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Review
. 2024 Sep;31(4S1):4S27-4S32.
doi: 10.1016/S0929-693X(24)00154-4.

Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2)

Thomas Edouard  1 , Agnès Linglart  2
Affiliations
Review

Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2)

Thomas Edouard et al. Arch Pediatr. 2024 Sep.

Abstract

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies.

Keywords: Autosomal recessive hypophosphatemic rickets type 2 (ARHR2); Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1 deficiency); Generalized arterial calcification of infancy (GACI).

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Conflict of interest statement

Declaration of competing interest T. Edouard declares competing interest for invitations to congresses as a speaker by Novonordisk, Biomarinand KyowaKirin; for invitations to congresses as a participant (expenses paid) by Merck-Serono; for his involvement in clinical trials (as principal investigator, coordinator, or principal experimenter) for Novonordisk and Biomarin; in clinical trials (as co-investigator, non-principal experimenter, or collaborator) for QED therapeutics; for receiving compensation for advisory consultancies from Novonordisk and Biomarin. A. Linglart declares competing interest for occasional advisory consultancy by Novonordisk, Merck, bridgebio and Alexion; invitations to congresses as a speaker by Novonordisk, Alexion and Kyowa Kirin; for her involvement in clinical trials (as principal investigator, coordinator, or principal experimenter) for Novonordisk, Recordati, Inozyme 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.

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