Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature.

Background Conradi-Hunermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X linked dominant variant of chondrodysplasia puttctata which primarily affects the skin, bones and eyes. CDPX2 results from mutations in EBP (emopamil binding protein), and presents with increased levels of sterol precursors 8(9) cholestenol and 8 dehydsocholesterol. Objectives To expand the understanding of CDPX2, clinically, biochemically and genetically. Methods We present one of the largest series reported to date, including 13 female patients belonging to nine Spanish families. Patients were studied biochemically using gas chromatography mass spectrometry, genetically using polymerase chain reaction and in their methylation status using the HUMARA assay. Results In our cases, there was a clear relationship between abnormal sterol profile and the EBP gene mutation. We describe three novel mutations in the EBP gene. EBP mutations were inherited in three out of nine families and were sporadic in the remaining cases. Conclusions No clear genotype phenotype correlation was found. Patients' biochemical profiles did not reveal a relationship between sterol profiles and severity of disease. A skewed X chromosome inactivation may explain the clinical phenotype in CDPX2 in some familial cases.