Genetics of congenital hypogonadotropic hypogonadism in Denmark.

[kallmann syndrome]

Congenital hypogonadotropic hypogonadism (CHH ) is a rare disorder characterized by incomplete /absent puberty caused by deficiency or defective action of gonadotropin-releasing hormone (GnRH ). The phenotypic features of patients with CHH vary from genital hypoplasia and absent puberty to reversal of HH later in life . We examined the genetics and clinical features of CHH in Denmark . Forty -one male patients were screened for mutations in KAL 1 , FGFR 1 , FGF 8 , PROK 2 , PROKR 2 , GNRHR , TAC 3 , TACR 3 , and KISS 1 R . CHD 7 was screened in two patients with hearing loss . In 12 patients , a molecular genetic cause for CHH was found . Four patients had mutations in KAL 1 (C 105 VfsX 13 , C 5 3 X , ex 5 -8 del , R 257 X ), and five in FGFR 1 (G 97 S , R 209 C , A 512 V , R 646 W , and c .1614 C >T , (p .I 538 I ), predicted to affect splicing ). All 9 had severe HH (cryptorchidism and /or micropenis ), and 2 had cleft lip /palate . One patient with a previously reported homozygous R 262 Q mutation in GNRHR displayed fascinating temporal variation in his phenotype . Two patients with hearing loss had CHD 7 mutations (c .7832 _7841 del (p .K 2611 MfsX 25 ) and c .2443 -2 A >C ), confirming that CHH patients with CHARGE syndrome -associated features should be screened for mutations in CHD 7 .