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Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.
J Bone Miner Res. 2021 Nov; 36(11):2193-2202.JB

Abstract

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Authors+Show Affiliations

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK.Centre de Référence Maladies Osseuses Constitutionnelles (CR MOC) et Filière OSCAR, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France.Center for Chronically Sick Children, Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany.Inozyme Pharma, Inc., Boston, MA, USA.National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.Quantitative & Regulatory Medical Science, LLC, Long Valley, NJ, USA.Inozyme Pharma, Inc., Boston, MA, USA.Inozyme Pharma, Inc., Boston, MA, USA.Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34355424

Citation

Ferreira, Carlos R., et al. "Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies." Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, vol. 36, no. 11, 2021, pp. 2193-2202.
Ferreira CR, Kintzinger K, Hackbarth ME, et al. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. J Bone Miner Res. 2021;36(11):2193-2202.
Ferreira, C. R., Kintzinger, K., Hackbarth, M. E., Botschen, U., Nitschke, Y., Mughal, M. Z., Baujat, G., Schnabel, D., Yuen, E., Gahl, W. A., Gafni, R. I., Liu, Q., Huertas, P., Khursigara, G., & Rutsch, F. (2021). Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research, 36(11), 2193-2202. https://doi.org/10.1002/jbmr.4418
Ferreira CR, et al. Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. J Bone Miner Res. 2021;36(11):2193-2202. PubMed PMID: 34355424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies. AU - Ferreira,Carlos R, AU - Kintzinger,Kristina, AU - Hackbarth,Mary E, AU - Botschen,Ulrike, AU - Nitschke,Yvonne, AU - Mughal,M Zulf, AU - Baujat,Genevieve, AU - Schnabel,Dirk, AU - Yuen,Eric, AU - Gahl,William A, AU - Gafni,Rachel I, AU - Liu,Qing, AU - Huertas,Pedro, AU - Khursigara,Gus, AU - Rutsch,Frank, Y1 - 2021/08/16/ PY - 2021/07/29/revised PY - 2021/05/21/received PY - 2021/08/01/accepted PY - 2022/11/01/pmc-release PY - 2021/8/7/pubmed PY - 2021/8/7/medline PY - 2021/8/6/entrez KW - ABCC6 deficiency KW - ENPP1 deficiency KW - Generalized Arterial Calcification of Infancy KW - diseases and disorders of/ related to bone KW - ectopic calcification KW - hypophosphatemic rickets KW - natural history study KW - osteomalacia KW - rickets KW - survival analysis SP - 2193 EP - 2202 JF - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JO - J Bone Miner Res VL - 36 IS - 11 N2 - Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA. SN - 1523-4681 UR - https://www.unboundmedicine.com/medline/citation/34355424/Ectopic_Calcification_and_Hypophosphatemic_Rickets:_Natural_History_of_ENPP1_and_ABCC6_Deficiencies_ L2 - https://doi.org/10.1002/jbmr.4418 DB - PRIME DP - Unbound Medicine ER -
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