Immunodeficiency 41 with Lymphoproliferation and AutoimmunityD82.1

Immunodeficiency-41 with lymphoproliferation and autoimmunity is a rare, autosomal recessive, complex immunodeficiency syndrome localized by mutations in the IL2RA gene (10p15.1). Affected individuals show recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features such as autoimmune enteropathy and features of atopic dermatitis as early as infancy. Immunological studies show that the receptor defect causes interleukin-10 not to be expressed, so that the clinical symptoms correspond to interleukin-10 deficiency.

Caudy et al (2007) reported an 8-year-old boy with a complex immunologic disorder. He presented at 6 weeks of age with diarrhea, insulin-dependent diabetes mellitus, and respiratory failure due to CMV infection. During childhood, he developed autoimmune enteropathy with villous atrophy, eczematous skin lesions, lymphadenopathy, hepatosplenomegaly, hypothyroidism, autoimmune hemolytic anemia, and autoimmune granulocytopenia. He suffered from recurrent infections, including Epstein-Barr virus (EBV) infection. The clinical features were reminiscent of IPEX (304790). However, the expression of FOXP3 (300292) on the patient's CD4+ T lymphocytes was normal. Immunological studies showed that the patient's cells did not express detectable interleukin-10 (124092) after stimulation with interleukin-2 (147680). This suggests a defect in the interleukin-2 receptor. Caudy et al (2007) demonstrate a heterozygous truncating compound mutation in the IL2RA gene (147730,0004 and 147730,0005). Each unaffected parent was heterozygous for one of the mutations.

Goudy et al (2013) reported an 8-year-old girl born to consanguineous Italian parents with early-onset recurrent viral, bacterial, and fungal infections, CMV infection, lymphadenopathy, and various autoimmune diseases, including autoimmune enteropathy, autoimmune thyroiditis, eczema, psoriasiform (atopic?) dermatitis, and alopecia. Skin biopsy showed infiltration of CD8+ T lymphocytes. Immunologic studies revealed changes in the peripheral T-cell compartment, with an increase in the number of CD8+ T cells compared with CD4+ T cells and an increase in the number of memory T cells. The number of NK and B cells was also low. In vitro studies showed a weak proliferative response of T cells to polyclonal mitogens, fungi, and viruses. Evidence included a homozygous missense mutation in the IL2RA gene (S166N; 147730.0006).

Bezrodnik et al. (2014) reported on a five-year-old girl from Argentina who presented with severe atopic dermatitis, chronic diarrhea, and severe respiratory infections in the first week of life. She later developed alopecia, a severe varicella infection, and chronic pneumonia that required permanent oxygen therapy. Immunologic examination revealed hypergammaglobulinemia, absent IgG4, and impaired specific polysaccharide response. The number of regulatory T cells was markedly decreased. and the number of memory B cells was decreased. Activated CD4+ T cells showed no CD25 upregulation. Antinuclear antibodies were also present, but the patient had no significant features of autoimmune disease. Evidence included a homozygous missense mutation in the IL2RA gene (Y41S; 147730.0007). The patient's CD4+ T lymphocytes did not show upregulation of IL2RA upon activation.

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