Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Abstract

IntroductionProgressive granulomatous tissue destruction of the midface and the upper airways is most commonly caused by Wegener granulomatosis (WG) or malignancies such as natural killer (NK)/T-cell lymphomas and, to a lesser extent, cocaine abuse or infections. 1,2 The hallmark pathologic finding of destructive midline granulomatous (DMG) disease is caseating granulomas characteristically involving the nose, sinuses, palate, and upper airways, especially the subglottis. Although WG usually includes renal involvement and circulating antineutrophil antibodies (ANCAs), local nasopharyngeal WG without associated antibodies occurs. 3 Standard therapy for these diseases involves immunoablative chemotherapy to halt disease progression, in contrast to immunosupportive measures required to treat primary immune deficiencies. We describe in this report the first patient with clinical manifestations of a WG-like destructive midline granulomatosis with underlying novel compound heterozygote mutations in Rag1.The recombination activation genes, Rag1 and Rag2, perform a critical role in the somatic rearrangement and assembly of the modular genes for variable (V), diversity (D), and joining (J) gene segments of immunoglobulins and of antigen receptor genes. [4][5][6] After binding to conserved recombination signal sequences (RSSs) that flank individual V, D, or J gene segments, the Rag1/2 complex introduces a nick in the DNA, followed by formation of a coding end hairpin. Nonhomologous end joining DNA repair then takes place to generate the diverse VDJ contiguous regions that are essential for defense against many different pathogens. In addition to initiating the double-strand DNA breaks, the Rag complex stabilizes recombination intermediates to promote repair and editing of the modified genes. 6,7 Rag proteins are indispensable for lymphocyte development and differentiation, and defects in Rag manifests as T-and B-deficient severe combined immunodeficiency (T-B-SCID) or Omenn syndrome (OS) in infancy. These syndromes are characterized by early-onset profound deficiency in T and B cells for SCID and by early-onset erythroderma, hepatosplenomegaly, eosinophilia, and hyper immunoglobulin E (IgE) in OS.In stark contrast, our patient presented for evaluation of a DMG process at 14 years of age with normal numbers of CD3 ϩ T and CD19 ϩ /CD20 ϩ B cells and with normal total IgG levels. Evaluation in subsequent years showed dysregulated hyperinflammatory responses with appearance of new granulomatous lesions after environmental or viral triggers. This report further extends the clinical spectrum of Rag mutations, and our data support the view that, in addition to susceptibility to infections and autoimmunity, hyperinflammation is an important component of Rag deficiency and may be the primary clinical manifestation leading to diagnosis when lymphocyte counts are normal. Hypomorphic Rag mutations should be considered in "idiopathic" destructive granulomatous disease. MethodsThe subjects were enrolled on protocol 05-I-213 approved by...

Granulomatous inflammation: The overlap of immune deficiency and inflammation

“…Destructive midline granulomatous disease mimicking local nasopharyngeal granulomatous polyangiitis (GPA) [77] and necrotizing granulomatous bone lesions mimicking sterile chronic multifocal osteomyelitis were also reported in patients carrying hypomorphic RAG mutations [78].…”

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

“…The reported 4 patients with late onset of illness were characterized by hypogammaglobulinemia, diminished numbers of T and B cells, and formation of granulomas in skin, lungs, tongue, adenoids and spleen [13,14]. De Ravin et al [15] described a teen-ager patient presenting with myasthenia gravis treated with thymectomy who subsequently developed destructive midline granulomatous disease. In peripheral blood (PB) he had relatively normal numbers of T and B cells, and a diverse T-cell receptor (TCR) repertoire.…”

Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

“…10 Hypomorphic mutations with residual RAG activity occur in typical Omenn syndrome, 10 or rare cases with lympocytopenia, hypogammaglobulinemia, granulomas in the skin, mucosa, internal organs and viral complications, including EBV-related lymphomas. 11,12 In the present paper, we describe hypomorphic RAG1 mutations that corresponds with mild CD4 ϩ T lymphocytopenia, normal in vitro lymphocyte function and in vivo vaccination responses.…”