Tags

Type your tag names separated by a space and hit enter

Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI).
Genet Med. 2021 02; 23(2):396-407.GM

Abstract

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.

Authors+Show Affiliations

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. ferreiracr@mail.nih.gov.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.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.Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.Medical Genetics Branch, National Human Genome Research 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.ICON plc, Vancouver, BC, Canada.Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.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.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.Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

33005041

Citation

Ferreira, Carlos R., et al. "Prospective Phenotyping of Long-term Survivors of Generalized Arterial Calcification of Infancy (GACI)." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 23, no. 2, 2021, pp. 396-407.
Ferreira CR, Hackbarth ME, Ziegler SG, et al. Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genet Med. 2021;23(2):396-407.
Ferreira, C. R., Hackbarth, M. E., Ziegler, S. G., Pan, K. S., Roberts, M. S., Rosing, D. R., Whelpley, M. S., Bryant, J. C., Macnamara, E. F., Wang, S., Müller, K., Hartley, I. R., Chew, E. Y., Corden, T. E., Jacobsen, C. M., Holm, I. A., Rutsch, F., Dikoglu, E., Chen, M. Y., ... Gahl, W. A. (2021). Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). Genetics in Medicine : Official Journal of the American College of Medical Genetics, 23(2), 396-407. https://doi.org/10.1038/s41436-020-00983-0
Ferreira CR, et al. Prospective Phenotyping of Long-term Survivors of Generalized Arterial Calcification of Infancy (GACI). Genet Med. 2021;23(2):396-407. PubMed PMID: 33005041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prospective phenotyping of long-term survivors of generalized arterial calcification of infancy (GACI). AU - Ferreira,Carlos R, AU - Hackbarth,Mary E, AU - Ziegler,Shira G, AU - Pan,Kristen S, AU - Roberts,Mary S, AU - Rosing,Douglas R, AU - Whelpley,Margaret S, AU - Bryant,Joy C, AU - Macnamara,Ellen F, AU - Wang,Sisi, AU - Müller,Kerstin, AU - Hartley,Iris R, AU - Chew,Emily Y, AU - Corden,Timothy E, AU - Jacobsen,Christina M, AU - Holm,Ingrid A, AU - Rutsch,Frank, AU - Dikoglu,Esra, AU - Chen,Marcus Y, AU - Mughal,M Zulf, AU - Levine,Michael A, AU - Gafni,Rachel I, AU - Gahl,William A, Y1 - 2020/10/02/ PY - 2020/07/06/received PY - 2020/09/18/accepted PY - 2020/09/15/revised PY - 2020/10/3/pubmed PY - 2021/6/4/medline PY - 2020/10/2/entrez KW - ABCC6 deficiency KW - ENPP1 deficiency KW - autosomal recessive hypophosphatemic rickets type 2 KW - generalized arterial calcification of infancy KW - pseudoxanthoma elasticum SP - 396 EP - 407 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 23 IS - 2 N2 - 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/33005041/Prospective_phenotyping_of_long_term_survivors_of_generalized_arterial_calcification_of_infancy__GACI__ L2 - https://doi.org/10.1038/s41436-020-00983-0 DB - PRIME DP - Unbound Medicine ER -