Case Report: A Novel TNFAIP3 Mutation Causing Haploinsufficiency of A20 With a Lupus-Like Phenotype

Abstract

Genetic mutations that result in loss-of-function of the protein A20 result in an early-onset autoinflammatory disease-haploinsufficiency of A20 (HA20). The reported clinical presentations of HA20 include a Behcet's disease-like phenotype and a more lupus-like phenotype. We have identified a novel mutation in the gene encoding A20 in a pediatric patient with chronic lymphadenopathy, lupus-like symptoms, and progressive hypogammaglobulinemia. This case illustrates the wide range of clinical symptoms, including immunodeficiency, that can occur in patients with HA20.

Keywords: A20; case report; haploinsufficiency of A20; hypogammaglobulinemia; lupus; lymphadenopathy; tumor necrosis factor alpha-induced protein 3.

Figure 1

Total IgG and anti-dsDNA levels over time and compared to treatment regimen. Between ages 11 and 14, progressive hypogammaglobulinemia was observed and persisted despite discontinuation of mycophenolate mofetil (MMF) and rituximab infusions, with normalization of IgG levels at age 15 following monthly intravenous immunoglobulin (IVIG) infusions. Anti-dsDNA antibody levels decreased to within normal range (<10 IU/ml) following immunosuppressive therapy initiation at age 10. Treatment with hydroxychloroquine (HCQ), prednisone, MMF, rituximab, and IVIG are indicated by grey lines, and when specific dosing was identified by chart review, is additionally overlaid on the gray line at the time of therapy initiation or dosing change. MMF is twice daily dosing (BID) and was initiated at 500 mg per dose and increased to 1,000 mg twice daily at age 15. At age 10, she received two doses of 500 mg rituximab; at age 15, she received two doses of 1000 mg rituximab.

Figure 2

Histology and immunohistochemistry (IHC) of a right cervical lymph node biopsy. (A) Low power magnification showing reactive follicular hyperplasia with variably sized and shaped germinal centers with visible mantle zones (H&E). (B) Medium power magnification of a reactive germinal center with scattered tangible body macrophage (H&E). (C) CD20 IHC labels B cells which are predominantly located within the germinal centers. (D) CD3 IHC labels T cells predominantly located in the interfollicular areas and scattered within the germinal centers. In panels (C, D), brown indicates positive staining.

Figure 3

Flow cytometric immunophenotyping dot plots of a right cervical lymph node biopsy. The sample had a viability of 84% as determined by lack of 7-AAD labeling (not shown). (A) After exclusion of debris and monocytes, B lineage cells are identified by CD19 labeling (V450) and lineage cells are identified by CD5 (PerCP-Cy5). (B) CD19-positive B cells express normal levels of CD20 (APC-H7) with a subset expressing CD10 (APC). (C) The entire population of CD19-positive B cells show polytypic expression of kappa (PE) and lambda (FITC) light chain expression, albeit with less than optimal separation kappa and lambda. (D) The CD10-positive B cells also demonstrate polytypic light chain expression and are interpreted to represent the reactive germinal centers.