Low C1q alone should not be taken as diagnostic of acquired angioedema in a kindred with familial type 1 C1-inhibitor deficiency and overlapping systemic lupus erythematosus

Dear Editor, Low C1q alone should not be taken as diagnostic of acquired angioedema due to C1inhibitor (C1-INH) deficiency (AAE-C1-INH). Although low C1q is common in AAE-C1-INH and usually normal in hereditary angioedema due to C1-INH deficiency (HAE-C1-INH), current diagnostic evaluation still requires interpretation with age at onset, family history, and confirmatory testing (1,2). We report a Japanese kindred with biochemical type 1 C1-INH deficiency in which the proband had overlapping systemic lupus erythematosus (SLE) and profoundly suppressed C1q, thereby closely mimicking AAE-C1-INH.The proband, a woman in her late 40s, had recurrent non-pitting edema of the face, extremities, and abdomen from her mid-teens, with an estimated 15-20 attacks annually. Attacks lasted 2-4 days, occurred without urticaria, and were unresponsive to antihistamines, glucocorticoids, or epinephrine. She had no exposure to angiotensinconverting enzyme inhibitors, angiotensin-receptor blockers, dipeptidyl peptidase-4 inhibitors, or exogenous estrogens. Her SLE had been diagnosed in adolescence but was clinically quiescent at re-evaluation, with stable low-dose prednisolone and no recent flare, clinically significant proteinuria, serositis, or active mucocutaneous disease.Repeated testing in 2020 and 2022 showed persistently low C4 (3.0/3.0 mg/dL), low C1-INH antigen (7/5 mg/dL), and low C1-INH function (31%/<25%), consistent with type 1 C1-INH deficiency. However, C1q was below the assay detection limit at both time points (<1.5/<1.5 mg/dL). Because profoundly low C1q is classically associated with AAE-C1-INH, this result initially raised concern for an acquired process (1,2). Serum protein electrophoresis with immunofixation showed no monoclonal protein, and computed tomography showed no lymphadenopathy. Anti-C1q antibodies, anti-C1-INH antibodies, and SERPING1 sequencing had not been performed at the time of writing and are planned; therefore, we do not claim definitive exclusion of AAE-C1-INH.The key discriminator was the family pattern (Figure 1). Five biologically related individuals across three generations, including a collateral line, underwent repeat testing. The proband's son, sister, niece, and father all showed reproducibly low C4 and low C1-INH antigen/function, whereas none had SLE. C1q remained within the reference range in the son (14.7/13.8 mg/dL), sister (10.1/11.0 mg/dL), and niece (12.4/10.7 mg/dL). Only the father showed subnormal C1q (6.9/6.1 mg/dL), but his position in the multigenerational pedigree still favored hereditary transmission over independent AAE-C1-INH. Thus, the overall pattern was not "AAE-C1-INH with low Our report adds two points to the previous family description (5): serial C1q measurements in all tested relatives, and demonstration that profound C1q reduction can coexist with hereditary C1-INH deficiency in a patient with overlapping SLE. The limitation is the absence of molecular and autoantibody confirmation. Even so, the most parsimonious interpretation is hereditary type 1 C1-INH deficiency with SLE-associated or immune-mediated C1q reduction in the proband, rather than AAE-C1-INH diagnosed by C1q alone.In summary, low C1q alone should not be taken as diagnostic of AAE-C1-INH. In patients with recurrent angioedema, especially when onset is early and family clustering is evident, very low C1q should trigger confirmatory evaluation for acquired disease, but should not override a hereditary pattern. Generative artificial intelligence (AI) tools were used solely to assist with English-language editing, manuscript proofreading, and refinement of wording and formatting. The tools used were OpenAI ChatGPT (GPT-5; OpenAI, San Francisco, CA, USA) and Anthropic Claude (Claude Opus 4.7; Anthropic PBC, San Francisco, CA, USA). These tools were not used for clinical decision-making, data collection, laboratory analysis, interpretation of clinical or laboratory findings, literature selection, or generation of scientific conclusions. All AI-assisted edits were reviewed and approved by the authors, who take full responsibility for the accuracy, integrity, and final content of the manuscript.