HYPOGONADOTROPIC HYPOGONADISM / KALLMANN SYNDROME

Kallmann syndrome is characterized by two main symptoms: hypogonadotropic hypogonadism (HH) and absent or diminished sense of smell (anosmia). The incidence is reported to be 1:8,000 (males) and 1:40,000 (females). There are three modes of inheritance:

• an X-linked recessive form with pathogenic variants or deletions in the ANOS1 gene (KAL1; seen in approximately 8% of patients),
• an autosomal dominant form with variants in the FGFR1 gene (fibroblast growth factor receptor 1 gene, KAL2; seen in approximately 10% of patients), and
• an autosomal recessive form with variants in the PROKR2 (prokineticin receptor 2 gene, KAL3) and PROK2 (prokineticin 2 gene, KAL4) genes (seen in approximately 9% of patients).

Variants in CHD7 (chromodomain helicase DNA-binding protein-7 gene, KAL5; 6-8% of patients) have also been described for Kallmann syndrome or idiopathic hypogonadotropic hypogonadism (IHH) with normosmia as clinically milder forms of CHARGE syndrome. Another autosomal dominant form is caused by variants in FGF8 (fibroblast growth factor-8 gene, KAL6; approximately 2% of patients). Diagnostic testing also includes examination of the genes DUSP6, FEZF1, FGF17, FLRT3, FSHB, GNRH1, GNRHR, HS6ST1, IL17RD, KISS1, KISS1R, LHB, NSMF, SEMA3A, SOX10, SPRY4, TAC3, TACR3, and WDR11, in which causative variants for HH have been identified as well. Furthermore, a digenic cause for HH has been reported several times, where the combination of one variant in each of two different genes (e.g. in FGFR1 and FGF8 or in FGFR1 and GNRHR) leads to the development of the disease. Through the examination of these 25 genes, diagnostic sensitivity of approximately 50% is achieved.

References

Stamou et Georgopoulos 2018, Metabol 86:124 / Marcos et al. 2014, J Clin Endocrinol Metab 99:E2138 / Miraoui et al. 2013, Am J Hum Genet 92:725 / Dode et Hardelin 2009, Eur J Hum Genet17:139 / Pitteloud et al 2007, J Clin Invest 117:457