The role of the abnormalities in the distal pathway of cholesterol biosynthesis in the Conradi–Hünermann–Happle syndrome

• CDPX2 exhibits intense phenotypic variation and affects the skin, bones and eyes.
• Ichthyosis following Blaschko's lines, chondrodysplasia punctata, and cataracts are typical.
• CDPX2 results from mutations in EBP gene (Xp11.22–p11.23).
• There is an increase in 8(9)-cholestenol and 8-dehydrocholesterol (8DHC) in CDPX2.
• We introduce how the biochemical and genetic abnormalities lead to the clinical phenotype of CDPX2.

Conradi–Hünermann–Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata (CP) caused by mutations in one gene of the distal pathway of cholesterol biosynthesis. It exhibits intense phenotypic variation and primarily affects the skin, bones and eyes. The ichthyosis following Blaschko's lines, chondrodysplasia punctata and cataracts are the typical clinical findings. The cardinal biochemical features are an increase in 8(9)-cholestenol and 8-dehydrocholesterol (8DHC), which suggest a deficiency in 3β-hydroxysteroid-Δ8,Δ7-isomerase, also called emopamil binding protein (EBP). The EBP gene is located on the short arm of the X chromosome (Xp11.22–p11.23) and encodes a 230 amino acid protein with dual function. Explaining the clinical phenotype in CDPX2 implies an understanding of both the genetics and biochemical features of this disease. CDPX2 displays an X-linked dominant pattern of inheritance, which is responsible for the distribution of lesions in some tissues. The clinical phenotype in CDPX2 results directly from impairment in cholesterol biosynthesis, and indirectly from abnormalities in the hedgehog signaling protein pathways. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.