Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Genet Med. 2021 Feb;23(2):396-407. doi: 10.1038/s41436-020-00983-0. Epub 2020 Oct 2.
Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion.
We performed deep phenotyping of 20 GACI survivors.
Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies.
GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.
婴儿全身性动脉钙化症（GACI）的特征是血管钙化，通常在出生后不久就会致命，其病因通常是由于缺乏 ENPP1。一小部分 GACI 病例是由 ABCC6 缺乏引起的，ABCC6 是一种膜转运蛋白。GACI 幸存者的自然病史尚未以前瞻性方式确定。
我们对 20 名 GACI 幸存者进行了深度表型分析。
20 名受试者中有 16 名出现动脉钙化，但只有 5 名在评估时仍有残留病变。ENPP1 缺乏症患者要么患有低磷血症性佝偻病，要么预计到 14 岁时会发生该病；16 名中有 14 名患者的完整成纤维细胞生长因子 23 水平升高（iFGF23）。血磷酸盐水平与 iFGF23 呈负相关。对于 ENPP1 缺乏症患者，颈椎融合的终生风险为 25%，听力损失的风险为 75%，成年患者的主要发病机制与肌腱钙化有关。4 名 ENPP1 缺乏症患者表现出 PXE 的典型皮肤或视网膜表现。我们估计，ENPP1 缺乏症的最小发病率约为每 20 万次妊娠 1 例。
GACI 的发病率似乎比以前认为的要高，其重叠表型的范围也在扩大。ENPP1 减少、iFGF23 增加和佝偻病之间的关系可能为未来的治疗提供信息。
