Background Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are ...sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown. Objective We wanted to identify the genetic cause of CID in 2 siblings, the products of a first-cousin marriage, who experienced recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death. Methods We performed immunologic, genetic, and biochemical studies in the 2 siblings, their family members, and healthy controls. Reconstitution studies were performed with T cells from mucosa-associated lymphoid tissue lymphoma-translocation gene 1–deficient ( Malt1 −/− ) mice. Results The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing of 1 patient and her parents, followed by DNA sequencing of family members and healthy controls, showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients showed severely impaired IκBα degradation and IL-2 production after activation, 2 events that depend on MALT1. In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-κB activation and IL-2 production in MALT1-deficient mouse T cells. Conclusions An autosomal recessive form of CID is associated with homozygous mutations in MALT1 . If future patients are found to be similarly affected, they should be considered as candidates for allogeneic hematopoietic cell transplantation.
Complete deficiency of either RAG1 or RAG2 results in classical severe combined immunodeficiency lacking T and B cells, since RAG1 mediates DNA binding and cleavage, while RAG2 is an essential ...cofactor for RAG1 function.1 Hypomorphic missense mutations that preserve residual RAG activity and allow the development of oligoclonal T cells, but virtually no B cells, result in recurrent infections, erythroderma, hepatomegaly, colitis, and αβ T-cell expansion (Omenn syndrome).2RAG1/2 mutations can also cause γδ T-cell expansion and immunodeficiency with granulomas.3 Hyper-IgM syndrome is characterized by normal or increased IgM levels with decreased IgG and IgA levels. Because her phenotype was consistent with Omenn syndrome, RAG1 and RAG2 were sequenced.
Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with ...CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures.
Background Mutations in the SP110 gene result in infantile onset of the autosomal recessive primary immunodeficiency disease veno-occlusive disease with immunodeficiency syndrome (VODI), which is ...characterized by hypogammaglobulinemia, T-cell dysfunction, and a high frequency of hepatic veno-occlusive disease. Objectives We sought to further characterize the clinical features, B-lineage cellular immunologic findings, and molecular pathogenesis of this disorder in 9 patients with new diagnoses, including 4 novel mutations from families of Italian, Hispanic, and Arabic ethnic origin. Methods Methods used include clinical review; Sanger DNA sequencing of the SP110 gene; determination of transfected mutant protein function by using immunofluorescent studies in Hep-2 cells; quantitation of B-cell subsets by means of flow cytometry; assessments of B-cell function after stimulation with CD40 ligand, IL-21, or both; and differential gene expression array studies of EBV-transformed B cells. Results We confirm the major diagnostic criteria and the clinical utility of SP110 mutation testing for the diagnosis of VODI. Analysis of 4 new alleles confirms that VODI is caused by reduced functional SP110 protein levels. Detailed B-cell immunophenotyping demonstrated that Sp110 deficiency compromises the ability of human B cells to respond to T cell–dependent stimuli and differentiate into immunoglobulin-secreting cells in vitro . Expression microarray studies have identified pathways involved in B-lymphocyte differentiation and macrophage function. Conclusion These studies show that a range of mutations in SP110 that cause decreased SP110 protein levels and impaired late B-cell differentiation cause VODI and that the condition is not restricted to the Lebanese population.
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