Rapid publication - Abnormal sterol metabolism in patients with Conradi-Hunermann-Happle syndrome and sporadic lethal chondrodysplasia punctata

The term, "chondrodysplasia punctata" (CDP) denotes a pattern of abnormal p unctate calcification of dystrophic epiphyseal cartilage and certain other cartilaginous structures, such as the larynx. CDP occurs in a variety of ge netic disorders associated with skeletal dwarfism and can also be caused by prenatal exposure to warfarin, Although the most studied clinical syndrome with CDP, rhizomelic chondrodysplasia punctata (RCDP), is known to be caus ed by several different abnormalities of plasmalogen biosynthesis, there ar e many other genetic disorders with CDP for which the biochemical cause is unknown. Because patients with Smith-Lemli-Opitz syndrome, a primary disord er of sterol biosynthesis, often have rhizomesomelic limb shortness and, le ss commonly, CDP, we assessed sterol levels and metabolism in patients with different clinical forms of CDP, By quantitative sterol analysis of a vari ety of tissues, we identified 5 patients with similar radiological findings and abnormally increased levels of 8-dehydrocholesterol and cholest-8(9)-e n-3 beta-ol, suggesting a deficiency of 3 beta-hydroxysteroid-Delta(8),Delt a(7)-isomerase, a principal enzyme of cholesterol biosynthesis, Cultured ce lls available from one patient showed increased levels of the same two ster ols, decreased synthesis of cholesterol, and a pattern of inhibition by tri paranol and AY-9444 consistent with a deficiency of 3 beta-hydroxysteroid-D elta(8),Delta(7)-isomerase. Clinical diagnoses among the 5 patients include d X-linked dominant Conradi-Hunermann-Happle syndrome and nonspecific letha l CDP, We conclude that abnormal cholesterol biosynthesis is a characterist ic of some clinical syndromes with rhizomesomelic dwarfing and CDP.(C) 1999 Wiley-Liss, Inc.