Hypophosphatemic rickets developed after treatment with etidronate disodium in a patient with generalized arterial calcification in infancy

Abstract

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6–3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part.

Inhibition of vascular smooth muscle cell calcification by ATP analogues

“…β,γ-meATP can be hydrolysed to produce methylene diphosphonate, a bisphosphonate-like compound. Bisphosphonates adhere strongly to a mineralised matrix and have been shown to inhibit both vascular calcification [16,[32][33][34] and bone mineralisation [35,36]. This study found that both methylene diphosphonate and α,β-meADP blocked VSMC calcification at a similar potency to the parent compounds.…”

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency

“…The calcifications arise as a consequence of the generalized deficiency of pyrophosphate resulting from biallelic mutations that inactivate the genes encoding either the ectoenzyme ENPP1 (type 1, about 75% of patients), which hydrolyzes ATP to generate pyrophosphate, or ABCC6 (type 2, about 25% of patients), a transmembrane protein that when mutated results in low plasma pyrophosphate (PPi). If affected individuals reach the age of 6 months they are likely to survive and over time may experience spontaneous reversal of vascular calcifications, but severe vascular narrowing may persist along with the development of skeletal deformities described below.…”

Magnesium and Anti-phosphate Treatment with Bisphosphonates for Generalised Arterial Calcification of Infancy: A Case Report

“…A consequence of the hyperphosphaturia is osteomalacia and rickets, seen in ARHR2. This may indicate an association between ARHR2 and GACI (25). Since arterial calcifications could be lethal in infancy, thesepreviously reported observations encouraged the hypothesis that creating a controlled hypophosphatemia could decrease mortality.…”