Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis

TL;DR

This study examines the genetic and physical traits of ABCC6 deficiency in children, revealing early and varied complications that suggest the condition is underdiagnosed.

Contribution

The study provides the first comprehensive analysis of ABCC6 deficiency in the pediatric population, highlighting its clinical variability and early manifestations.

Findings

ABCC6 deficiency in children shows high prevalence of ectopic calcification and complications in cardiovascular, dermatologic, neurologic, and ocular systems.

Many pediatric patients exhibit overlapping features of GACI and PXE, with significant phenotypic variability among those with the same genetic variants.

Clinical manifestations are most frequent before age 6, with a decline in frequency from ages 7 to 18.

Abstract

ABCC6 deficiency is caused by variants in the ABCC6 gene, leading to dysfunction of the ABCC6 protein. This can result in the development of the infantile phenotype, generalized arterial calcification of infancy type 2 (GACI2), or the adolescent-adult phenotype, pseudoxanthoma elasticum (PXE). To date, the impact of ABCC6 deficiency in a pediatric population has not been comprehensively studied. This analysis aimed to collectively characterize the genotypic and phenotypic presentation of ABCC6 deficiency in the pediatric population.

A literature review and analysis identified 95 individuals with ABCC6 variant(s) and documented clinical manifestations occurring from ages 0 to < 18 years. Of the 133 ABCC6 variants found, 57.1% were pathogenic, 26.3% were likely pathogenic, and 10.5% were of uncertain significance. A high prevalence of ectopic calcification with cardiovascular, dermatologic, neurologic, and ocular complications was observed across this pediatric ABCC6 deficiency cohort. While 56% were diagnosed with GACI and 44% with PXE, many individuals exhibited overlapping features of both conditions. There was a relatively high frequency of clinical manifestations through 6 years of age with lower frequency from ages 7 to 18 years. There was significant phenotypic variability observed across patients harboring the same ABCC6 variant(s).

These findings demonstrate the wide spectrum and early emergence of cardiovascular, neurologic, and ocular complications in pediatric patients with ABCC6 deficiency. Given the variability of clinical presentations and absence of systematic phenotype characterization, pediatric ABCC6 deficiency is likely underdiagnosed. Establishing guidelines for assessment, genetic diagnosis, monitoring, and prognostic counseling would assist in the timely diagnosis and multidisciplinary management of pediatric patients with ABCC6 deficiency.

The online version contains supplementary material available at 10.1186/s13023-025-04102-7.

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