Incidence, Phenotypic Features and Molecular Genetics of Kallmann Syndrome in Finland

Herein, we investigated epidemiological, clinical, and genetic features of KS in Finland.The minimal incidence estimate of KS in Finland was 1:48 000, with clear difference between males (1:30 000) and females (1:125 000) (p = 0.02). The reproductive phenotype of 30 probands (25 men; 5 women) ranged from severe HH to partial puberty. Comprehensive mutation analysis of all 7 known KS genes (KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11) in these 30 well-phenotyped probands revealed mutations in KAL1 (3 men) and FGFR1 (all 5 women vs. 4/25 men), but not in other genes.Our results suggest that Finnish KS men harbor mutations in gene(s) yet-to-be discovered with sex-dependent penetrance of the disease phenotype. In addition, some KS patients without CHD7 mutations display CHARGE-syndrome associated phenotypic features (e.g. ear or eye anomalies), possibly implying that, in addition to CHD7, there may be other genes associated with phenotypes ranging from KS to CHARGE.Kallmann syndrome (KS; MIM# 147950), a combination of congenital hypogonadotropic hypogonadism (HH; MIM# 146110) and decreased/absent sense of smell, results from disturbed intrauterine migration of gonadotropin-releasing hormone (GnRH) neurons from the olfactory placode to the hypothalamus [1-3]. Patients with KS usually lack puberty, but the reproductive phenotype may vary from severe hypogonadism (cryptorchidism or micropenis in male infants) to reversal of hypogonadotropism later in life [4,5]. Associated phenotypic features include cleft lip/palate, hearing impairment, dental agenesis, limb anomalies, renal agenesis, and mirror movements [6]. The incidence estimates of KS are scarce and variable, and the condition appears to be 3-5 times more frequent in men [6-8].KS is genetically heterogeneous, and the majority of cases (~60%) present as sporadic cases (only one person affected in the family). In familial KS, autosomal recessive, autosomal dominant, and X-chromosomal recessive inheritance have be