A novel ATM mutation associated with elevated atypical lymphocyte populations, hyper-IgM, and cutaneous granulomas

Minto, Heather; Mensah, Kofi A.; Reynolds, Paul; Meffre, Eric; Rubtsova, Kira; Gelfand, Erwin W.

doi:10.1016/j.clim.2019.01.002

Cited by 8 publications

(6 citation statements)

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“…As noted previously (13), the patient had elevated numbers of Tfh, reduced Tregs, and an abundance of CD21lo B cells—all of which showed evidence of chronic IFNγ stimulation. This immunophenotypic pattern is frequently seen in rheumatic disease and complicated common variable immune deficiency (CVID) (22, 23); however, this pattern has not yet been studied in a large group of HIgM A-T patients.…”

Section: Discussionsupporting

confidence: 78%

“…We report the extended follow up of a 6-year-old girl with HIgM A-T and a history of rubella-positive cutaneous granuloma whose initial evaluation was reported previously (13). Her initial immunological findings included elevated serum IgM levels with absent IgA and IgG, increased percentage of CD19 + CD38 lo CD27 − CD10 − CD21 −/low B cells, increased percentage of circulating T follicular helper cells (Tfh cells), and decreased percentage and function of regulatory T cells.…”

Section: Case Reportmentioning

confidence: 94%

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

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 78%

Section: Case Reportmentioning

confidence: 94%

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

et al. 2019

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“…Defective DNA repair, impaired oxidative metabolism, immunodeficiency with immune dysregulation are important contributing factors, playing a role in the pathophysiology of cutaneous, visceral, and deep-organ granulomatous disease in A-T. Whereas cutaneous granulomatous lesions have been extensively reported thus far (8)(9)(10)(11), with live vaccine-derived rubella virus considered to be a unique contributor to the development of granulomatous skin disease (12,13), but extra-dermal manifestations of granulomas in the internal organs, such as the lungs or liver (14,15) and in other localizations (16) have been infrequently described in the A-T pediatric patients.…”

Section: Introductionmentioning

confidence: 99%

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report

2020

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Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by neurodegeneration, combined immunodeficiency, and oculocutaneous telangiectasia. The hyper-IgM phenotype of AT , correlating with a class-switch recombination defect, IgG and IgA deficiency, T helper and B cell lymphopenia, immune dysregulation, proinflammatory immune response, autoimmune disease, and a high risk of lymphomagenesis. Progressive liver disease is a hallmark of classical AT with the hyper-IgM phenotype and manifests as non-alcoholic hepatic steatosis and fibrosis. We report a case of a 17-year-old male AT patient, in whom a progressive granulomatous liver disease with portal hypertension, has led to massive splenomegaly and hypersplenism, metabolic liver insufficiency, bleeding from esophageal varices and pancytopenia. In this patient, an unusual severe disease course with a highly variable constellation of AT symptomatology includes granulomatous skin, visceral, and internal organs disease with liver involvement. The liver disease is associated with the hyper-IgM immunophenotype and escalating neurodegeneration, creating a vicious circle of immune deficiency, permanent systemic inflammatory response, and organ-specific immunopathology.

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“…Numbers of T cells, in particular CD4+ cells, may decline over time in 30-75% of cases. However, profound lymphopenia in neonates was not well-recognized prior to the introduction of NBS (13)(14)(15), and the AT cases that have since been identified by TREC/KREC in infants (16)(17)(18) are likely an underestimate of the true number of patients affected. The complete absence of ATM enzyme activity is much more likely to result in clinical and/or immunological features of immunodeficiency compared to those who retain residual activity (19).…”

Section: Introductionmentioning

confidence: 99%

Ataxia Telangiectasia Diagnosed on Newborn Screening–Case Cohort of 5 Years' Experience

et al. 2019

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Ataxia telangiectasia (AT) is a genetic condition caused by mutations involving ATM (Ataxia Telangiectasia Mutated). This gene is responsible for the expression of a DNA double stranded break repair kinase, the ATM protein kinase. The syndrome encompasses combined immunodeficiency and various degrees of neurological abnormalities and increased risk of malignancy. Typically, patients present early in life with delay in neurological milestones, but very infrequently, with life threatening infections typical of a profound T cell deficiency. It would therefore be unexpected to identify this condition immediately after birth using T cell receptor excision circle (TREC)-based newborn screening (NBS) for SCID. We sought to evaluate the frequency of AT detected by NBS, and to assess immunity as well as the genetic aberrations associated with this early presentation. Here, we describe the clinical, laboratory, and genetic features of patients diagnosed with AT through the Ontario NBS program for SCID, and followed in our center since its inception in 2013. Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic. All of our patients had compound heterozygous mutations involving the FRAP-ATM-TRRAP (FAT) domain of the ATM gene, which appears critical for kinase activity and is highly sensitive to mutagenesis. Our patients presented with profound lymphopenia involving both B and T cells. The ratio of naïve/memory CD45+RA/RO T cells population was variable. T cell repertoire showed decreased T cell diversity. Two out of four patients had decreased specific antibody response to vaccination and hypogammaglobulinemia requiring IVIG replacement. In two patients, profound decreased responses to phytohemagglutinin stimulation was observed. In the other two patients, the initial robust response declined with time. In summary, the rate of detection of AT through NBS had been surprisingly high at our center. One case was identified per year, while the total rate for SCID has been five new cases per year. This early detection may allow for better prospective evaluation of AT shortly after birth, and may assist in formulating early and more effective interventions both for the neurological as well as the immune abnormalities in this syndrome.

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A novel ATM mutation associated with elevated atypical lymphocyte populations, hyper-IgM, and cutaneous granulomas

Cited by 8 publications

References 50 publications

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

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

Granulomatous Liver Disease in Ataxia-Telangiectasia With the Hyper-IgM Phenotype: A Case Report

Ataxia Telangiectasia Diagnosed on Newborn Screening–Case Cohort of 5 Years' Experience

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