From “Congenital Urticaria” to CAPS: An Atypical Presentation Within the NLRP3-AID Spectrum

Introduction Cryopyrin-associated periodic syndromes (CAPS) are rare, monogenic autoinflammatory diseases caused by gain-of-function variants in NLRP3. Traditionally classified into three phenotypes—familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular syndrome (CINCA/NOMID)—recent evidence supports a continuum of disease within the NLRP3-associated autoinflammatory disease (NLRP3-AID) spectrum. Case Presentation A 10-year-old girl presented with a lifelong history of daily urticarial rash since the first month of life. Lesions were spontaneous, painless, and non-pruritic. Symptoms worsened with cold exposure, temperature changes, and emotional stress, but also occurred spontaneously. She reported intermittent episodes (every 2–3 months) of self-limited low-grade fever, headache, abdominal pain, arthralgias, and non-purulent conjunctivitis lasting 2–3 days. At age 1, she was diagnosed with “congenital urticaria” based on skin biopsy (interstitial urticarial dermatitis without mast cell proliferation) and treated with H1-antihistamines, without improvement, severely impacting her quality of life. Repeated labs during asymptomatic periods showed persistent anemia, neutrophilic leukocytosis, elevated C-reactive protein/erythrocyte sedimentation rate, and increased IgG/IgD levels. No history of recurrent infections, autoimmunity, consanguinity, or similar family symptoms was reported. Examination revealed widespread urticarial lesions but no other abnormalities. A next-generation sequencing panel for inborn errors of immunity identified a heterozygous pathogenic NLRP3 variant (c.913G>A, p.Asp305Asn). A diagnosis of autosomal dominant NLRP3-AID was made. No neurologic, auditory, or joint damage was found. Colchicine was started while awaiting canakinumab approval. Interestingly, the Auto-Inflammatory Disease Activity Index (AIDAI) score improved from 51 to 39 points on colchicine. Discussion Despite cold sensitivity and a relatively mild course, this patient’s persistent rash and systemic inflammation differ from classic FCAS, highlighting the relevance of adopting the broader NLRP3-AID term. In resource-limited settings, colchicine may offer temporary benefits while awaiting access to IL-1 inhibition targeted therapy.