Chronic Spontaneous Urticaria with Biochemical C1 Inhibitor Deficiency: A Case Report of Suspected Overlap with Hereditary Angioedema

Abstract

Rationale

Chronic spontaneous urticaria (CSU) and hereditary angioedema caused by C1 inhibitor (C1-INH) deficiency are mechanistically distinct disorders. When persistent wheals coexist with recurrent throat or abdominal symptoms, however, assigning individual episodes to mast-cell- or bradykinin-mediated pathways can be difficult.

Patient Concerns

A 36-year-old Chinese woman developed recurrent wheals and pruritus in 2020. Beginning in 2024, she also reported episodic throat tightness and intermittent abdominal pain despite high-dose H1 antihistamines, systemic corticosteroids, and omalizumab.

Diagnoses

Repeated complement testing in 2025 showed low C4, reduced C1-INH concentration, and impaired C1-INH function. Her mother had similar biochemical abnormalities. These findings supported biochemical C1-INH deficiency in a patient with active CSU, but the mechanism of individual throat and abdominal episodes remained uncertain. Whole-exome sequencing, including exome-based copy-number analysis, identified no reportable pathogenic or likely pathogenic variant in the prioritized angioedema-related genes; however, not all currently recognized HAE-associated genes were included, and gene-level coverage metrics were unavailable.

Interventions

Documented treatment included H1 antihistamines, systemic corticosteroids, cyclosporine, and omalizumab. Subcutaneous icatibant and lanadelumab were also administered, but the retrospective records did not permit reliable assessment of icatibant response, and lanadelumab exposure was too brief to assess prophylactic efficacy.

Outcomes

Following methylprednisolone, cyclosporine, and reintroduction of omalizumab, symptoms remitted briefly but recurred the day after discharge. At follow-up in February 2026, the patient reported fewer episodes, a lower wheal burden, less pruritus, and milder throat tightness and chest pain while receiving omalizumab plus an H1 antihistamine.

Lessons

In patients with CSU, recurrent throat tightness or abdominal pain should prompt complement testing and episode-level assessment. Objective airway findings, abdominal evaluation, attack timing, complement results, and response to on-demand therapy should be documented before symptoms are attributed to a specific mechanism.

Introduction

In routine practice, chronic spontaneous urticaria (CSU) and C1 inhibitor (C1-INH)-deficient hereditary angioedema (HAE) are usually considered separately.¹ CSU typically presents with recurrent pruritic wheals, with or without angioedema.^2,3 By contrast, C1-INH-deficient HAE is a bradykinin-mediated disorder that more often causes recurrent edema of the skin, upper airway, or gastrointestinal tract.¹ The diagnostic picture becomes more complicated when persistent wheals coexist with recurrent throat symptoms or abdominal pain, because individual attacks may not be easily attributed to a single mechanism.

The genetic spectrum of hereditary angioedema with normal C1-INH (HAE-nC1-INH) has expanded to include variants in HS3ST6 and CPN1.^4–6 CPN1-associated disease is particularly relevant to the differential diagnosis because affected families may have both angioedema and urticarial lesions.⁵ These phenotypes are distinct from HAE with C1-INH deficiency and do not explain reproducibly reduced C1-INH concentration and function, but they show that wheals do not invariably exclude a hereditary angioedema-associated disorder.

Here, we report a patient with persistent wheals, recurrent throat tightness, and intermittent abdominal pain in whom repeated testing showed biochemical C1-INH deficiency. The clinical challenge was to distinguish established CSU from a possible coexisting C1-INH-deficient disorder without assigning all episodes to a single mechanism.

Case Report

This case report was prepared in accordance with the CARE guidelines.⁷

A 36-year-old Chinese woman first presented on April 17, 2020, with generalized erythema, wheals, and pruritus and was diagnosed with acute urticaria. Double-dose second-generation H1 antihistamines, including loratadine or levocetirizine, did not adequately control her symptoms. She was hospitalized on June 5, 2020, and improved after systemic corticosteroid therapy, although the dose was not documented. Persistent symptoms subsequently became consistent with CSU. During the following years, she received intermittent antihistamines, traditional Chinese medicine, and acupuncture. Symptoms recurred after corticosteroids were discontinued in November 2023, and olopatadine plus ketotifen were used for maintenance. Recurrent throat tightness and intermittent abdominal pain emerged in July 2024.

