Characterization of mutations in 22 females with X-linked dominant chondrodysplasia punctata (Happle syndrome)

Purpose: Human X-linked dominant chondrodysplasia punctata (CDPX2) or Happle syndrome is associated with mutations in the human emopamil binding protein (EBP), a Delta(8)-Delta(7)-sterol isomerase involved in cholesterol biosynthesis. The purpose of the current study was to determine the spectrum of EBP mutations in females with CDPX2 and the utility of biochemical screening for the disorder by analysis of plasma sterols. Methods: Genomic sequencing of the coding exons of the human Delta(8)-Delta(7)-sterol isomerase gene was performed on DNA from 26 females with suspected X-linked dominant chondrodysplasia punctata. Clinical data and sterol analyses were obtained for 24 and 23 of the patients, respectively. Results: Mutations in the human EBP Delta(8)-Delta(7)-sterol isomerase gene were found in 22 (85%) of 26 females studied, including 20 (91%) of 22 patients who demonstrated an abnormal sterol profile. Thirteen of the mutations have not been reported previously. All of the females in whom mutations were found demonstrated typical skin manifestations of CDPX2, and all but one had a skeletal dysplasia. Conclusions: Plasma sterol analysis was a highly specific and sensitive indicator of the presence of an EBP mutation in females with suspected CDPX2, including a clinically unaffected mother of a sporadic case. No clear genotype/phenotype correlations were ascertained, probably because phenotypic expression is influenced substantially by the pattern of X-inactivation in an affected female.