Widespread Granulomatous Dermatitis of Infancy

Schaffer, Julie V.; Chandra, Pranil; Keegan, Brian R.; Heller, Patricia; Shin, Helen T.

doi:10.1001/archderm.143.3.386

Cited by 44 publications

(22 citation statements)

References 51 publications

(99 reference statements)

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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: 83%

“…Up to 30% of normal Rag1 activity has been reported from some hypomorphic Rag mutations. 21 The residual recombinase activity in this patient's cells may explain his relatively mild phenotype that permits adequate recombination to generate overall normal numbers of lymphocytes, including sufficient B cells to produce normal numbers of B cells and specific antibody production. It is of interest that his IgG2 and IgG4 subclasses were deficient, and his response to polysaccharide vaccines was impaired.…”

Section: Discussionmentioning

confidence: 94%

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Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

112

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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: 83%

Section: Discussionmentioning

confidence: 94%

Hypomorphic Rag mutations can cause destructive midline granulomatous disease

Ravin

Cowen

Zarember

et al. 2010

Blood

112

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“…[40][41][42][43] Skin examination reveals nonpruritic, generalized, densely populated erythematous papules. 44,45 Recalcitrant, tender leg ulcers with granulating bases and poorly demarcated flat borders have been described (in contrast to the well-defined undermined borders of PG ulcers). 46 Histopathology reveals noncaseating granulomata.…”

Section: Blau Syndromementioning

confidence: 99%

“…46 Histopathology reveals noncaseating granulomata. 44,45,47 Granulomatous infiltration of the lungs, kidneys, liver, and of the arterial and nervous systems may also occur. [48][49][50][51][52] Missense mutations in the CARD15 (caspaserecruiting domain 15) gene, also known as NOD2 (nucleotide-binding oligomerization domain) gene, are responsible for Blau syndrome.…”

Section: Blau Syndromementioning

confidence: 99%

Autoinflammation: From monogenic syndromes to common skin diseases

Nguyen

Cowen

Leslie

2013

Journal of the American Academy of Dermatology

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Autoinflammation is characterized by aberrant regulation of the innate immune system and often manifests as periodic fevers and systemic inflammation involving multiple organs, including the skin. Mutations leading to abnormal behavior or activity of the interleukin 1 beta (IL-1ß)-processing inflammasome complex have been found in several rare autoinflammatory syndromes, for which anticytokine therapy such as IL-1 or tumor necrosis factor-alfa inhibition may be effective. It is becoming clear that features of autoinflammation also affect common dermatoses, some of which were previously thought to be solely autoimmune in origin (eg, vitiligo, systemic lupus erythematosus). Recognizing the pathogenetic role of autoinflammation can open up new avenues for the targeted treatment of complex, inflammatory dermatoses.

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“…Despite the increasing use of genetic testing, the real prevalence of BS and EOS remains unknown: both familial and sporadic forms have been reported in Caucasians [46,55,70,85,98], Spanish [72], Asian [47,51,69,87], and American [61,75,83] individuals. Rough incidence data could be derived from analysis of a total of 48 Danish childhood-onset sarcoidosis patients, obtained from a nationwide patient registry during the period 1979-1994, and estimating that sarcoidosis incidence per 100,000 person/year was 0.06 for children under 5 and 0.10 for those between 5 and 9 years of age.…”

Section: The Epidemiologic Factsmentioning

confidence: 99%