ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification

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.

Case Report and Review of Literature: Autosomal Recessive Hypophosphatemic Rickets Type 2 Caused by a Pathogenic Variant in ENPP1 Gene

“…As ENPP1 produces PPi, a potent endogenous inhibitor of hydroxyapatite crystal formation, it has been reported that certain ENPP1-deficient patients develop PXE, a disorder characterized by ectopic mineralization of the matrix in the skin, eyes, and cardiovascular system (5,26). Reduced concentration of PPi is important in pathogenesis of both GACI and PXE (26), although it is not evaluated in this case report. To date, there have been no reports of PXE in ARHR2 patients until now (Table 2).…”

“…A radiologic evaluation should be performed before conducting surgery in ARHR2 patients, since careful endotracheal intubation is needed to avoid hyperextension in cervical OPLL (25). As ENPP1 produces PPi, a potent endogenous inhibitor of hydroxyapatite crystal formation, it has been reported that certain ENPP1-deficient patients develop PXE, a disorder characterized by ectopic mineralization of the matrix in the skin, eyes, and cardiovascular system (5,26). Reduced concentration of PPi is important in pathogenesis of both GACI and PXE (26), although it is not evaluated in this case report.…”

Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma

“…Some GACI survivors with ENPP1 variants develop PXE‐like skin and eye findings (Ferreira, Hackbarth, et al, 2021; Ferreira, Kintzinger, et al, 2021), whereas some adult PXE patients harboring ENPP1 variants do not manifest with vascular phenotypes (Jin et al, 2015; Ralph et al, 2022b). The reduced plasma PPi concentrations of varying degrees are reported to correlate, in general, with the severity of pathologic calcification in several monogenic disorders of pathologic calcification, including ABCC6‐deficient PXE (60%–70% reduction) and ENPP1‐deficient GACI (90‐100% reduction) (Ralph et al, 2022a).…”

“…Some GACI survivors with ENPP1 variants develop PXE-like skin and eye findings Ferreira, Kintzinger, et al, 2021), whereas some adult PXE patients harboring ENPP1 variants do not manifest with vascular phenotypes (Jin et al, 2015;Ralph et al, 2022b).…”

“…Some GACI patients, initially diagnosed prenatally or neonatally with vascular calcification, were reported to develop skin lesions and/or angioid streaks, similar to those in PXE (Ferreira, Hackbarth, et al, 2021; Ferreira, Kintzinger, et al, 2021). Subsequently, inactivating variants in ENPP1 were associated with classic PXE in adult patients (Ralph et al, 2022b; Jin et al, 2015). The same ENPP1 variant can cause both PXE and GACI, highlighting the genotypic and phenotypic overlap between these two disorders (Table 1).…”