D2.384 - Early inflammatory manifestations in a child carrying a heterozygous TREX1 variant: possible evolving interferonopathy?

Background 

Type I interferonopathies are an emerging group of monogenic disorders caused by dysregulated interferon signaling. Their clinical presentation is highly variable and can resemble infectious, autoimmune, or allergic diseases, which often makes diagnosis challenging. The TREX1 gene encodes a DNA exonuclease enzyme involved in nucleic acid metabolism and innate immunity regulation. Pathogenic TREX1 variants have been linked to disorders such as Aicardi–Goutières syndrome, familial chilblain lupus and other interferon-mediated disorders. Importantly, several TREX1-associated conditions demonstrate autosomal dominant inheritance, making heterozygous pathogenic variants clinically relevant.

Case Description  

A 5-year-old girl was first referred to our institute at the age of 2 due to recurrent unexplained febrile episodes accompanied by elevated inflammatory markers, including increased C-reactive protein (CRP) and leukocytosis. Over time, she developed recurrent small erythematous to violaceous papules and plaques, some with central crusting and erosions, mainly localized on the gluteal region, extremities, and trunk. The skin lesions tend to worsen during the winter months. During follow-up, intermittent episodes of non-bloody diarrhea lasting longer than a month were also reported. Extensive infectious and allergic evaluations were unremarkable. Immunoglobulin levels were within normal limits, and antinuclear antibodies (ANA) were negative. 

Results 

Next-generation sequencing using a targeted autoinflammatory gene panel identified a heterozygous TREX1 c.341G>A (p.Arg114His) pathogenic variant. This variant has been previously reported in association with TREX1-related interferonopathies and affects a conserved residue within the TREX1 dimer interface. Functional studies have shown reduced exonuclease activity, which may lead to impaired clearance of cytosolic DNA and increased interferon pathway activation, potentially contributing to the patient’s systemic inflammatory and cutaneous phenotype.  

Conclusion 

This case highlights the phenotypic variability of heterozygous TREX1-associated disease and suggests that patients may manifest with subtle autoinflammatory features in early childhood. Early genetic testing in children with unexplained recurrent inflammation can reduce diagnostic delay, enable closer monitoring for potential progression, and guide therapeutic decision-making.