CSU With Biochemical C1 Inhibitor Deficiency: Case Report Raises Diagnostic Questions

A recent case report highlights the diagnostic challenge of distinguishing chronic spontaneous urticaria (CSU) from possible hereditary angioedema (HAE) when a patient has persistent wheals along with recurrent throat tightness and abdominal pain.¹ In standard practice, CSU and C1 inhibitor (C1-INH)-deficient HAE are considered separately.² However, this unique report describes a 36-year-old Chinese woman with active CSU and repeatedly abnormal complement testing consistent with C1-INH deficiency.

Clinical History and Symptom Onset

The patient first developed generalized erythema, wheals, and pruritus in 2020. Her symptoms were inadequately controlled with double-dose second-generation H1 antihistamines and improved temporarily with systemic corticosteroids. Over the following years, persistent symptoms became consistent with CSU. In July 2024, she began experiencing recurrent throat tightness and intermittent abdominal pain, creating uncertainty about whether these symptoms represented manifestations of her urticaria or a separate bradykinin-mediated process.

Her cutaneous symptoms consisted of daily pruritic wheals that generally resolved within 24 hours. During flares, annular erythematous wheals affected the face, trunk, and extremities. Throat symptoms were described as tightness or obstruction, although objective upper-airway findings were not available during a severe episode. Similarly, abdominal pain was not accompanied by imaging-confirmed bowel edema.

Laboratory and Genetic Findings

Repeated complement testing in March and April 2025 showed reduced C1-INH functional activity, reduced C1-INH concentration, and low C4. On March 16, C1-INH functional activity was 35.65%, compared with a reference value of at least 58.9%; C1-INH concentration was 56.69 μg/mL, compared with a reference range of 81.46–291.29 μg/mL. C4 was 65.46 μg/mL, below the reference range of 72.85–372.95 μg/mL. Results remained abnormal in repeat testing on April 2. Her mother also had reduced C1-INH function and concentration and low C4 on a single testing panel, although she was asymptomatic and did not undergo repeat testing.

Whole-exome sequencing did not identify a reportable pathogenic or likely pathogenic variant in the prioritized angioedema-related genes. However, the testing did not include all currently recognized HAE-associated genes, including CPN1, and gene-level coverage metrics were unavailable. The report also did not establish the sensitivity of exome-based copy-number analysis for SERPING1 deletions or duplications. As a result, the negative genetic findings did not exclude HAE.

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Treatment Course and Response

Treatment was complicated by the uncertainty surrounding the mechanism of the patient's episodes. She had received H1 antihistamines, systemic corticosteroids, omalizumab, and cyclosporine. Icatibant and lanadelumab were also administered, but the retrospective records did not permit reliable assessment of icatibant's attack-specific response, while lanadelumab exposure was too brief to evaluate prophylactic efficacy. C1-INH concentrate was not administered.

During hospitalization for uncontrolled symptoms, intravenous methylprednisolone produced transient improvement, while cyclosporine did not provide clear benefit before omalizumab was reintroduced. A brief remission followed, but symptoms recurred the day after discharge. By February 2026, while receiving omalizumab with an H1 antihistamine, the patient reported fewer episodes, a lower wheal burden, less pruritus, and milder throat tightness and chest pain.

Clinical Takeaways

The authors characterized the presentation as a suspected overlap phenotype rather than assigning every symptom to a single mechanism. Daily pruritic wheals resolving within 24 hours supported active CSU, while repeated reductions in C1-INH concentration, function, and C4 established biochemical C1-INH deficiency. However, the mechanism of individual throat and abdominal episodes remained uncertain.

For dermatology clinicians, the case underscores the importance of considering complement testing when patients with CSU report recurrent throat tightness or abdominal pain. The authors recommend documenting attack timing, objective airway findings, vital signs, abdominal evaluation or imaging when indicated, complement results, and response to on-demand therapy before attributing individual episodes to a bradykinin-mediated mechanism. The case also demonstrates that negative routine exome sequencing does not necessarily exclude HAE when biochemical findings remain suggestive.

References

1. Chen F, Yang F, Li X, Li T. Chronic Spontaneous Urticaria with Biochemical C1 Inhibitor Deficiency: A Case Report of Suspected Overlap with Hereditary Angioedema. Clin Cosmet Investig Dermatol. 2026;19:634574. Published 2026 Aug 5. doi:10.2147/CCID.S634574

2. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214