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Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility |
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| Authors: | M. C. Crank J. K. Grossman S. Moir S. Pittaluga C. M. Buckner L. Kardava A. Agharahimi H. Meuwissen J. Stoddard J. Niemela H. Kuehn S. D. Rosenzweig |
| Affiliation: | 1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 2. Division of Hematology and Hematologic Malignancies, Alberta Health Services, Calgary, Alberta, Canada 3. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 4. Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 5. Primary Immune Deficiency Clinic, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 6. Department of Pediatrics, Albany Medical Center, Albany, NY, USA 7. Immunology Service, Department of Laboratory Medicine, National Institutes of Health, 10 Center Dr, Bldg 10, 2C410F, Bethesda, MD, 20892, USA |
| Abstract: | Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in PIK3CD. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro, PIK3CD mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients’ elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with PIK3CD mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies. |
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