ABSTRACTBackgroundChondrodysplasia punctata 1 (CDPX1) is an X‐linked recessive disorder of cartilage and bone development characterized by stippling on the cartilage and bone, flattened nasal bridge, and brachydactyly, or short fingers. CDPX1 has been associated with variants in the ARSL gene and is known to manifest prenatally, however, there has been no systematic literature review on this evidence.AimsHere, we reviewed the current literature on prenatal manifestations of CDPX1, and additionally introduce previously unpublished cases.Materials & MethodsA systematic review of the literature was performed. Additionally, a GeneMatcher submission was created and a call for cases was presented at the Fetal Sequencing Consortium meetings to find previously unpublished cases.ResultsFor the 22 fetuses reported here, we found that 55% had nasal hypoplasia, 41% had bony stippling or calcifications, 32% had polyhydramnios, 5% had oligohydramnios, 23% had shortened long bones, 23% had spinal canal stenosis, 18% had ventriculomegaly, 9% had brachydactyly/brachytelephalangy, 9% had clubbed feet, 9% had premature rupture of membranes, and 9% had intraventricular hemorrhage detected through sonography or radiography. We also found 17 unique variants in ARSL for these 22 fetuses.DiscussionA previously unpublished association of ARSL variants with intrauterine fetal death or stillbirth has been noted in this study. It is also possible that intracranial hemorrhage is an underrecognized feature associated with CDPX1 variation. However, there have been challenges in applying ACMG criteria to ARSL, a gene without an associated Variant Curation Expert Panel.ConclusionThis literature review and case series highlights which features of CDPX1 manifest prenatally, as well as introduces new phenotypes that have not been previously identified.
