Two novel frameshift variations in the gene expand the mutational spectrum of DEX: case report and literature review.

Background: Variants in the gene have recently been reported to cause a primary immune dysregulation disease called deficiency in , X-linked (DEX). Its clinical spectrum includes fever of unknown origin, recurrent oral ulcers, inflammatory bowel disease (IBD)-like symptoms, anemia, arthritis, and systemic lupus erythematosus. Although the condition is increasingly recognized, it remains rare in pediatric populations.

Case Description: We report our experience of two patients with DEX. The first patient, a 7-year-and-4-month-old boy, initially developed recurrent oral ulcers at 6 years of age. He later experienced fever and perianal ulcers, with laboratory tests showing elevated inflammatory marker levels. Colonoscopy revealed multiple ulcers in the colon and terminal ileum. Despite exclusive enteral nutrition, there was no clinical improvement. Next-generation sequencing revealed the novel hemizygous variant c.835_836insTATACTACCAGTATACCAAAGAGGCATACTGG (p.Ala279ValfsTer103) in the gene. Following induction therapy and maintenance treatment with the anti-tumor necrosis factor-α (TNF-α) agent adalimumab, intestinal ulcers nearly healed. The second patient, a 12-year-6-month-old boy, presented with a 1-year history of recurrent oral ulcers, reduced appetite, intermittent abdominal pain, and notable weight loss. Laboratory findings revealed elevated inflammatory markers. Endoscopic examination revealed a large ulcer in the ileocecal region that extended into the ascending colon. Treatment with corticosteroids and partial enteral nutrition led to symptomatic improvement. Next-generation sequencing revealed a frameshift variant in [exon 3: c.87delC (p.S30Lfs*6), XLR]. To contextualize these findings, we also reviewed previously reported genotypes and phenotypes of patients treated for DEX.

Conclusions: Patients with DEX may present as nonspecific ulcers in the gastrointestinal tract and can be misinterpreted as IBD or Behçet's disease. Genetic testing plays a crucial role in achieving an accurate diagnosis in pediatric patients. The present study also expands the spectrum of mutation-induced immune dysregulation.