The episodes varied in pattern. Cutaneous manifestations consisted of daily or near-daily pruritic wheals that usually resolved within 24 hours. During active flares, annular erythematous wheals involved the face, trunk, and extremities (Figure 1). Laryngeal symptoms were described as throat tightness or obstruction; however, no objective upper-airway assessment was available during a severe acute episode. Abdominal symptoms consisted of intermittent severe pain without imaging-confirmed bowel edema. Vital signs were not recorded systematically during attacks, and no documented hypotension was identified.

Figure 1.

Generalized annular erythematous wheals during active disease: (A) face and upper trunk; (B) anterior trunk and upper limbs; (C) posterior trunk; and (D) thighs. The eyes were masked to reduce identifiability, and written consent for publication was obtained.

Omalizumab 300 mg every 4 weeks had been used for antihistamine-refractory CSU before May 2025; the exact first administration date could not be verified from the available treatment record. Disease control remained poor, with frequent annular wheals and pruritus as well as recurrent throat tightness and chest pain. During more severe episodes, she also reported weakness, palpitations, and lightheadedness. Contemporaneous vital signs were unavailable, so objective hemodynamic instability could not be assessed.

Repeated complement testing showed a consistent pattern of biochemical C1-INH deficiency. On March 16, 2025, C1-INH functional activity was 35.65% (reference ≥58.9%), C1-INH concentration was 56.69 μg/mL (reference 81.46–291.29 μg/mL), and C4 was 65.46 μg/mL (reference 72.85–372.95 μg/mL). On April 2, 2025, the corresponding values were 34.39%, 40.60 μg/mL, and 54.04 μg/mL. On the same date, the patient’s mother had C1-INH functional activity of 27.62%, C1-INH concentration of 49.15 μg/mL, and C4 of 59.57 μg/mL (Table 1). The mother was asymptomatic, had no repeat complement/C1-INH testing, and had no other relevant family history; her single abnormal panel suggested a possible familial trait but did not establish inheritance.

Table 1.

Complement and C1 Inhibitor Test Results

Analyte	Abbreviation	Patient (Mar 16, 2025)	Patient (Apr 2, 2025)	Mother (Apr 2, 2025)	Reference Range
Functional C1-INH activity	fC1-INH	35.65%	34.39%	27.62%	≥58.9%
C1-INH concentration	C1-INH	56.69 μg/mL	40.60 μg/mL	49.15 μg/mL	81.46–291.29 μg/mL
C4 concentration	C4	65.46 μg/mL	54.04 μg/mL	59.57 μg/mL	72.85–372.95 μg/mL

Abbreviations: C1-INH, C1 inhibitor; fC1-INH, functional C1 inhibitor activity.

Whole-exome sequencing included single-nucleotide variant/small insertion-deletion and exome-based copy-number variant (CNV) analyses. The prioritized genes were KNG1, F12, PLG, ANGPT1, MYOF, SERPING1, and HS3ST6; no reportable pathogenic or likely pathogenic variant was identified. Gene-level coverage metrics were unavailable, CPN1 was not included, and the report did not establish the sensitivity of exome-based CNV analysis for SERPING1 deletions or duplications. An unrelated 0.76-Mb 16p11.2 duplication was also reported, for which confirmatory CNV testing was recommended. Thus, the WES findings did not exclude HAE.

Because of recurrent throat swelling or obstruction and dyspnea with poor response to corticosteroids and antihistamines, flexible laryngoscopy was performed on March 11, 2025, to exclude structural laryngopharyngeal disease. It showed pharyngitis without structural lesions or overt laryngeal edema. The examination was clinically indicated and was not performed as routine HAE screening; a negative finding at one time point did not exclude episodic laryngeal angioedema.

She was admitted on May 16, 2025, because of uncontrolled symptoms. She had no documented history or established clinical diagnosis of a systemic autoimmune or lymphoproliferative disease. Available autoimmune serology, including antinuclear antibody testing and a specific autoantibody panel, did not establish a systemic autoimmune diagnosis. Because symptoms remained uncontrolled despite antihistamines and only transient corticosteroid response, cyclosporine was added.

