Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy

Generalized arterial calcification of infancy (GACI, MIM#208000) is a rare autosomal recessive disorder characterized by extensive calcifications in the media of large- and medium-sized muscular arteries. Most affected children die in early infancy because of cardiac failure. GACI is linked to mutations in the ENPP1 gene, which encodes for an enzyme that generates inorganic pyrophosphate (PP_i), a potent inhibitor of hydroxyapatite crystal formation. Treatment with bisphosphonates, which are synthetic PP_i analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. We report on the long-term survival of a severe case of GACI linked to a novel homozygous missense mutation c.583T/C in the ENPP1 gene, diagnosed prenatally, and treated with bisphosphonates. Intravenous disodium pamidronate (three infusions at days 8, 15, and 18 of 0.25, 0.50, and 0.50 mg/kg, respectively) was changed to oral disodium etidronate (starting dose of 20 mg/kg daily, 50 mg die) at 3 weeks of age. Although the etidronate dose was maintained at 50 mg daily in our patient (corresponding to a progressive decrease from 20 to 5 mg/kg daily), the progressive resolution of arterial calcifications seen by 3 months of age was maintained until 2 years of age. Throughout the 2-year follow-up, our patient developed mild hypophosphatemia, due to renal phosphate wasting, without clinical, biochemical, or radiological sign of rickets. Conclusion: High-dose bisphosphonate therapy may not be necessary for an extended period of time in children with GACI.