RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias

• Published in: Journal of allergy and clinical immunology 2018-04, Vol.141 (4), p.1507-1510.e8
• Main Authors: Comrie, William A., Faruqi, Aiman J., Price, Susan, Zhang, Yu, Rao, V. Koneti, Su, Helen C., Lenardo, Michael J.
• Format: Article
• Language: English
• Subjects: Apoptosis; Autoimmune Diseases - immunology; Autoimmune Lymphoproliferative Syndrome - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Child; Child, Preschool; Cytokines; Cytopenia; Enzymes; Genotype & phenotype; Haploinsufficiency; Haploinsufficiency - immunology; Humans; Immunoglobulins; Kinases; Lymphocytes; Lymphoproliferative Disorders - immunology; Male; Metabolism; Mutation; NF-kappa B - immunology; Proteins; Regulation; RelA protein; T cell receptors; Transcription Factor RelA - immunology; Transcription factors; Zinc finger proteins
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.11.036

[...]the patient complained of severe recurrent headaches, abdominal pain, vomiting, diarrhea, and weight loss. Patient T cells may be further activated because of decreased regulatory responses, because we found decreased inducible regulatory T cells differentiation despite normal levels of CD25+/CD127low natural regulatory T cells (see Fig E2, B-D, in this article's Online Repository at www.jacionline.org); this may be attributable to either increased IFN-γ or decreased p65/c-Rel–dependent FOXP3 transcription.3 Finally, B-cell populations and immunoglobulins appeared normal (see Fig E3 in this article's Online Repository at www.jacionline.org). [...]the disease was apparently largely driven by augmented T-cell activation and effector function. [...]the patient's disease likely results from insufficient p65 dimers and altered regulation of their specific targets.4 Given the differences between our case and those previously reported, we conclude that RELA haploinsufficiency, like NF-κB1 haploinsufficiency, can cause widely different clinical manifestations.2,5 Although the variant type and overall genetic/environmental variability are key modifying factors, variants in other genes also determine the observed clinical phenotype in an apparently “monogenic” disease. Gene Variant type CADD score No. in ExAC Description Mutation-positive family members RELA Nonsense 37 0 NF-kB family member p65 None/De novo IKBKE Missense 33 8 Serine/Threonine kinase capable of phosphorylating and inactivating inhibitors of NF-kB Father IKBIP Missense 16.5 0 IkB kinase (IKK) interacting protein Father LAG3 Missense 26.3 0 Lymphocyte-activating protein Mother FGR Missense 25.4 0 Tyrosine protein-kinase; proto oncogene, known role in the immune system Mother KLHL42 Missense 25.7 0 Substrate-specific adapter of BCR E3 ubiquitin ligase complex; involved in class I MHC antigen processing and presentation Father ADRA1B Missense 24.9 0 Adrenergic receptor, GPCR signaling through calcium-phosphatidylinositol second messenger system Father/Sister LPIN2 Missense