Before admission, lanadelumab 300 mg was administered subcutaneously on May 7, 2025, and icatibant was administered subcutaneously on May 14, 2025. During hospitalization, subcutaneous icatibant was administered on May 16 and lanadelumab 300 mg on May 22. The retrospective records did not include standardized, attack-specific response assessments after icatibant, so its efficacy could not be reliably determined. The two lanadelumab doses were insufficient to assess prophylactic efficacy. C1-INH concentrate was not administered during hospitalization.

Initial supportive therapy and antihistamines did not produce meaningful improvement. Intravenous methylprednisolone provided only transient relief, and episodes of severe abdominal pain continued. Cyclosporine 75 mg three times daily was added, but no clear benefit was observed before omalizumab 300 mg was reintroduced on May 27, 2025. A brief remission followed, with no wheals, pruritus, throat tightness, or abdominal symptoms before discharge after 13 days. Symptoms recurred the following day during outpatient treatment with cyclosporine and oral prednisolone, although the lesions were less extensive and throat tightness was milder.

During the second half of 2025 and at follow-up in February 2026, she continued omalizumab with an H1 antihistamine. Compared with the relapse in May 2025, she reported fewer and less severe episodes, a lower wheal burden, less pruritus, and milder throat tightness and chest pain. This assessment was descriptive and based on patient report rather than prospective scoring. The clinical course, key investigations, and treatment sequence are summarized in Table 2.

Table 2.

Clinical Timeline

Time	Key Findings and Management
April 17, 2020	First presentation with generalized erythema, wheals, and pruritus; diagnosed as acute urticaria
June 5, 2020	Hospitalized; improved after systemic corticosteroid therapy
2020-2023	Persistent or recurrent symptoms, later evolving into CSU; intermittent antihistamines, traditional Chinese medicine, and acupuncture
November 2023	Symptoms recurred after corticosteroid discontinuation; olopatadine and ketotifen used for maintenance
July 2024 onward	Episodic throat tightness and intermittent abdominal pain emerged
Before May 2025	Omalizumab 300 mg every 4 weeks used for refractory CSU; exact first administration date unavailable
March 11, 2025	Flexible laryngoscopy performed for recurrent throat swelling/obstruction and dyspnea to exclude structural disease; pharyngitis without structural lesion or overt laryngeal edema
March 16, 2025	C1-INH function 35.65%, C1-INH concentration 56.69 μg/mL, and C4 65.46 μg/mL
April 2, 2025	Repeat patient values were 34.39%, 40.60 μg/mL, and 54.04 μg/mL; asymptomatic mother had 27.62%, 49.15 μg/mL, and 59.57 μg/mL, respectively
May 7, 2025	Lanadelumab 300 mg administered subcutaneously before admission
May 14, 2025	Icatibant administered subcutaneously before admission
May 16–28, 2025	Hospitalized for uncontrolled symptoms; icatibant on May 16 and lanadelumab on May 22; efficacy could not be reliably assessed; no C1-INH concentrate was administered
May 27, 2025 to discharge	Omalizumab reintroduced after methylprednisolone and cyclosporine; brief symptom remission before discharge
Day after discharge	Early recurrence during outpatient cyclosporine plus oral prednisolone
Second half of 2025 to February 2026	Continued omalizumab plus H1 antihistamine; fewer episodes, lower wheal burden, less pruritus, and milder throat tightness and chest pain

Abbreviations: C1-INH, C1 inhibitor; CSU, chronic spontaneous urticaria.

Discussion

Repeated reductions in C1-INH concentration, C1-INH function, and C4 established reproducible biochemical C1-INH deficiency.⁸ Although no systemic autoimmune or lymphoproliferative disorder was established clinically, C1q and anti-C1-INH antibodies were not measured; therefore, acquired C1-INH deficiency could not be fully excluded.⁹ The mother’s single abnormal biochemical panel raised the possibility of a familial trait, but her asymptomatic status and absence of repeat testing did not establish inheritance. Daily pruritic wheals resolving within 24 hours supported concurrent active CSU.¹⁰ We therefore use the term suspected overlap phenotype to describe coexistence of CSU and reproducible biochemical C1-INH deficiency without assigning every episode to a single mechanism.

