Endocrine Abstracts

Patients with congenital hypogonadotropic hypogonadism (cHH; also referred to as idiopathic HH) have inadequately low gonadotropin and sex steroid levels for age without an underlying organic or functional cause. The combination of cHH and deficient sense of smell is called Kallmann syndrome (KS; incidence 1:30 000 in Finnish boys, and 1:125 000 in girls), which is due to misrouting of primitive GnRH neurons in utero from the olfactory placodal area to the developing hypothalamus.

The phenotypic features of cHH are variable. Hallmarks of severe reproductive phenotype include micropenis and/or cryptorchidism, whereas those with a partial reproductive phenotype may show some signs of gonadotropin and sex steroid action. Examples of associated phenotypes include cleft lip/palate, hearing loss, synkinesia, and limb anomalies. Approximately 10% of male cHH patients display reversal of hypogonadotropism later in life after androgen exposure.

Patients with cHH may have family members with cHH, delayed puberty, cleft lip/palate, infertility, cryptorchidism, or hyposmia/anosmia. In clinical examination, special attention should be paid on the stage of puberty, size of the testes, and on the presence of associated phenotypes. Chronic diseases, multiple pituitary hormone deficiency, syndromes, and organic and functional causes of HH should be ruled out. In addition to measurement of gonadotropin and sex steroid levels, Sertoli cell-derived inhibin B and AMH levels together with GnRH and hCG stimulation tests are usually of diagnostic value.

All patients with cHH should be referred to genetic counseling. Currently, 30-40% of cHH patients can be given a molecular genetic diagnosis. Certain phenotypic cues help to prioritize mutation screening. For example, semicircular canal hypoplasia should prompt testing of the CHD7 gene, and patients with anosmia in combination with bimanual synkinesia should be first screened for a mutation in KAL1. Biallelic defects in GNRHR, GNRH1, TAC3, TACR3, KISS1, KISS1R underlie normosmic cHH, and mutations in FGFR1, FGF8, PROKR2, PROK2, or CHD7 have been reported in cHH patients with normal or deficient sense of smell.