Summary Background Conradi–Hünermann–Happle syndrome [X-linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X-linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype.
Objectives To describe new mutations in patients with variable manifestations of the disease.
Methods We studied three patients with CDPX2. We performed mutation analysis of the EBP (formerly known as CDPX2) gene and gas chromatography–mass spectroscopy on serum of two patients.
Results We found two novel (3G→T and 419-422delTTCT) and one known mutation in the EBP gene. We demonstrated the presence of increased levels of dehydrocholesterol and 8(9)-cholestenol in the two patients with new mutations, confirming the diagnosis of CDPX2 and strongly suggesting that the mutations are indeed pathogenic. One patient had a very mild phenotype, presenting with linear alopecia and a mild symmetrical epiphyseal dysplasia. X-inactivation studies in peripheral blood of all patients showed skewing in only the most severely affected patient.
Conclusions The strong phenotypic variability in our patients suggests that there is no clear genotype–phenotype correlation.