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Published at www.nejm.org September 23, 2009 (10.1056/NEJMoa0905506)

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ABSTRACT

Background Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown.

Methods We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase–polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry.

Results Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma–leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes.

Conclusions Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.

Source Information

From the Laboratory of Host Defenses (Q.Z., I.T.L., H.J., H.C.S.), the Laboratory of Clinical Infectious Diseases (A.F.F., J.D., G.U., S.M.H.), the Research Technologies Branch (A.J.F.), and the Laboratory of Immunology (H.F.M.), National Institute of Allergy and Infectious Diseases; the Howard Hughes Medical Institute (J.C.D.); and the Dermatology Branch, National Cancer Institute (M.L.T.) — all in Bethesda, MD.

This article (10.1056/NEJMoa0905506) was published on September 23, 2009, at NEJM.org.

Address reprint requests to Dr. Su at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, CRC 5W3940, MSC 1456, Bethesda, MD 20892, or at hsu{at}niaid.nih.gov.

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