Lesson from hypomorphic recombination-activating gene (RAG) mutations: Why asymptomatic siblings should also be tested

摘要

An increasing number of patients with combined immunodeficiencies have been found to carry hypomorphic variants of genes that, with null mutations, cause severe combined immunodeficiency (SCID). These patients not only present with recurrent and sometimes life-threatening infections but also with a plethora of imrnunodysregulatory symptoms and are a diagnostic challenge.We report on 2 siblings of consanguineous descent from Saudi Arabia: the clinically affected younger brother and his unaffected older brother who would have qualified as an HLA-identical donor.The younger brother presented at the age of 9 years with stunted growth, chronic diarrhea, immune complex glomerulo-nephritis with severe glomerulosclerosis, and arteriosclerosis. He had been under medical care since the age of 2 months; his disease had been classified clinically as immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Other findings included recurrent non-life-threatening pulmonary infections with development of bronchiectases, autoimmune hemolytic anemia, tinea capitis, and recurrent urticarial rashes. Immunologically, the patient was lymphopenic, with severely diminished thymus-derived CD4+CD45RA+ T cells, low T-cell receptor excision circle and kappa-deleting recombination excision circle numbers, and a restricted T-cell receptor repertoire. CD19+ B cells and IgG and IgA levels were low, and IgM levels were normal. T-cell function was severely impaired. Table I5 and Fig I, A, show this patient's immunologic evaluations before hematopoietic cell transplantation (subject 4) in comparison with other patients with hypomorphic recombination-activating gene (RAG) mutations undergoing transplantation at our center (patients 1-3 and 6, see Table El in this article's Online Repository at www.jacionline.org).