Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
Genetics, Genomics and Cancer Biology Ph.D. Program, Jefferson College of Life Sciences, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2022 Apr 28;18(4):e1010192. doi: 10.1371/journal.pgen.1010192. eCollection 2022 Apr.
Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy inheritance. Functional assessment of five previously unreported ENPP1 variants suggested pathogenicity. The two PXE patients, currently 57 and 27 years of age, had diagnostic features of PXE and had not manifested the GACI phenotype. The similarly reduced PPi plasma concentrations in the PXE and GACI patients in our study correlate poorly with their disease severity. This study demonstrates that in addition to GACI, ENPP1 variants can cause classic PXE, expanding the clinical and genetic heterogeneity of heritable ectopic calcification disorders. Furthermore, the results challenge the current prevailing concept that plasma PPi is the only factor governing the severity of ectopic calcification.
弹性假黄瘤（PXE）和婴儿型全身动脉钙化（GACI）是两种临床特征明显的异位钙化遗传疾病，其特征是循环中无机焦磷酸盐（PPi）水平降低，PPi 是一种有效的内源性钙化抑制剂。GACI 中突变的基因 ENPP1 的变异与经典 PXE 无关。在此，我们报告了分别在 GACI 全球和 PXE 国际数据库中注册的五个和两个无关家族的 10 名 GACI 和 2 名 PXE 患者的临床、实验室和分子评估结果。所有患者均被发现携带 ENPP1 的双等位基因突变。在十种 ENPP1 变异体中，一种纯合变异体表现为单亲二倍体遗传。对五种以前未报道过的 ENPP1 变异体的功能评估表明其具有致病性。这两名 PXE 患者，目前分别为 57 岁和 27 岁，具有 PXE 的诊断特征，且未表现出 GACI 表型。我们研究中的 PXE 和 GACI 患者的血浆 PPi 浓度同样降低，与疾病严重程度相关性差。这项研究表明，除了 GACI，ENPP1 变异体还可导致经典 PXE，扩展了遗传性异位钙化疾病的临床和遗传异质性。此外，结果还挑战了目前普遍认为的血浆 PPi 是唯一控制异位钙化严重程度的因素的观点。
