Clinical Guidance

Marked phenotypic heterogeneity, even among surviving sibs with identical genotypes, argues against a genotype-phenotype correlation in GACI . (full text; see Supporting Information, Appendix) reported an affected individual with biallelic ENPP1 pathogenic variants and a heterozygous pathogenic variant in ABCC6, which theoretically could have contributed to the severity of GACI. The individual's healthy mother and brother both were doubly heterozygous for an ENPP1 pathogenic variant and the ABCC6 pathogenic variant; thus, it appears that the presence of one heterozygous ENPP1 pathogenic variant and one ABCC6 pathogenic variant does not cause GACI.

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"

Diagnostic Criteria

No consensus clinical diagnostic criteria for generalized arterial calcification of infancy (GACI) have been published.

Suggestive Findings

GACI should be suspected in individuals with a combination of the following.

Clinical findings

• Typical cardiovascular findings including heart failure, respiratory distress, edema, cyanosis, hypertension, and/or cardiomegaly

• Characteristic imaging findings of widespread arterial calcification and/or narrowing of large and medium-sized vessels

• Appearance of typical clinical and histologic skin findings of pseudoxanthoma elasticum (PXE) and/or angioid streaks on fundoscopy

• Development of hypophosphatemic rickets after infancy

Imaging

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"

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"

Management Guidelines

No clinical practice guidelines for GACI have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with generalized arterial calcification of infancy (GACI), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with GACI

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"

Surveillance Guidelines

No specific guidelines address the issue of surveillance. The appropriate intervals for monitoring depend on clinical findings and need to be more frequent in those with a more severe presentation. Table 6. Recommended Surveillance for Individuals with GACI

Source: GeneReviews — "Generalized Arterial Calcification of Infancy"