Paediatric angioedema without wheals: spectrum and possible HAE at a Japanese allergy centre

Angioedema is classified into mast cell-mediated, bradykinin-mediated, intrinsic endothelial dysfunction-related, drug-induced, and idiopathic forms, yet the diagnostic spectrum in Japanese paediatric patients has not been described. Because many individuals with hereditary angioedema (HAE) experience onset in childhood and diagnostic delay can be prolonged, early recognition is essential. We retrospectively reviewed 14 pediatric patients referred to our center between July 1, 2023, and January 31, 2024, primarily for evaluation of possible HAE, including angioedema without wheals. Clinical features, family history, laboratory findings, and response to antihistamines were assessed. Patients were 5–16 years old, and 57% had a family history of angioedema. All had normal C4 and C1 inhibitor (C1-INH) levels, and no cases of HAE-C1INH were identified. Seven patients were diagnosed with mast cell-mediated angioedema. Other diagnoses included pollen–food allergy syndrome, suspected inducible laryngeal obstruction, granulomatous cheilitis associated with Crohn’s disease, and Kimura disease. Two patients were suspected of having HAE with normal C1-INH (HAE-nC1INH) based on family history and lack of response to antihistamines or corticosteroids, although no pathogenic variants were detected on insurance-covered gene panels. One patient was diagnosed with idiopathic nonmast cell-mediated angioedema. This first report from Japan highlights that most pediatric referrals for suspected HAE ultimately reflect mast cell–mediated disease. Careful evaluation of clinical course and treatment response is critical, especially when laboratory findings are normal. Expanded genetic panels and structured diagnostic approaches may support earlier diagnosis.