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 .

Diseases
Validation

Diseases presenting "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated