Cutaneous Granulomatous Lesions in Common Variable Immunodeficiency: Complete Resolution after Intravenous Immunoglobulins

Nadal, C. Figueras; Ferrer, Rosa Taberner; Diaz, Clara Delfa García; Miralles, Julia; Alomar, A.

doi:10.1159/000018093

Cited by 31 publications

(22 citation statements)

References 18 publications

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“…The dysregulated hyperinflammation in this Rag 1-deficient phenotype expands the currently known Rag-deficient clinical spectrum ( Figure 6). Granulomas have been reported in primary immunodeficiencies, including chronic granulomatous disease, 20 Blau syndrome, 14 Rag1/Rag2, 21 common variable immunodeficiency, 22,23 and Nijmegen syndrome, 24 although generally not associated with extensive tissue destruction as observed in patient P.…”

Section: Discussionmentioning

confidence: 86%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

114

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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...

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Section: Discussionmentioning

confidence: 86%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

114

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“…Tissue biopsy may be required not only for diagnosis of granulomas but also to differentiate these lesions from other complications such as lymphoid hyperplasia or lymphoma, which also occur in CVID [36; 37]. Lungs, lymph nodes and spleen are the most commonly affected sites, although other organs such as skin, liver, bone-marrow, kidney, gastrointestinal tract and brain can be involved [30; 31; 32; 33; 38; 39; 40; 41; 42]. In our cohort, lungs were the primarily affected site, followed by lymph nodes and liver.…”

Section: Discussionmentioning

confidence: 99%

Granulomatous disease in common variable immunodeficiency

Ardeniz

Cunningham‐Rundles

2009

Clinical Immunology

181

153

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Granulomatous disease occurs in 8-22% of patients with common variable immunodeficiency (CVID). We examined the clinical and immunologic information of all 37 of 455 (8.1%) CVID subjects with this complication. The median age at diagnosis of CVID was 26 (2 - 59). 14 had granulomas 1 - 18 years before diagnosis of CVID. In 6 detection of granulomas coincided with this diagnosis; for 17, granulomas were documented later. 54% had lung granulomas, 43% in lymph nodes and 32% in liver. 54% of the group had had autoimmune diseases, mostly immune thrombocytopenia and hemolytic anemia. 24% had had a splenectomy. Nineteen (51.3%) required steroid treatment for granulomas; other immune suppressants were used in some. Over 25 years 28.5% died (median age 37.5), but not significantly more when compared to our CVID patients without granulomas (19.8%). Those with lung granulomas had similar mortality to those with granulomas in other tissues.

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“…687,688 In chronic granulomatous disease, despite the name, true granulomas are not common in cutaneous lesions. [698][699][700][701][702][703][704][705] This disease, which has multiple phenotypes, is the most commonly diagnosed primary immunodeficiency disease in adults, after selective IgA deficiency. 686,[689][690][691][692][693][694][695] Carriers of X-linked chronic granulomatous disease (OMIM 306400) may present with lupus erythematosus-like lesions.…”

Section: Granulomas In Immunodeficiency Disordersmentioning

confidence: 99%

The granulomatous reaction pattern

Weedon

2010

Weedon's Skin Pathology

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Cutaneous Granulomatous Lesions in Common Variable Immunodeficiency: Complete Resolution after Intravenous Immunoglobulins

Cited by 31 publications

References 18 publications

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Granulomatous disease in common variable immunodeficiency

The granulomatous reaction pattern

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