Generalized Arterial Calcification of Infancy (GACI).

Generalized arterial calcification of infancy (GACI) is an ultra-rare autosomal recessive disorder associated with pathogenic variants in ENPP1, the major gene involved in this condition, and in ABCC6, which is involved in a small fraction of affected individuals. Loss-of-function pathogenic variants of ENPP1 and ABCC6 lead to perturbations in the PPi/Pi ratio, thereby promoting hydroxyapatite mineralization in peripheral tissues. GACI is initially characterized by an abnormal ectopic mineralization process in arteries and soft tissue. Nearly half of the patients die within the first 6 months of life from cardiovascular complications, hence the poor prognosis associated with an early diagnosis. In recent years, progress has been made in our understanding of the long-term natural history of GACI, the intricate symptoms due to vascular calcifications, the overmineralization of soft tissues, of hypophosphatemia designated as ARHR2, and of the consequences such as undermineralization of the skeleton, but also of the features possibly seen in pseudoxanthoma elasticum (PXE). Indeed, GACI, PXE, and ARHR2 share common pathophysiological pathways and clinical features beyond the vascular calcifications. Treatment options for severe forms of GACI are mostly based on symptomatic management, including the option of starting bisphosphonates early after birth, such as etidronate and pamidronate, analogues of PPi. Follow-up within an expert and coordinated multidisciplinary team includes treatment of arterial hypertension, calcitriol and phosphorus adjustments, hearing aids, and early detection of possible angioid streaks. It is hoped that ongoing basic and clinical research will lead to the development of effective therapies that specifically target the abnormal PPi regulation and the other mechanisms involved in this disorder.

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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 G. Baujat declares competing interest for occasional advisory consultancy and for the occasional production of expert's reports for Biomarin, Inozyme, Ipsen, Sanofi and Alexion; for participations in scientific work and studies for Incyte, Ipsen, Qed, Ascendis, Biomarin, Alexion, Clementia and Therachon Pfizer; for writing articles and interventions in congresses, conferences, symposia, various public meetings for Elsevier, Biomarin, Ipsen and Alexion. A. Besançon declares no competing interest related to this article. This article is part of a supplement entitled Mineral metabolism disorders: what if it was ENPP1 deficiency? published with institutional support from Inozyme.