More recently, mutations in TAC3 and TACR3 genes, which encode neurokinin B and its receptor, have been implicated in normosmic IHH, although their precise functions in reproduction remain unclear.
New evidence has now emerged that loss of function of neurokinin B (NKB) or its receptor, the neurokinin-3 receptor, produces IHH of similar severity to that caused by KISS1R mutations in humans.
Since then, several loss-of-function mutations affecting the kisspeptin receptor and neurokinin B and its receptor were associated with sporadic and familial IHH without olfactory abnormalities or other associated developmental alterations.
The results suggest hypothalamic dysfunction as the primary cause for IHH in patients with biallelic TACR3 mutations and clinical manifestation in heterozygous females, together with the rarity of TAC3 and TACR3 mutations in patients with IHH.