Congenital hypogonadotropic hypogonadism presents as hypogonadism, e.g., reduced or absent puberty,[1] low libido, infertility, etc. due to an impaired release of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and a resultant lack of sex steroid and peptides production by the gonads.[2][3]
In Kallmann syndrome, a variable non-reproductive phenotype occurs with anosmia (loss of the sense of smell) including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis.[4]
IHH is divided into two syndromes: IHH with olfactory alterations or anosmia, Kallmann syndrome and IHH with normal smell (normosmic IHH).[4]
Kallmann syndrome is responsible for approximately 50% of all cases of the condition. It is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROKR2, NELF, CHD7(which positively regulates GnRH secretion), HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, and WDR11 (gene), genes which are related to defects in neuronal migration.[4]
Gene defects associated with IHH and normal smell include PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11, as in KS, but in addition
mutations in KISS1R, TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB.[4] GnRH insensitivity is the second most common cause of IHH, responsible for up to 20% of cases.[citation needed]A minority of less than 5-10% is due to inactivating mutations in genes which positively regulate GnRH secretion such as CHD7, KISS1R, and TACR3.[citation needed]
The causes of about 25% of all IHH cases are still unknown.[5]
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