Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management

Abstract

Purpose of review: This review summarizes current understanding of generalized arterial calcification of infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management.

Recent findings: Identification of causative ENPP1 mutations revealed that GACI arises from deficiencies in inorganic pyrophosphate (leading to calcifications) and adenosine monophosphate (leading to intimal proliferation). Identification of genotypic and phenotypic overlap with pseudoxanthoma elasticum and autosomal recessive hypophosphatemic rickets further advanced understanding of GACI as a complex, multisystemic disease. Clinical data is limited to small, retrospective samples; it is therefore unknown whether commonly used medications, such as bisphosphonates and hypophosphatemia treatment, are therapeutic or potentially harmful. ENPP1-Fc replacement represents a promising approach warranting further study. Knowledge gaps in natural history place clinicians at high risk of assigning causality to interventions that are correlated with changes in clinical status. There is thus a critical need for improved natural history studies to develop and test targeted therapies.

Keywords: ABCC6; ENPP1; Fibroblast growth factor 23; Metabolic bone disease.

Figure 1.

Clinical images of vascular calcifications in patients with GACI. A. Coronal views of a computed tomography scan shows diffuse calcification involving the descending aorta (red arrow) and multiple branching arteries (yellow asterisks). B. Prenatal ultrasound demonstrates calcification and severe narrowing in the distal aorta (red arrow). C. Axial views of a computed tomography scan show a calcified and severely narrowed descending aorta (red arrow). D. Medium-sized pancreatic artery showing calcification (red arrows) along the internal elastic lamina (hematoxylin and eosin stain).

Figure 2.

Clinical images of extravascular features in patients with GACI. A. Skin findings consistent with PXE. Note the characteristic yellowish papules occurring in a patchy, reticular pattern (white arrows). B. Fundus autofluorescence imaging in an adult patient with ENPP1 deficiency revealing a large area of hypoautofluorescence (red arrowheads) due to atrophy of the retinal pigment epithelium atrophy, with spots of hyperautofluorescence surrounding the area of atrophy. C. Large area of periarticular calcifications involving the shoulder joint (arrow). D. Periarticular calcifications involving the ankle joint (arrow). E. Irregularities in the distal femoral metaphyses consistent with hypophosphatemic rickets (arrowheads). Note the bowing of the bilateral femoral shafts (white arrows), resulting in a genu valgum deformity of the knees.