Vasculitis in a Child With the Hyper-IgM Variant of Ataxia-Telangiectasia

Abstract

A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a "hyper-IgM phenotype" (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.

Keywords: CD21lo; ataxia-telangiectasia; granuloma; hyper IgM; primary immunodeficiency; tumor necrosis factor; vasculitis.

Figure 1

Axillary lymph node biopsy from an HIgM A-T patient. (A) Lymph node biopsy with paracortical expansion (A, 20X) consisting of a mixture of small lymphocytes, plasma cells, and immunoblasts (B, 200X). Immunohistochemical staining for IgD (C) and IgM (D) demonstrate cytoplasmic staining of plasma cells and lymphocytes.

Figure 2

Baseline B cell abnormalities worsened following TNF blockade. Two-dimensional flow cytometry plot of the patient's CD20+ B cells 1 year before (A) and 1 year after (B) initiating adalimumab therapy. The patient's plots are on top and underneath each plot is the same day normal control sample.

Figure 3

Renal biopsy at age 6 years. Necrotic and inflamed arteries (black arrows; A—hematoxylin eosin stain; B—trichrome stain). IgG (C), IgM (D), C3 (E), C1q (F), and fibrinogen (G) deposition seen in a small necrotic artery by immunofluorescent staining. (H) Electron micrograph demonstrating subendothelial widening along a glomerular capillary loop (black arrows).