Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis.

backgroundABCC6 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.

resultsA 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).

conclusionsThese 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.