Cardioacrofacial dysplasia 1: a case report and literature review

Cardioacrofacial dysplasia 1 [CAFD1; Online Mendelian Inheritance in Man (OMIM): #619142] is a rare skeletal ciliopathy caused by pathogenic variants in the PRKACA gene, exhibiting phenotypic overlap with conditions such as Ellis-van Creveld (EvC) syndrome. To date, only five cases have been reported worldwide, all carrying the identical p. Gly137Arg mutation.

A 10-year-old male patient presented with short stature, progressive bilateral knee deformities, post-axial posterior polydactyly, and hypoplasia of teeth and nails since infancy. He had a history of partial atrial septal defect, functional single atrium, and pulmonary valve stenosis, undergoing cardiac repair at age 5 and bilateral polydactyly resection at age 7. Whole-exome sequencing (WES) confirmed a de novo heterozygous mutation in the PRKACA gene: c.409G>A (p.Gly137Arg). At age 10, the patient underwent robot-assisted bilateral proximal tibial epiphyseal fixation. One-month postoperative follow-up demonstrated significant improvement in gait and mobility.

To our knowledge, this expands the known geographic distribution with PRKACA c.409G>A (p.Gly137Arg). The finding adds to prior reports that repeatedly implicate this variant; broader ascertainment is needed to establish whether it represents a true hotspot. In patients with an EvC-like phenotype who test negative for EVC/EVC2, screening of PRKACA can be considered. Prior work suggests that increased protein kinase A (PKA) catalytic activity may dampen Hedgehog (Hh) signaling, providing a plausible mechanism for the skeletal and cardiac findings. Early molecular diagnosis facilitates multidisciplinary management and genetic counseling.