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

Abstract

Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27-CD10-CD21-/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. KEY MESSAGES: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. CAPSULE SUMMARY: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.

• Authors: Heather Minto, Kofi A Mensah, Paul R Reynolds, Eric Meffre, Kira Rubtsova, Erwin W Gelfand
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 200 Pg. 55-63 (03 2019) ISSN: 1521-7035 [Electronic] United States
• PMID: 30639167 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Codon, Nonsense
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Ataxia Telangiectasia (genetics, immunology)
• Ataxia Telangiectasia Mutated Proteins (genetics)
• B-Lymphocyte Subsets (immunology)
• B-Lymphocytes (immunology)
• Child, Preschool
• Codon, Nonsense
• Female
• Granuloma (genetics, immunology)
• High-Throughput Nucleotide Sequencing
• Humans
• Hyper-IgM Immunodeficiency Syndrome (genetics, immunology)
• Immunologic Memory
• Sequence Analysis, DNA
• Skin Diseases (genetics, immunology)
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes (immunology)