Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Kallmann's Syndrome [E23.0]

OMIM numbers: 308700, 300836 (KAL1), 147950, 136350 (FGFR1), 244200, 607123 (PROKR2), 610628, 607002 (PROK2), 612702, 600483 (FGF8)

Dr. rer. nat. Annett Wagner, Dr. med Julia Höfele,
Dr. med. Dagmar Wahl

Scientific Background

The Kallmann's or olfacto-genital syndrome is characterized by genetic heterogeneity and may occur sporadically or in a familial form that is transmitted in an autosomal dominant, autosomal recessive or X chromosomal manner (frequency 1:8,000 men, 1:40,000 women). There are two major clinical signs: absent or impaired sense of smell (anosmia or hyposmia) an hypogonadotropic hypogonadism (HH). During puberty, the development of secondary sex characteristics does either not take place or is delayed. The serum concentration of FSH, LH and testosterone or estrogen is lower than usual, resulting in impairment of spermatogenesis in men and of the menstrual cycle in women (amenorrhea).

The X chromosomal recessive form of the Kallmann's syndrome (Xp22.3) is caused by deletions or mutations in the KAL1 gene (approx. 8% of all affected patients). The KAL1 gene contains 14 exons on 210 kb and encodes for the protein anosmin-1, a 95 kD glycoprotein of the extracellular matrix. If anosmin-1 is absent or defective, olfactory neurons producing GnRh (gonadotropin-releasing hormone) cannot migrate into the hypothalamus. The autosomal dominant form of the Kallmann's syndrome is caused by mutations in the FGFR1 (fibroblast growth factor receptor 1) gene (approx. 10% of all affected patients) and the FGF8 (fibroblast growth factor 8) gene (approx. 2% of all affected patients). The FGFR1 (or KAL2) gene contains 18 exons on 55 kb (8p11.2 - p11.1). Mutations in the genes PROKR2 (20p13) and PROK2 (3p21.1) cause the autosomal recessive form of Kallmann's syndrome (approx. another 9% of all affected patients).