Long-term survival and phenotypic expansion in siblings with generalized arterial calcification of infancy

Abstract Generalized arterial calcification of infancy (GACI) is a rare, autosomal recessive disorder caused by pathogenic variants in ENPP1 or ABCC6. While typically fatal in infancy, survival into childhood is increasingly recognized. We report a family with 3 affected siblings homozygous for an ENPP1 variant (c.1367G A, p.Arg456Gln). The oldest died in infancy, the surviving 2 received early bisphosphonate therapy. Both survivors demonstrate persistent vascular calcifications, early-onset pseudoxanthoma elasticum (PXE)-like skin lesions, and chronic hypophosphatemia without radiographic rickets. Uniquely, this report contrasts the clinical course of a late preterm sibling against a sibling born extremely premature. Additional findings include auricular cartilage, renal and retinal calcifications, highlighting the systemic nature of ENPP1 deficiency. Our report expands the phenotypic spectrum of ENPP1-related GACI.