Clinical presentation and burden of ENPP1 deficiency in adults.

While the clinical consequences of severe ENPP1 deficiency leading to the rare disorders generalized arterial calcification of infancy (GACI) and autosomal recessive hypophosphatemic rickets type 2 (ARHR2) are well defined and understood, much less is known about how this evolves into adulthood and how moderate ENPP1 deficiency can first manifest in adulthood. Moreover, growing evidence substantiates an association of genetic variants in the ENPP1 gene with a wide range of further clinical manifestations including early-onset osteoporosis, osteoarthritis, and different forms of spinal ligament calcifications, i.e., diffuse idiopathic skeletal hyperostosis (DISH) and ossification of the posterior/anterior longitudinal ligament (OPLL/OALL). Furthermore, conditions with primarily extraskeletal signs and symptoms such as Cole disease, coagulopathies, and metabolic syndrome can seemingly result from ENPP1 variants. The causality and the pathophysiology behind these different clinical presentations appear complex and require further research, especially since the coincidence of these different phenotypes is rarely described and available evidence suggests that part of the aforementioned manifestations may result from ENPP1 effects beyond the catalytic activity of processing ATP to AMP and inorganic pyrophosphate (PPi). Growing awareness of the additional ENPP1-related manifestations across the lifespan will advance our understanding of this complex condition and help to standardize diagnostic approaches and develop individually tailored treatment concepts.

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Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved. Published by Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest L. Seefried declares competing interest for lectures and advice from Amgen, AM-Pharma, Alexion, Biomarin, Chiesi, GedeonRichter, GSK/Haleon, Inozyme, Ipsen, KyowaKirin, Mereo, Novartis, Stadapharm, Theramex, and Ultragenyx and research grants to the Institution (University of Würzburg) from Alexion, Chiesi, and Kyowa Kirin. This article is part of a supplement entitled Mineral metabolism disorders: what if it was ENPP1 deficiency? published with institutional support from Inozyme.