Compound Heterozygous Variants in the PAICS Gene Integrate the Previously Described Divergent Phenotypes.

Biallelic variants in PAICS, one of the 10 genes involved in the de novo purine synthesis (DNPS), were originally associated with an extremely rare phenotype characterized by multiple and severe congenital abnormalities, such as polyhydramnios due to esophageal atresia, congenital heart disease, and urogenital anomalies, which were lethal within the first days of life. Vertebral and limb defects, as well as distinctive craniofacial features, were also described. To date, three patients with these clinical characteristics but without neurologic involvement have been described in the literature. More recently, two siblings with none of these features but presenting a severe neurodevelopmental phenotype with regression and ocular involvement have been reported. We describe a new patient with two compound heterozygous variants in the PAICS gene, p.Ser35Phe and p.Cys281Ter, born with multiple congenital malformations overlapping those reported in the originally described patients: esophageal atresia, lung hypoplasia, vertebral anomalies, cryptorchidism, short stature, and dysmorphic facial features. He also had developmental delay; however, epilepsy did not occur. The features presented by our patient and the relatively longer follow up allowed us to detect in a single patient almost all the features previously described in different families.