 and KAL-1 may be functionally inter-related in that the KAL-1 gene product anosmin may function as a coreceptor for FGF signaling.

Mutations in the genes PROK2 and PROKR2 which encode prokineticin and its G-protein-coupled prokineticin receptor-2 have been found in approximately 10 % of Kallmann syndrome patients. Prokineticins are widely expressed and have diverse biological functions. PROKR2 is expressed in the olfactory bulb, and mice deficient in PROKR2 have hypoplasia of the olfactory bulbs and hypogonadotropic hypogonadism. Most CHH patients with mutations in these genes are heterozygotes, but the same mutations have also been found in apparently unaffected individuals. Among those heterozygotes with hypogonadism, a digenic disorder has been found in a few patients with mutations in other genes implicated in KS (KAL1, FGFR1 PROKR2, or PROK2), or in genes causing CHH without developmental defects (see below). The absence of mutations in other genes known to cause CHH implies that those hypogonadotropic patients with heterozygous mutation solely of PROK2 or PROKR2 must have mutations in other disease-causing genes that remain to be identified.

Semaphorins are proteins secreted by target tissues that repel or attract a wide range of neuronal and non-neuronal cells depending on the cellular targets and the expression of different subunits of its receptor complexes. Mice with deletion of the SEMA3A receptor have altered migration of GnRH neurons into the brain, and a few CHH patients heterozygous for mutations which disrupt secretion of SEMA-3A in vitro have been reported.

Less common causes of CHH with developmental defects are mutations in CHD7, WDR11, and HS6S. CHARGE syndrome, with ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies and deafness, results from mutation of CHD7. WDR11 interacts with EMX1, a homeodomain transcription factor involved in the development of olfactory neurons. Like Kal-1, HS6ST, FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are genes involved in FGF receptor signaling and have been found to be mutated in a few CHH patients [3].