This case illustrates the risk of diagnostic anchoring. Persistent wheals may direct attention toward CSU, but recurrent throat tightness and episodic severe abdominal pain should prompt complement testing when the course appears atypical for urticaria alone. Recently described HS3ST6- and CPN1-associated forms belong to HAE-nC1-INH and are distinct from the reproducible C1-INH deficiency observed here.^4–6 Nevertheless, urticarial lesions have been reported in CPN1-associated disease, and coexisting C1-INH-deficient HAE and CSU has also been described.^5,11 Negative routine exome sequencing did not exclude HAE because disease-causing variants may remain undetected when gene coverage is incomplete or deep intronic and structural variants are not adequately assessed.¹² A validated SERPING1 deletion/duplication assay may therefore be considered when biochemical findings are suggestive.

HAE-specific treatment response remained difficult to interpret. The retrospective records did not permit reliable assessment of the attack-specific response to icatibant, and the brief lanadelumab exposure was insufficient to evaluate prophylactic efficacy. These treatment records were therefore not used to infer the mechanism of individual episodes.

During hospitalization, remission occurred after methylprednisolone, cyclosporine, and reintroduction of omalizumab. Continued omalizumab plus antihistamine therapy was associated with partial improvement at follow-up. This pattern supports a substantial CSU component but does not establish the mechanism of the throat or abdominal symptoms.^13,14 Partial improvement during omalizumab treatment is consistent with a mast-cell-mediated component, although incomplete response can occur in treatment-refractory CSU.^15,16

When CSU is accompanied by recurrent throat tightness or abdominal pain, it may be unsafe to assume that all symptoms are attributable to urticaria alone.¹ Complement studies should be obtained early, and attack-phase documentation should include symptom timing, objective airway findings, vital signs, abdominal evaluation or imaging when indicated, complement testing, and response to treatment. Without this information, both diagnostic interpretation and assessment of treatment response remain limited.

Limitations

This report is limited by its retrospective reconstruction from incomplete clinical records. No objective upper-airway assessment was available during a severe acute episode, and bowel edema was not confirmed by imaging. The WES report lacked gene-level coverage metrics, did not include CPN1, and did not establish the sensitivity of exome-based CNV analysis for SERPING1 deletions or duplications. Acquired C1-INH deficiency could not be fully excluded because C1q and anti-C1-INH antibodies were not measured. The mother’s asymptomatic phenotype was supported by one abnormal complement/C1-INH panel without repeat testing. Treatment records did not permit reliable assessment of icatibant response or lanadelumab prophylactic efficacy, and follow-up outcomes were based on patient report rather than prospective disease-activity scores. Thus, this case supports coexistence of CSU and reproducible biochemical C1-INH deficiency but does not establish inheritance or the mechanism of individual throat or abdominal episodes.

Conclusion

Recurrent throat tightness or abdominal pain in a patient with CSU should prompt complement testing and careful episode-level documentation. Reproducible C1-INH deficiency warrants continued differentiation of hereditary and acquired C1-INH deficiency even when routine exome sequencing is negative. Objective attack-phase evidence remains essential before symptoms are attributed to a bradykinin-mediated mechanism.

Funding Statement

This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Patient Perspective

A formal patient-perspective statement was not available for this retrospective case report.

Abbreviations

CARE, CAse REport guidelines; C1-INH, C1 inhibitor; CNV, copy-number variant; CSU, chronic spontaneous urticaria; HAE, hereditary angioedema; ORCID, Open Researcher and Contributor ID.

Data Sharing Statement

All data supporting the findings of this case report are included in this article. Additional de-identified clinical information is not publicly available to protect patient privacy but may be made available from the corresponding author upon reasonable request and with appropriate institutional approval.

Ethics Approval and Informed Consent

This case report was conducted in accordance with the Declaration of Helsinki. Institutional approval was required for publication of the case details and was granted by the Ethics Committee of Leshan Hospital of Traditional Chinese Medicine, Affiliated to Chengdu University of Chinese Medicine (Ethics Review Approval No. 8 (2026); February 1, 2026). Written informed consent was obtained from the adult patient for inclusion in this case report. Separate written informed consent was also obtained from the patient’s mother for inclusion of her own de-identified complement and C1-INH test results.

Consent for Publication

The adult patient was shown the final manuscript contents, including the de-identified clinical details and accompanying clinical images, and provided written informed consent for their publication. Separate written informed consent was also obtained from the patient’s mother for publication of her own de-identified laboratory data included in this case report.

Author Contributions

Fang Chen and Fan Yang contributed equally to this work. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests in this work.