Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by dysregulated calcium-phosphate metabolism, leading to mineral deposition within the internal elastic lamina of medium- and large-sized arteries. This results in arterial wall thickening and luminal narrowing due to intimal hyperplasia, causing significant vascular disruption. Approximately 70% of cases (GACI type 1) are caused by biallelic loss-of-function mutations in the ENPP1 gene, with nearly 40 pathogenic variants reported. We report a case of an infant diagnosed with GACI type 1 who died at 7 weeks of age. The patient was delivered via cesarean section at 36 weeks of gestation after a pregnancy complicated by polyhydramnios. The parents were second-degree cousins, with a history of two neonatal deaths of unknown etiology and one miscarriage. Autopsy revealed diffuse arterial calcification with prominent involvement of the coronary arteries. Notably, the liver showed fibrosis progressing to cirrhosis. Genetic analysis through trio exome sequencing identified a novel homozygous nonsense variant in ENPP1 (c.553C > T; p.Gln185Ter), inherited from both parents. This stop-gain variant is predicted to produce a severely truncated, non-functional or absent protein. This case is notable for two key aspects: a previously unreported association between GACI and progressive hepatic fibrosis evolving into cirrhosis, and the identification of a novel pathogenic ENPP1 variant not previously described in the literature.
Buccoliero et al. (Sun,) studied this question.