Unmet needs in SLC29A3-related disorders.

Abstract

SLC29A3-related disorders are autosomal recessive conditions characterized by histiocytic infiltration, autoinflammatory and autoimmune manifestations, and variable degrees of immune deficiency. SLC29A3-related disorders are rare and complex, with a broad spectrum of manifestations, even among individuals carrying the same pathological genetic variants. Initially reported as H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis or familial Rosai-Dorfman disease (RDD), genetics enabled to unify this syndrome under the SLC29A3-related disorders, an autosomal recessive disease. SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). The advent of high-throughput sequencing technologies such as exome and genome sequencing has facilitated the identification of new causing variants of SLC29A3 in patients with atypical or previously unrecognized phenotypes. Functional studies have demonstrated that damaging variants in SLC29A3 result in aberrant activation of inflammatory and proliferative signaling cascades, including the MAPK pathway and Toll-like receptor 7/8 (TLR7/8) overactivation. These molecular events lead to macrophage hyperactivation and excessive pro-inflammatory cytokine production, establishing SCL29A3-related disorders as a histiocytic inflammatory condition. Despite these advances, several immunopathological mechanisms remain incompletely understood, warranting further investigation. This article underscores the unmet clinical and research needs in SLC29A3-related disorders, emphasizing the immunological perspective to support the development of new diagnostic and therapeutic approaches for this rare disease with complex immunogenetic landscape.