Ataxia-Telangiectasia Presenting With a Novel Immunodeficiency

Abstract

Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene. The patient presented at age 3 years with a perineal cellulitis associated with profound neutropenia and T-cell lymphopenia. Serum immunoglobulin levels and antibody titers were normal. Neurologic evaluation revealed minimal hypotonia and wide-based gait, without other signs of cerebellar dysfunction. The alpha-fetoprotein level was elevated, and molecular genetic testing confirmed the diagnosis of ataxia-telangiectasia, uncovering a novel ATM gene mutation c.3931C>T (p.Gln1311X) in exon 28. This patient presents a unique immunologic pattern with normal immunoglobulin levels, significant lymphopenia, and profound neutropenia. The diagnosis of ataxia-telangiectasia should be considered in children presenting with gait disorder and immunologic defects, regardless of subtype and severity.

Introduction

Ataxia-telangiectasia is an autosomal recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, susceptibility to sinopulmonary infections, radiation hypersensitivity, and a predisposition to malignancies, premature aging, and oculocutaneous telangiectasias [1]. The incidence of ataxia-telangiectasia is approximately 1 in 100,000 live births, and occurs equally among males and females. Regional variations are observed, depending on the prevalence of parental consanguinity [2], [3]. Ataxia-telangiectasia results from mutations in the ataxia-telangiectasia mutated (ATM) gene on chromosome 11q22-23 [4]. It encodes for a 370 kDa protein belonging to the phosphoinositide 3-kinase-related protein kinase family, which plays an important role in cell cycle control and double-stranded DNA repair [1], [5].

Ataxia is usually the earliest clinical manifestation, and is typically observed during the first year of age. The gait instability progresses slowly and typically becomes obvious after 5 years of age. On average, children with this disorder become wheelchair-bound at 10 years of age [6]. Oculocutaneous telangiectasias, the second diagnostic hallmark, usually appear between ages 3 and 6 years [1]. Patients with ataxia-telangiectasia are at risk for malignancies, especially lymphocytic leukemias and non-Hodgkin lymphomas, but also solid tumors such as breast, prostate, and neck cancers [7]. Another typical feature involves a highly variable primary immunodeficiency involving both the humoral and cellular arms of the immune system. Commonly, patients present with decreased immunoglobulin levels, in particular immunoglobulin A, immunoglobulin E, and immunoglobulin G2, or moderate lymphopenia with a reduction in absolute total and naive CD4 T-cell numbers [8], [9]. Most patients manifesting ataxia-telangiectasia usually die from bronchopulmonary infection or malignancy [10].

Elevated serum levels of alpha-fetoprotein are evident in 80-85% of patients, making it an excellent screening tool [1]. Increased lymphocyte chromosomal instability upon exposure to radiation or radiomimetic chemicals is typically demonstrated [11]. The diagnosis is confirmed by the absence of the ataxia-telangiectasia mutated protein or the presence of a mutation of the ataxia-telangiectasia mutated gene.