Redox imbalance and NLRP3 activation: H syndrome mistaken for CAPS—a case report

Objectives H syndrome is a rare autosomal recessive disorder caused by mutations in SLC29A3, encoding the nucleoside transporter hENT3. Its heterogeneous clinical presentation often includes skin hyperpigmentation, systemic inflammation, endocrinopathies and sensorineural hearing loss. However, typical cutaneous signs may be absent, leading to diagnostic challenges. The objective was to describe a patient with H syndrome misdiagnosed until adulthood as having cryopyrin-associated periodic syndrome (CAPS), due to overlapping clinical and functional features. Methods We conducted clinical, immunological, genetic and functional assessments in a 24-year-old male with a complex history of early-onset urticarial rash, fever, hearing loss, oral ulcers, colitis and episodic inflammation. Genetic analyses included whole-exome sequencing (WES) and segregation study by quantitative PCR (qPCR). Functional assays evaluated IL-1β secretion, ASC speck formation, reactive oxygen species (ROS) production and type I interferon signature. Results The patient showed enhanced and accelerated IL-1β secretion and increased ASC speck formation in CD14+ cells after lipopolysaccharide (LPS) stimulation, indicating NLRP3 inflammasome hyperactivation, hallmark features of CAPS. ROS production was significantly elevated in both granulocytes and monocytes, even at baseline. A type I interferon signature was intermittently positive. Genetic testing ultimately revealed a homozygous deletion of exon 2 in the SLC29A3 gene, confirming H syndrome. Conclusion This case highlights the phenotypic overlap between H syndrome and CAPS, including shared inflammasome dysregulation. Absence of typical skin hyperpigmentation delayed diagnosis despite early-onset systemic inflammation and partial response to IL-1 blockade. Functional assays may support diagnostic refinement in autoinflammatory syndromes with atypical features or inconclusive genetics.