Chronic Spontaneous Urticaria and C1 Inhibitor Deficiency: A Diagnostic Challenge

Why this case matters

Doctors recently reported a puzzling case that shows how hard it can be to tell two different kinds of swelling apart. A 36-year-old woman had long-standing hives plus repeated throat tightness and belly pain. Her skin symptoms looked like one condition, but blood tests suggested a second, rarer condition. Understanding the difference matters because the two problems are treated differently and can need different tests during flares. (Source: the case report below.)

A short plain-language summary

This woman had daily, itchy hives that came and went quickly — a typical pattern for chronic spontaneous urticaria (CSU), which means ongoing hives without an obvious trigger. Later she developed recurring throat tightness and abdominal pain. Blood tests showed low levels and low function of a protein called the C1 inhibitor (C1‑INH) and a low complement protein called C4. Low C1‑INH and C4 can point to hereditary angioedema (HAE), a genetic condition that causes swelling through a molecule called bradykinin, not through the usual allergic chemicals that cause hives. Genetic testing did not find a clear mutation, but the testing had limits, so HAE could not be ruled out. (Source: the case report below.)

What the patient experienced

The woman first developed widespread redness, itchy wheals, and scratching in 2020. Her hives did not respond well to high-dose non-sedating antihistamines. Steroid pills helped for a short time.

Over the next few years her hives became persistent in a pattern typical for CSU: daily itchy bumps that usually went away within 24 hours. During bad flares the hives sometimes formed ring-shaped red patches on the face, trunk, and limbs.

In July 2024 she began having repeated episodes of throat tightness and occasional belly pain. The throat feeling was described as tightness or a sense of obstruction. Imaging or documented airway findings were not available during a severe throat episode, and the abdominal pain was not linked to imaging that showed bowel swelling.

What the blood tests showed

Repeat complement blood tests in March and April 2025 were abnormal in a way that fits C1‑INH deficiency.

On March 16, lab results showed:

• C1‑INH functional activity: 35.65% (reference: at least 58.9%)
• C1‑INH concentration: 56.69 μg/mL (reference: 81.46–291.29 μg/mL)
• C4: 65.46 μg/mL (reference: 72.85–372.95 μg/mL)

These values stayed low on repeat testing April 2. The patient’s mother had a single test showing reduced C1‑INH function and concentration and low C4, yet she had no symptoms and did not have repeat testing.

What genetic testing showed — and didn’t show

Whole-exome sequencing did not find a clearly disease-causing change in the angioedema-related genes that were checked. But the test did not include every gene now known to be linked with HAE (for example, CPN1 was not included), and the lab did not provide coverage details. The report also did not confirm how well the exome test would detect larger deletions or duplications in the SERPING1 gene, which can cause HAE.

Because of those limits, a negative genetic result did not rule out hereditary angioedema when the bloodwork suggested C1‑INH deficiency.

Treatments tried and how she did

Doctors treated her for several possible causes because it wasn’t clear which problem was driving each symptom. Treatments used included:

• H1 antihistamines (standard for hives)
• Systemic corticosteroids (steroid pills and intravenous methylprednisolone while hospitalized)
• Omalizumab (an injection often used for difficult-to-treat CSU)
• Cyclosporine (an immunosuppressant)
• Icatibant and lanadelumab (drugs that target bradykinin-driven swelling)

It was hard to judge how well some treatments worked. Records were incomplete for how she responded to icatibant given during attacks. Lanadelumab was given only briefly, so its preventive effect couldn’t be judged. C1‑INH concentrate (the usual replacement product for C1‑INH deficiency) was not given.

While hospitalized, an IV steroid gave only temporary relief. Cyclosporine did not show clear benefit before omalizumab was restarted. She had a short remission, but symptoms recurred soon after discharge. By February 2026, while taking omalizumab plus an H1 antihistamine, she reported fewer episodes overall, fewer hives, less itching, and milder throat tightness and chest discomfort.

How doctors interpreted this case

The authors described this as a suspected “overlap” picture rather than saying every symptom came from one single cause. Daily itchy hives that clear within a day fit active CSU. Repeated low C1‑INH function, low C1‑INH level, and low C4 point to biochemical C1‑INH deficiency, which is the hallmark of some forms of HAE.

That said, it remained unclear whether the individual throat and abdominal episodes were due to histamine (the usual cause in hives), or due to bradykinin (the chemical that causes swelling in HAE and that does not respond to antihistamines). The difference matters because treatments for bradykinin-driven angioedema are different from those for histamine-driven hives.

Practical points for clinicians and people with hives

The case highlights a few practical items:

• If someone with chronic hives also has repeated throat tightness or recurrent abdominal pain, doctors should consider checking complement tests (including C1‑INH level and function, and C4).
• Before deciding that an episode is bradykinin-related, it helps to document the timing of attacks, any objective airway findings or vital signs during events, abdominal exams or imaging when needed, lab results, and how the episode responds to on-demand therapies.
• A negative routine exome genetic test does not completely exclude hereditary angioedema if the blood tests suggest C1‑INH deficiency, because not all genes or types of DNA changes are always detected by that testing method.

When to see a doctor

If you have chronic hives and start to notice repeated throat tightness, difficulty breathing, fainting, or severe belly pain, seek medical care promptly. Those symptoms can be serious. Discuss with your doctor whether complement testing is appropriate, and ask about what to do during an attack. Treatment choices should be made together with your healthcare team.

Tracking skin changes

If your hives are visible, keeping a simple photo diary or notes about when lesions appear, how long they last, and what helped or didn’t help may be useful when you see a clinician. This can help your doctor understand patterns and timing.

Disclaimer

This article summarizes a single reported case and is for information only. It is not medical advice. Treatment decisions should be discussed with your doctor or dermatologist, and emergency care should be sought for breathing problems, severe swelling, or other urgent symptoms.

Sources

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. Published 2026 Aug 5. doi:10.2147/CCID.S634574 (Source: Chen F et al., case report, Clin Cosmet Investig Dermatol, 2026)
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. 2022;77(7):1961-1990. doi:10.1111/all.15214 (Source: WAO/EAACI guideline, 2022)