Fig. 5.

Genes causing GnRH deficiency in relation to their site of action on the ontogeny of GnRH neurons. Genes on the left half of this developmental picture typically are associated with anosomia and impair GnRH neuronal migration and/or olfactory bulb/track development and thus are neurodevelopmental in their action. Examples are KAL1, FGF8, FGFR1, and NELF. In contrast, genes on the right half of this developmental map affect the function of GnRH neurons after their migration into the hypothalamus and hence are neuroendocrine in their sites of action. These include the genes encoding the kisspeptin-, neurokinin B-, and GnRH-signaling system. Typically, patients with mutations in these genes exhibit a normal sense of smell. In the middle are genes referred to as “overlap” genes because they seem to be able to act in either mode and include the prokineticin- and FGF-signaling systems that produce individuals and families with both anosomia and normal sense of smell often within the same pedigree.