Omenn syndrome does not live by V(D)J recombination alone

Abstract

Impaired but not abolished V(D)J recombination process leads to the generation of a few T cells which expand in the periphery, infiltrate target organs such as skin and gut, resulting in severe erythroderma and colitis, both typical signs of Omenn syndrome. Extensive molecular studies now demonstrate that genes other than V(D)J molecules have a role in the pathogenesis of this disease, supporting the evidence that 'Omenn' defines an inflammatory condition associated with various genetic defects.

Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14years old male

“…Null mutations of both alleles of RAG1 and RAG2 cause the classical T cell-B cell-severe combined immunodeficiency (T-B-SCID) presenting in early infancy with opportunistic infections and failure to thrive [1][2][3][4][5]. Hypomorphic mutations of RAG1 or RAG2, which make possible residual RAG activity, may be the reason of Omenn syndrome (OS) [6,7], characterized by severe erythroderma, colitis, oligoclonal-activated T cells, high level IgE and autoantibodies and the absence of circulating B cells [8][9][10]. However, it has recently been recognized that the clinical spectrum of RAG deficiency is much broader and includes combined immunodeficiency (CID) with cd T cells, CMV and partially functioning B-lymphocytes with retained ability for antibody production [11,12].…”

Human syndromes of immunodeficiency and dysregulation are characterized by distinct defects in T-cell receptor repertoire development

“…1–4 The heterogeneity can, in part, be explained by the degree of residual activity in recombination activating gene 1/2 ( RAG1/2 ) 1,5–7 or other SCID-related genes. 8,9 …”

Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency

“…It has previously been proposed that this is caused by a dysbalanced partial inactivation of effector and regulatory T cells. 10 However, the lack of the disseminated oligoclonal lymphoproliferation in these mice and patients (including sibling P2) suggests that the predisposition to eczema conferred by some CARD11 mutations was not sufficient to explain an OS phenotype. We would like to argue that the functional reversion caused by a somatic second-site mutation in the affected CARD11 codon was a relevant factor favoring the evolution of OS in our patient.…”