Cutaneous Noncaseating Granulomas Associated With Nijmegen Breakage Syndrome

Yoo, Jane; Wolgamot, Greg; Torgerson, Troy R.; Sidbury, Robert

doi:10.1001/archderm.144.3.418

Cited by 22 publications

(20 citation statements)

References 5 publications

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“…Given the autoimmune cytopenias and early death of patient P's sister, she probably carried the same mutations, although her phenotype appears somewhat different. Variability in phenotypes from the same mutations in Rag even within the same family is well-recognized, [25][26][27] highlighting the importance of environmental factors influencing the disease manifestation.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

114

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“…Included were all primary publications published in English, German and French. Ten primary reports were found describing cutaneous granulomas in A-T [4,5,6,7,8,9,10,11,12,13] and a series of articles reporting skin granulomas in other PIDs [14,15,16,17,18,19,20,21,22,23,24,25,26]. For common variable immunodeficiency (CVID), often associated with granulomas in various organs, only the recently published article of Ardeniz and Cunningham-Rundles [23] dealing with skin granulomas was included.…”

Section: Methodsmentioning

confidence: 99%

Cutaneous Granulomas in Ataxia Telangiectasia and Other Primary Immunodeficiencies: Reflection of Inappropriate Immune Regulation?

Chiam¹,

Verhagen²,

Haraldsson

et al. 2011

Dermatology

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Background: Non-infective cutaneous granulomas with unknown pathogenesis occur in various primary immunodeficiencies (PIDs) including ataxia telangiectasia (A-T). Objective: To find a common immunological denominator in these cutaneous granulomas. Methods: The dermatological and immunological features of 4 patients with A-T and cutaneous granulomas were described. The literature on skin granulomas in A-T and in other PIDs is reviewed. Results: All 4 A-T patients had progressive granulomas on their limbs and showed decreased IgG and IgA concentrations with normal IgM levels. They had a marked decrease in B cells and naïve T cells coinciding with the appearance of the cutaneous granulomas. Similar B- and T-cell abnormalities were described in patients with other PIDs with skin granulomas. Conclusions: We hypothesize that the pathogenesis of these skin granulomas is related to immune dysregulation of macrophages due to the absence of naïve T cells with an appropriate T-cell receptor repertoire and the unopposed activity of γδ T cells and/or natural killer cells.

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“…Nijmegen breakage syndrome has also been reported in many other European countries [2,8,14,23,36,[39][40][41][42], as well as in North and South America, Morocco and New Zealand [12,15,22,27,32,35,[43][44][45][46].…”

Section: Epidemiologymentioning

confidence: 98%

“…In three patients, appearance of cutaneous, sarcoidlike granulomatous lesions localised mainly on limbs and face, which were refractory to treatment, preceded diagnosis of diffuse large B-cell lymphoma (DLBCL) by 1-6 years [32,35,49].…”

Section: (B) Skin and Hairmentioning

confidence: 99%

“…The majority of NBS patients identified to date are homozygous for the NBN mutation c.657_661del5 (p.K219fsX19): all but one patient in the Czech Republic, Poland and Ukraine; the majority in Russia; about 70% in the USA and many individual cases in other countries all over the world [11,14,18,[21][22][23]27,[30][31][32]34,35,141,142]. The remaining patients are either compound heterozygotes of the c.657del5 mutation and another unique mutation [11,18,28] or carry a unique mutation in both alleles [11,15,24,51,74,76].…”

Section: Molecular Diagnosismentioning

confidence: 99%

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Nijmegen Breakage Syndrome (NBS)

SpringerReference

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Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów. Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest pr...

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Cutaneous Noncaseating Granulomas Associated With Nijmegen Breakage Syndrome

Cited by 22 publications

References 5 publications

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Cutaneous Granulomas in Ataxia Telangiectasia and Other Primary Immunodeficiencies: Reflection of Inappropriate Immune Regulation?

Nijmegen Breakage Syndrome (NBS)

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