Authors
Douglas Ralph, 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; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
Yvonne Nitschke, Münster University Children's Hospital, Münster, Germany
Michael A Levine, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America
Matthew Caffet, PXE International, Inc., Damascus, Maryland, United States of America
Tamara Wurst, PXE International, Inc., Damascus, Maryland, United States of America
Amir Hossein Saeidian, 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
Leila Youssefian, 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
Hassan Vahidnezhad, 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
Sharon F Terry, PXE International, Inc., Damascus, Maryland, United States of America
Frank Rutsch, Münster University Children's Hospital, Münster, Germany
Jouni Uitto, 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; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
Qiaoli Li, 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; PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
Publication Date
4-28-2022
Abstract
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.
Recommended Citation
Ralph, Douglas; Nitschke, Yvonne; Levine, Michael A; Caffet, Matthew; Wurst, Tamara; Saeidian, Amir Hossein; Youssefian, Leila; Vahidnezhad, Hassan; Terry, Sharon F; Rutsch, Frank; Uitto, Jouni; and Li, Qiaoli, "ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification." (2022). Department of Medicine Faculty Papers. Paper 362.
https://jdc.jefferson.edu/medfp/362
Comments
This article is the author's final published version in PLoS Genetics, Volume 18, Issue 4, April 2022, Article number e1010192.
The published version is available at https://doi.org/10.1371/journal.pgen.1010192.
Copyright © 2022 Ralph et al
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.