X-linked brachytelephalangic chondrodysplasia punctata: a simple trait that is not so simple

Brachytelephalangic chondrodysplasia punctata (CDPX1) is an X-linked recessive disorder caused by mutations in the arylsulfatase E (ARSE) gene, characterized by the presence of stippled epiphyses on radiograms in infancy and early childhood. Other features include hypoplasia of the midface and of the nasal bone, short stature, brachytelephalangy, and ectopic calcifications. Patients display marked clinical variability and there is no clear genotype-phenotype correlation. We report on a 14-month-old boy who presented with respiratory stridor due to tracheal calcifications. He had mild midface hypoplasia and brachytelephalangy, but lacked other features of CDPX1, such as short stature and epiphyseal stippling. Analysis of ARSE detected a deletion involving exons 7-10. His maternal grandfather harbored the same defect but lacked any clinical manifestation. These findings underscore two important points. First, the absence of stippled epiphyses on radiograms should not be considered an exclusion criteria for ARSE mutation screening in patients with other features of the disease, especially after the neonatal period. Second, counseling to parents of affected children should be cautious because although the theoretical risk of inheriting the ARSE mutation is 50% for every male child of a carrier mother, it is not possible to determine whether he will develop features of CDPX1 and the eventual severity of symptoms. The actual risk of developing the disease is probably lower than 50%. Conversely, normal prenatal sonography does not rule out potentially severe complications such as tracheal stenosis.