Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive immunologic disorder associated with defective B-cell differentiation and decreased or absent antibody production. Affected individuals have early-childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune ... Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive immunologic disorder associated with defective B-cell differentiation and decreased or absent antibody production. Affected individuals have early-childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease (summary by Lopez-Herrera et al., 2012). For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).
Lopez-Herrera et al. (2012) reported 5 patients from 4 unrelated consanguineous families with early-childhood onset of humoral immune deficiency and autoimmunity. In an Arabian family, 2 sibs presented in infancy with idiopathic thrombocytopenic purpura (ITP) followed by recurrent ... Lopez-Herrera et al. (2012) reported 5 patients from 4 unrelated consanguineous families with early-childhood onset of humoral immune deficiency and autoimmunity. In an Arabian family, 2 sibs presented in infancy with idiopathic thrombocytopenic purpura (ITP) followed by recurrent respiratory infections or otitis media. They both developed chronic lung disease and bronchiectasis. One had early-onset asthma and steroid-responsive monoarthritis, whereas the other developed a cerebral mass suggestive of a granuloma. Both showed poor overall growth. Laboratory studies showed low immunoglobulin levels, consistent with a diagnosis of CVID. A Sicilian boy presented with recurrent warts and perineal molluscum contagiosum at age 12 years. He later developed recurrent severe respiratory infections with interstitial pneumonitis and bronchiectasis, ITP, autoimmune hemolytic anemia, atrophic gastritis due to autoantibodies against intrinsic factor, a submaxillary abscess, and colitis. Laboratory studies showed low IgG and complete IgA deficiency with normal neutrophil count. Hilar and mediastinal lymph node biopsies showed lymphoid follicular hyperplasia with the absence of the follicular mantle zone. He also developed a brain tumor of the right temporal lobe which was shown to be a granulomatous infiltration with T cells, plasma cells, and macrophages, but few B cells. An Iranian boy presented at age 2 years with recurrent respiratory infections, autoimmune hemolytic anemia, and ITP. He developed finger clubbing due to chronic lung disease, hepatosplenomegaly, and failure to thrive. During 10 years' follow-up, he developed Crohn disease, cor pulmonale with right heart failure, and recurrent conjunctivitis. The fifth patient was an Iranian women who died at age 19 years after respiratory failure. She also had allergic dermatitis, recurrent diarrhea, recurrent upper respiratory infections, hypothyroidism, and myasthenia gravis. All homozygous individuals with LRBA deficiency showed reduced counts of switched-memory B cells, consistent with CVID. Two patients lacked marginal-zone-like B cells, and 1 had reduced counts of total B cells. Two patients had low natural killer (NK) cells, and 1 had low T-cell levels.
In 5 patients from 4 unrelated consanguineous families with CVID8 with autoimmunity, Lopez-Herrera et al. (2012) identified 4 different homozygous mutations in the LRBA gene (606453.0001-606453.0004). The first mutation was found by linkage analysis followed by candidate gene ... In 5 patients from 4 unrelated consanguineous families with CVID8 with autoimmunity, Lopez-Herrera et al. (2012) identified 4 different homozygous mutations in the LRBA gene (606453.0001-606453.0004). The first mutation was found by linkage analysis followed by candidate gene sequencing. Heterozygous mutation carriers were unaffected. Cultured patient B cells showed a failure to proliferate, differentiate into plasma cells, or produce antibodies under inducible conditions. Patient cells also showed an increased susceptibility to apoptosis, most likely due to impaired autophagy and abnormal accumulation of cellular organelles. No LRBA mutations were found in 12 additional families with suspected autosomal recessive CVID.