Extraskeletal Calcifications in Hutchinson-Gilford Progeria Syndrome

Abstract Purpose Children with Hutchinson-Gilford progeria syndrome(HGPS), a rare premature agingdisease, exhibit extraskeletal calcificationsdetected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcificationsin HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development. Methods Children from two successive clinical trials administering 1) lonafarnib(n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3–4.3 years after the baseline visit). Calcium supplementation(oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcificationswas obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcificationswas determined by x-ray diffraction. Results Extraskeletal calcificationswere detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcificationsincreased with age ( p  = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonatesupplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications( p  = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutisshowed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnibinitiation ( p p  = 0.03). Conclusions Extraskeletal calcificationsincreased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnibtherapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcificationsby an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonateaccelerated their development and is, therefore, not recommended for routine supplementation in these children.