Differential Diagnosis

Disorders with Vascular Calcification

Singleton-Merten syndrome (OMIM 182250 and 616298) is an autosomal dominant disorder caused by pathogenic variants in IFIH1 or DDX58.

• Severe aortic calcification, dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion), osteopenia, and acroosteolysis are salient features of the disease .

• Unlike generalized arterial calcification of infancy (GACI), aortic calcification in Singleton-Merten syndrome starts later in life (age range at diagnosis: 6-39 years).

Metastatic calcification due to hypervitaminosis D, hyperparathyroidism, or end-stage renal disease

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"

Clinical Guidance

Although no clinical studies have been conducted, it seems prudent to avoid the use of warfarin if possible. The matrix Gla protein (MGP), a potent anti-mineralization factor, needs to be activated by a vitamin K-dependent enzyme, and warfarin interferes with the vitamin K cycle. Warfarin has also been shown to accelerate ectopic mineralization in Abcc6 knockout mice . One question is whether burosumab, an anti-FGF23 monoclonal antibody approved by the FDA for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, could also treat the hypophosphatemic rickets of ENPP1 deficiency. This approach, however, remains controversial due to theoretic concerns that it could worsen ectopic calcification by lowering pyrophosphate concentrations. However, one individual with ENPP1-related rickets, who was initially thought to have X-linked hypophosphatemia, received burosumab for months without developing any vascular calcification .

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"

Therapies Under Investigation

Enzyme replacement therapy. The administration of a recombinant form of ENPP1 prevents calcification and mortality , improves hypertension and cardiac function , and prevents intimal proliferation in mouse models of ENPP1 deficiency. It also prevented the osteomalacia, increased bone density, and markedly improved bone strength in mutant mice, while preventing the development of nephrocalcinosis . Magnesium. In a mouse model of ENPP1 deficiency, increased dietary magnesium during pregnancy and continued postnatally was shown to prevent ectopic mineralization, likely by competing with calcium for phosphate binding .

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"