GACI

Generalized arterial calcification of infancy (GACI) is a rare genetic disorder characterized by calcification and thickening of the walls of large- and medium-sized arteries. It most often presents in infancy, frequently in the neonatal period, and can cause hypertension, heart failure, and vascular insufficiency due to progressive arterial stenosis.

Genetics and pathophysiology: The majority of cases are due to loss-of-function mutations in ENPP1, with a smaller number linked to ABCC6 mutations. The condition is inherited in an autosomal recessive manner. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, an enzyme that generates pyrophosphate, a natural inhibitor of hydroxyapatite crystal formation. Deficiency reduces pyrophosphate and permits abnormal calcium deposition in arterial walls, often accompanied by intimal proliferation and vessel narrowing.

Clinical features and diagnosis: In affected infants, imaging may reveal extensive arterial calcifications, especially along the aorta and coronary arteries, with accompanying vascular stenoses on ultrasound or CT angiography. Hypertension, heart failure, renal impairment, and growth disturbances can occur. Diagnosis is based on imaging findings plus genetic testing for ENPP1 and ABCC6 mutations and by exclusion of other causes of neonatal arterial calcification.

Management and prognosis: There is no cure. Treatment is supportive and aims to manage heart failure, hypertension, and vascular complications. Some case reports describe use of bisphosphonates to slow calcification, but evidence is limited. The prognosis varies; mortality is high in infancy, but some individuals survive into childhood or adulthood with ongoing vascular disease and potential complications.