Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata.

X-linked Recessive Chondrodysplasia Punctata (CDPX1) is due to a defect in arylsulfatase E (ARSE), located on Xp22.3. Neither the substrate nor function of the encoded warfarin-sensitive arylsulfatase has been identified and molecular analysis remains the only confirmatory diagnostic test. Nevertheless, the majority of patients evaluated have not had identifiable mutations in ARSE, and thus far 23 patients have been reported. The major clinical features in these patients are also present in a group now recognized as phenocopies, due to vitamin K deficiency in early gestation or maternal autoimmune disease. We evaluated the ARSE gene in 11 patients who met clinical criteria for CDPX1. We amplified all exons and intronic flanking sequence from each patient, and investigated suspected deletions or rearrangements by southern analysis. We identified mutations in seven individuals. Of the remainder, three had maternal conditions that further expand the phenocopy group. Thus, this group might represent a proportion of the mutation-negative patients in previous studies. We extracted clinical information from all prior reports over the past decade and show that there are few distinguishing features on examination between these two groups of patients. This study supports heterogeneity for CDPX1-like phenotypes and sorting these out will help to define the biological pathway and genetic contributors.