Severe Conradi-Hünermann Syndrome (CDPX2) is a phenocopy of peroxisomal Rhizomelic Chondrodysplasia Punctata (RCDP)

Abstract

RCDP was initially diagnosed in a newborn female who had typical symmetric rhizomelic shortening of the extremities, metaphyseal changes, multiple punctate skeletal calcifications, icthyosis, bilateral cataracts and Koala bear facies. The patient succumbed at 12 weeks of age. Diagnostic evaluations were unrevealing, including normal peroxisomal very long chain fatty acids, phytanic acid hydrolase and plasmalogen biosynthesis. Fibroblasts where reanalyzed for defects in 3-beta-hydroxysteroid-Δ(8), Δ(7)-isomerase, which was recently identified to cause X-linked Conradi-Hünermann Syndrome. GC/MS analysis revealed a pattern of metabolites consistent with this enzymatic defect in cholesterol biosynthesis, specifically showing increased levels of 8-dehydrocholesterol and 8(9)-cholesterol. Genomic DNA was isolated from the patient's fibroblasts and the gene for 3-beta-hydroxysteroid-Δ(8), Δ(7)-isomerase (EBP, located at Xpll.2) was sequenced (all exons and intronic junctions). Results showed 3 mutations in cis in exon 2 : L42X (125T>A), W47X (140G>A) and L49L (147G>A)(a synonymous change). The other allele showed a wild type sequence. The EBP gene were sequenced in blood lymphocytes from both parents and were normal.This case highlights the heterogeneity of CDPX2. The range of phenotypic severity seen in this disorder is presumably due to variable lyonization. We show that severe CDPX2 is a phenocopy of peroxisomal RCDP. We have also identified a novel mutation that could have originated from a pseudogene or another unknown mechanism.