ESPE Yearbook of Paediatric Endocrinology

J Bone Miner Res. 2021 Nov;36(11):2193-2202Abstract: https://pubmed-ncbi-nlm-nih-gov.proxy.kib.ki.se/34355424/

In brief: Generalised arterial calcification of infancy (GACI) is clinically and genetically a heterogeneous disorder caused by mutations in ENPP1or ABCC6 variants. This multicentre study identified early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets in ENPP1, but not ABCC6 deficiency, and that heterogenous calcification and multiple organ complications occur with both ENPP1 and ABCC6 variants suggesting overlapping pathology.

Commentary: Generalized arterial calcification of infancy (GACI) is a rare autosomal recessive disorder characterized by calcification of arteries and marked neointimal proliferation leading to arterial stenoses and cardiac complications. The disease can manifest prenatally and has a mortality of ~55% in the first 6 months of life despite intensive therapy. However, the disease course after the initial 6 months is not well characterized, with reports limited to case series or small retrospective studies.

In this study, 247 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).

Despite lack of evidence bisphosphonates, especially first-generation, are routinely used for the management of GACI during infancy. This study, however, 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.

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) were found. However, mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157).

A higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared to individuals with ABCC6 (11.8%; p = 0.0001) variants. Eleven affected individuals presented with rickets and without a GACI diagnosis termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1variants. 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.

With the potential for recombinant human (rh)ENPP1-Fc protein to be trialled in GACI and ARHR2, this study will form a benchmark to compare outcomes of novel treatments with historic controls. This study also raises questions about using bisphosphonates in infancy given that it does not offer any survival benefits.