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Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility

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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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Abbreviations

AID:

Activated cytidine deaminase

AML:

Acute myeloid leukemia

HIGM:

Hyper IgM syndrome

IVIG:

Intravenous immunoglobulin

GC:

Germinal center

MALT:

Mucosal associated lymphoid tissue

PI(3)K:

Phosphoinositide 3 kinase

PIK3CD :

Phosphatidylinositol-4,5-Bisphosphonate 3-Kinase, Catalytic subunit delta

R-CHOP:

Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Vrednisone

UNG:

uracyl-N-glycosylase

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Acknowledgments

This research was supported by the Intramural Research Program of the NIH. The content of this publication does not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Correspondence to S. D. Rosenzweig.

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M. C. Crank and J. K. Grossman contributed equally to this work.

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Crank, M.C., Grossman, J.K., Moir, S. et al. Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility. J Clin Immunol 34, 272–276 (2014). https://doi.org/10.1007/s10875-014-0012-9

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  • DOI: https://doi.org/10.1007/s10875-014-0012-9

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