Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Abstract

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology.

Abcc6 Null Mice—a Model for Mineralization Disorder PXE Shows Vertebral Osteopenia Without Enhanced Intervertebral Disc Calcification With Aging

“…The tissues usually affected in PXE patients are more reliant on, and therefore more susceptible to, systemic plasma concentrations of PPi. This point is underscored by a recent study comparing the phenotypes of patients with ENPP1 and ABCC6 deficiencies (Ferreira et al, 2021). The authors reported a significantly lower incidence of joint calcification in ABCC6-deficient patients than patients with ENPP1-deficit, suggesting that local regulation of PPi and AMP levels may be critical in ectopic mineralization of cartilaginous tissues (Ferreira et al, 2021).…”

“…Surprisingly, reports of PXE-related calcifications in the musculoskeletal system have only until recently been investigated in zebrafish, where the knockout of the ABCC6 ortholog resulted in hypermineralization of the axial skeleton (Mackay et al, 2015). A very recent study showed that a small subset, 16.7%, of adult GACI patients with mutations in ABCC6 suffered from hypophosphatemic rickets (Ferreira et al, 2021), implying that bone is an affected tissue in relation to ABCC6 mutations. It is also important to note that the intervertebral disc contains an extensive elastin fiber network (Yu et al, 2007), which increases with aging and degeneration (Cloyd and Elliott, 1976).…”

Case Report: A Novel Genetic Mutation Causes Idiopathic Infantile Arterial Calcification in Preterm Infants

“…There is a genotypic overlap between IIAC and PXE, with some patients harboring mutations in ABCC6, and some patients with clinical manifestations consistent with PXE have mutations in ENPP1 ( Nitschke et al, 2012 ). The main manifestations are calcification of the skin elastic fibers, systemic arterial vascular calcification, and cervical vertebral fusion ( Ferreira et al, 2021a ).…”

“…Combined coronary artery calcification is a major risk factor for a poor prognosis. Most deaths occur in infancy, and rapidly progressive malignant heart failure is often the main cause of death ( Nael et al, 2014 ; Ferreira et al, 2021a ). Individuals may die suddenly due to myocardial infarction.…”

How FGF23 shapes multiple organs in chronic kidney disease

“…In contrast, autosomalrecessive hypophosphatemic rickets type 2 due to ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) variants is associated with vascular calcifications. However, these are thought not to be due to FGF23 excess but rather as a consequence of the reduced synthesis of inorganic pyrophosphate (PPi), a well-known inhibitor of calcium hydroxyapatite crystal deposition and preventor of ectopic soft tissue calcification [28]. Taken together, it is still questioned whether high FGF23 levels alone are a major driver of vascular alterations in CKD, i.e., endothelial dysfunction and vascular calcification.…”