Waldenstrom's Microglobulinemia Presenting with Recurrent Angioedema Secondary to C1q Esterase Inhibitor (C1 INH) Deficiency

A 57 year-old Bangladeshi man presented to the emergency room with a 4-day history of shortness of breath, productive cough and sensation of choking. He had a history of recurrent dyspnea, chest pain and chronic bilateral pedal edema. He had recent admissions for similar complaints at different hospitals where he was diagnosed with low grade non-Hodgkin lymphoma not requiring treatment and was discharged with bronchodilators and anti-tussives. He was symptom-free between episodes. There was no fever, night sweats or weight loss and there was no history of asthma. Physical exam revealed moderate dyspnea with some stridor, cervical lymphadenopathy with many firm and mobile small lymph nodes. There was no hepato-splenomegaly, urticaria or rashes. Results of routine blood tests including CBC and C-reactive protein were normal. Chest X-ray showed mild pulmonary congestion and CT images of the chest and abdomen showed multiple lymph nodes of about 1–1.5 cm in size. X-rays of the hands showed multiple small lytic lesions. Laryngoscopy showed laryngeal edema. Bone marrow biopsy showed a few paratrabecular areas with increased numbers of small lymphocytes and a lymph node biopsy revealed low grade B-cell lymphoma with plasmacytic differentiation, which was positive for CD19, 20, 22, 38, and CD44. Serum viscosity was 1.6. Immunological studies showed a low C4 at 4 mg/dl (normal range 10–40 mg/dl), low C1q at <3.6 (normal range 5–8.6), C1 esterase inhibitor low-normal at 16 (normal range 11–26). Serum immunoglobulins showed IgM gammopathy with low IgA and normal IgG levels. Beta-2 microglubulin was also elevated at 4.93 mg/dl (normal range < 2.51). Serum protein electrophoresis showed a monoclonal IgM spike measuring 1.5 g/dl with immunofixation positive for a IgM kappa band. Total protein, alpha2- and beta-globulins were elevated and urine electrophoresis was positive for kappa light chains. A diagnosis of Waldenström's macroglobulinemia with angioneurotic edema was made. He was treated with 4 cycles of bortezomib (Velcade®), dexamethasone and rituximab. The patient's angioedema and respiratory symptoms improved dramatically. Follow-up serum electrophoresis showed a very good response to treatment, with a major decrease in total protein and the M-spike. Complement levels returned to normal.

C1 is the first protein of the classical and kinin pathways which is an arm of the innate immune system. Triggering factors activate the complement cascade and lead to activation of C1 which in turn cleaves C2, the product of which is an inflammatory mediator responsible for angioedema by causing increased capillary permeability and extravasations. In C1INH deficiency, this process occurs uninhibited, triggered by minimal stimulation. C1q esterase inhibitor deficiency is a rare manifestation of Waldenström's macroglobulinemia with very few reported cases in literature. Symptoms are non-allergic, non-pruritic and clinical presentation depends on parts of the anatomy affected and may be as mild as inconvenient skin blotching up to life-threatening laryngeal edema or shock. They vary widely, often self limiting and recurrent. Angioedema, acquired or inherited, is complement mediated, characterized by low levels of complement proteins during attacks. C1INH deficiency can be acquired due to increased consumption or/and inactivation by circulating autoantibodies or secondary to lymphoproliferative diseases that lead to increased catabolism. These are often associated with B-cell disorders but may be associated with other disease patterns. Symptomatology is variable and periods of remission and recurrence lead to easy misdiagnosis and incomplete treatment. Proper diagnosis is dependent on awareness and knowledge of the various clinical presentations, adequate and focused use of laboratory analyses and immunopathology studies. The key to treatment is first therapy of the acute stage (in our patient with the use of intravenous steroids) and then more specific treatment of the underlying disease entity (in our patient with bortezomib, dexamethasone and rituximab).

Waldenstrom's macroglobulinemia presenting with angioedema is rare, often misdiagnosed and acquired C1 esterase inhibitor deficiency should be at least ruled out, as presentation is varied and could be potentially life-threatening.

No relevant conflicts of interest to declare.