Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy

Abstract

, MD; the GACI Study GroupBackground-Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results-We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion-ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in Ϸ75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment. ENPP1 encodes a type II transmembrane glycoprotein ectoenzyme that forms homodimers of identical disulfidebonded subunits. 7 NPP1 has an extracellular catalytic domain as well as somatomedin B-like and substrate-binding or substrate-specifying nuclease-like domains. 8 NPP1 regulates soft tissue calcification and bone and joint cartilage mineralization by generating PP i , which not only serves as an essential physiological inhibitor of hydroxyapatite crystal growth 9 but also is a suppressor of chondrogenesis. 10 In artery smooth muscle cells, deficiencies of NPP1 (or of extracellular PP i without NPP1 deficiency in ank/ank mice homozygous for functional inactivation of the PP i transporter ANK) promote chondrogenic transdifferentiation in vivo and also in vitro under circumstances where excess of an inorganic phosphate (P i ) source is provided. 10,11 Although the pathophysiologic role of NPP1-mediated PP i generation in GACI has come to light within recent years, the factors accounting for the variation of the GACI phenotype including the presence or absence of intracerebral artery calcification and periarticular calcification, early death in utero and long-term survival are not known. 12 PP i and ...

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

“…(12) Recent studies have associated BP therapy (predominantly EHDP) with improved survival in GACI. (18) However, rickets or osteomalacia can develop during protracted EHDP administration for any disorder, although few reports are in the medical literature. (23,24,(38)(39)(40)(41) Amino-BPs were formulated to be more potent antiresorptive agents, and therefore less likely to interfere with mineralization at therapeutic levels.…”

“…These biochemical findings excluded rickets from nutritional deficiencies, and rapidly corrected when dairy product consumption decreased. Some GACI patients develop hypophosphatemic rickets, (18,25,70) perhaps related to the disturbance of PPi metabolism. (71) Acquired hypophosphatemia and rickets (OMIM# 613312) caused by his two altered ENPP1 alleles was an unlikely cause of his bone problems because his serum Pi level fell below the normal range just once as we followed him and without hyperphosphaturia.…”

“…(17) In 2008, a retrospective, multicenter, observational analysis of 55 patients showed survival beyond infancy with EHDP therapy. (18) That same year, Chong and Hutchins (5) reported that 15 of 22 GACI survivors had received EHDP.…”

“…However, hypophosphatemic rickets has occurred in a few surviving GACI patients at varying ages both with and without bisphosphonate treatment. (18,19,24,25) We report a 7-year-old boy with GACI and severe skeletal toxicity from protracted EHDP therapy including rickets that mimicked severe hypophosphatasia (HPP) and bone modeling abnormalities found in osteopetrosis (OPT).…”

Clinical utility gene card: for pseudoxanthoma elasticum

“…It is characterized by hydroxyapatite deposits in the internal elastic lamina of large and medium-sized arteries associated with intimal proliferation, leading to severe arterial stenoses, and organs' ischemia. Causal variants in ENPP1 are found in approximatively 75% of cases [7,8]. Among the remaining 25%, some cases harbor mono-or biallelic ABCC6 pathogenic variants.…”