Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).

Autor: Ferreira CR; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. ferreiracr@mail.nih.gov., Hackbarth ME; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Ziegler SG; Departments of Pediatrics and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Pan KS; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA., Roberts MS; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA., Rosing DR; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Whelpley MS; Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Bryant JC; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Macnamara EF; Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA., Wang S; ICON plc, Vancouver, BC, Canada., Müller K; ICON plc, Vancouver, BC, Canada., Hartley IR; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA., Chew EY; Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA., Corden TE; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA., Jacobsen CM; Divisions of Endocrinology and Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA, USA., Holm IA; 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., Rutsch F; Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany., Dikoglu E; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Chen MY; Cardiovascular CT Laboratory, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA., Mughal MZ; Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester University Hospital's NHS Trust, Manchester, UK., Levine MA; 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., Gafni RI; Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA., Gahl WA; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Feb; Vol. 23 (2), pp. 396-407. Date of Electronic Publication: 2020 Oct 02.
DOI: 10.1038/s41436-020-00983-0
Abstrakt: 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.
Databáze: MEDLINE
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