National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.
J Bone Miner Res. 2021 Nov;36(11):2193-2202. doi: 10.1002/jbmr.4418. Epub 2021 Aug 16.
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.
婴儿全身性动脉钙化症（GACI）是一种由 ENPP1 或 ABCC6 变异引起的罕见疾病。GACI 的特征是焦磷酸盐水平低、动脉钙化和出生后第一年的高死亡率，但自然病程和致病基因之间可能存在的差异尚不清楚。本研究共回顾了 19 个国家的 247 名 GACI 患者（从出生到 58.3 岁）的个体记录。总体死亡率为 54.7%（宫内或死产 13.4%），6 个月以下（关键期）死亡的概率为 50.4%。与之前的文献不同，我们发现根据起始时间匹配分析，双膦酸盐治疗并没有生存获益，并且在出生后 2 周内开始治疗时结果不确定。尽管 ENPP1 和 ABCC6 缺乏症的 GACI 表型患病率相似，包括动脉钙化（分别为 77.2%和 89.5%）、器官钙化（分别为 65.8%和 84.2%）和心血管并发症（分别为 58.4%和 78.9%），但与 ABCC6 变体相比，ENPP1 变体的死亡率更高（分别为 40.5%对 10.5%；p=0.0157）。与 ABCC6 相比，ENPP1 中存活受影响个体的佝偻病患病率更高（70.8%对 11.8%；p=0.0001）。11 名表现为佝偻病而无 GACI 诊断的受影响个体，称为常染色体隐性低磷血症性佝偻病 2 型（ARHR2），均证实存在 ENPP1 变异。这些患者中有近 70%表现出异位钙化或类似于 GACI 患者的并发症的证据，这表明 ARHR2 不是与 GACI 不同的疾病，而是 ENPP1 缺乏症的一部分。总体而言，尽管尝试用双膦酸盐治疗，但本研究仍确定了 GACI 患者的早期死亡风险，ENPP1 缺乏症中佝偻病的高患病率，以及 ENPP1 和 ABCC6 变异均可导致异质钙化和多种器官并发症的范围，这表明存在重叠的病理学。© 2021 作者。由 Wiley 期刊出版社代表美国骨矿研究协会（ASBMR）出版的《骨与矿物研究杂志》刊登了这篇文章。本文的作者均为美国政府雇员，其工作在美国属于公有领域。
