Case Report: Reconciling genomic ambiguity with clinical certainty in refractory panniculitis.
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Panniculitis in adolescents often poses a diagnostic challenge for physicians. We report an adolescent girl presenting with recurrent steroid-responsive lymphocytic septal panniculitis, genital ulcer, and constitutional symptoms, later complicated by macrophage activation syndrome and steatohepatitis. Extensive evaluation excluded infectious, autoimmune, and malignant causes. Histopathology revealed septal panniculitis without vasculitis or atypical lymphoid cells. Whole-exome sequencing identified a heterozygous PSMB9 variant (c.595A>G; p.Thr199Ala) and a homozygous HAVCR2 variant (c.290T>C; p.Ile97Thr); the latter has not been reported in a homozygous state in existing genomic databases and is predicted to be deleterious. The coexistence of panniculitis, haemophagocytic lymphohistiocytosis (HLH)-like manifestations, and histologically lymphocytic rather than neutrophilic infiltrates suggests a distinct panniculitis-HLH overlap syndrome associated with the HAVCR2 mutation, which does not fit within the subcutaneous panniculitis-like T-cell lymphoma spectrum. A potential contribution (gene dosage effect) from the heterozygous PSMB9 mutation was uncertain, as parental testing was not feasible. The patient achieved sustained remission on corticosteroids and tacrolimus. This case broadens the phenotypic spectrum of HAVCR2-associated immune dysregulation and documents a novel homozygous HAVCR2 variant (p.Ile97Thr), underscoring the importance of comprehensive genetic evaluation in patients with unexplained recurrent panniculitis.