Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI),Genetics in Medicine

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Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI)
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-10-02 , DOI: 10.1038/s41436-020-00983-0
Carlos R Ferreira ₁ , Mary E Hackbarth ₂ , Shira G Ziegler ₃ , Kristen S Pan ₄ , Mary S Roberts ₄ , Douglas R Rosing ₅ , Margaret S Whelpley ₅ , Joy C Bryant ₂ , Ellen F Macnamara ₆ , Sisi Wang ₇ , Kerstin Müller ₇ , Iris R Hartley ₄ , Emily Y Chew ₈ , Timothy E Corden ₉ , Christina M Jacobsen _{10,

11} , Ingrid A Holm _{11,

12} , Frank Rutsch ₁₃ , Esra Dikoglu ₁₄ , Marcus Y Chen ₁₅ , M Zulf Mughal ₁₆ , Michael A Levine ₁₇ , Rachel I Gafni ₄ , William A Gahl ₂

Affiliation

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.
Departments of Pediatrics and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
ICON plc, Vancouver, BC, Canada.
Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children's Hospital, Boston, MA, USA.
Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany.
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Cardiovascular CT Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester University Hospital's NHS Trust, Manchester, UK.
Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Purpose

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.

Methods

We performed deep phenotyping of 20 GACI survivors.

Results

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.

Conclusion

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.

中文翻译：

婴儿全身动脉钙化 (GACI) 长期幸存者的前瞻性表型分析

目的

婴儿广泛性动脉钙化 (GACI) 的特点是血管钙化，通常在出生后不久就会致命，通常是由 ENPP1 缺乏引起的。一小部分 GACI 病例是由于膜转运蛋白 ABCC6 的缺乏引起的。GACI 幸存者的自然史尚未以前瞻性方式确定。

方法

我们对 20 名 GACI 幸存者进行了深度表型分析。

结果

20 名受试者中有 16 名出现动脉钙化，但在评估时只有 5 名有残余受累。患有 ENPP1 缺乏症的个体要么患有低磷性佝偻病，要么预计会在 14 岁时发生；14/16 具有升高的完整 FGF23 水平 (iFGF23)。血磷酸盐水平与 iFGF23 呈负相关。对于 ENPP1 缺陷的个体，颈椎融合的终生风险为 25%，听力损失的风险为 75%，成人的主要发病率与附着点钙化有关。四个 ENPP1 缺陷个体表现出 PXE 的典型皮肤或视网膜表现。我们估计在 200,000 例妊娠中 ENPP1 缺乏症的最低发生率约为 1 例。