Complex inflammatory phenotypes in children can pose significant diagnostic challenges, particularly when clinical, histopathologic, and immunologic findings do not conform to established diagnoses. We present a case of a child with recurrent severe aphthous stomatitis, abdominal pain, and constipation, with laboratory evidence of immune dysregulation and gastrointestinal inflammation on biopsy, whose underlying etiology remains undefined.
A 6-year-old boy presented with a history of recurrent aphthous stomatitis, abdominal pain, and constipation since toddlerhood. Previously, oral lesions were mild, self-resolving, and occurred bimonthly without significantly impacting oral intake. Recently, he developed worsening and persistent symptoms with severe mucosal lesions limiting oral intake, low-grade fevers, and flares lasting weeks to months. Prior workup revealed IgA deficiency. Infectious workup, including herpes simplex virus (HSV) and varicella zoster virus (VZV), was negative. Trials of systemic corticosteroids and azithromycin provided no significant improvement.
Immunological evaluation revealed elevated inflammatory markers, including TNF-alpha, IFN-gamma, soluble IL-2 receptor, IL-12, IL-10, IL-8, and elevated CXCL9, suggesting innate or adaptive immune activation. Lymphocyte subsets were normal.
Esophagogastroduodenoscopy and colonoscopy revealed patchy mucosal congestion with aphthous lesions in the rectum and scattered erythematous areas throughout the colon. Histopathology demonstrated focal reactive changes with increased lamina propria fibrosis and mild basement membrane thickening—nonspecific findings suggestive of inflammatory etiology, though not diagnostic of inflammatory bowel disease. Magnetic resonance (MR) enterography showed no bowel wall inflammation.
Targeted genetic panel testing identified several variants, including a heterozygous NOD2 risk allele, a novel heterozygous SLC2A2 splice-site variant, and additional variants of uncertain significance (VUSs). However, their contribution to the phenotype remains unclear. Given the severity of symptoms, the patient is planned for a trial of anti-TNF to assess clinical response while comprehensive immunologic and genomic analysis continues.
This case illustrates the complexity and need to balance diagnostic workup and empiric treatment in pediatric patients presenting with recurrent mucosal inflammation, atypical histopathology, and systemic hyperinflammatory features without a unifying diagnosis. The findings suggest an autoinflammatory or immune dysregulatory process but do not conclusively support classical diagnoses such as Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) syndrome, Behçet disease, or inflammatory bowel disease (IBD). Further genetic and functional studies are pending while clinical response to anti-TNF therapy is being evaluated.
