Generalized arterial calcification (AC) of infancy (
GACI) is an autosomal recessive disorder that features
hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of
GACI patients die by 6 months of age from cardiac
ischemia and
congestive heart failure. The first-generation
bisphosphonate etidronate (
EHDP;
ethane-1-hydroxy-1,1-diphosphonic
acid, also known as 1-hydroxyethylidene-
bisphosphonate) inhibits
bone resorption and can mimic endogenous inorganic
pyrophosphate by blocking mineralization. With
EHDP therapy for
GACI, AC may resolve without recurrence upon
treatment cessation. Skeletal disease is not an early characteristic of
GACI, but
rickets can appear from acquired
hypophosphatemia or prolonged
EHDP therapy. We report a 7-year-old boy with
GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of
EHDP therapy during infancy, but
GACI-related joint calcifications progressed. He was receiving
EHDP, 200 mg/day orally, and had odynodysphagia, diffuse
opioid-controlled
pain,
plagiocephaly, facial dysmorphism, joint calcifications,
contractures, and was wheelchair bound. Biochemical parameters of
mineral homeostasis were essentially normal. Serum
osteocalcin was low and the brain
isoform of
creatine kinase and
tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in
osteopetrosis. Skeletal radiographic findings resembled pediatric
hypophosphatasia with pancranial
synostosis, long-bone bowing, widened physes, as well as metaphyseal
osteosclerosis, cupping and fraying, and "tongues" of radiolucency. Radiographic features of
osteopetrosis included
osteosclerosis and femoral Erlenmeyer flask
deformity. After stopping
EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in
GACI from protracted
EHDP therapy. Although
EHDP treatment is lifesaving in
GACI, surveillance for toxicity is crucial.