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

Sharapova, Svetlana O.; Migas, Alexandr A.; Guryanova, Irina; Aleshkevich, Svetlana; Kletski, Semen; Durandy, Anne; Belevtsev, Michael

doi:10.1016/j.humimm.2012.10.010

Cited by 28 publications

(26 citation statements)

References 31 publications

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“…The c.256_257delAA, p.K86VfsX32 mutation reduced RAG1 activity to 2.7 % of wild-type levels in Abl- Rag1 −/− pro-B cells. The p.K86VfsX32 mutation also has been described previously as a pathogenic [6]. The c.1835A>G mutation is predicted to affect splicing, which could not be examined in Abl- Rag1 −/− pro-B system; however, a patient homozygous for the c.1835A>G mutation has been reported with a SCID phenotype [1].…”

Section: Case Reportmentioning

confidence: 99%

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

et al. 2014

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Purpose Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. Methods Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. Results Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. Conclusion Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.

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Section: Case Reportmentioning

confidence: 99%

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

et al. 2014

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“…These forms include Omenn syndrome (hepatosplenomegaly, lymphadenopathy, severe erythroderma, eosinophilia, elevated serum IgE levels and autoantibodies, colitis, and infiltration of oligoclonal populations of T cells) 13–15 , atypical Omenn syndrome (skin inflammation without T-cell expansion, a low proportion of CD31 cells, and more than 3% B cells) 16 , and atypical SCID with γδ T cell expansion (autoimmunity, severe cytomegalovirus infection and partially functioning B cells with a limited ability for antibody production) 17–19 . Finally, a delayed onset form, with generalized granulomatous lesions, severe varicella infection, normal frequencies of T and B cells, progressive hypogammaglobulinemia, defective specific antibody production and autoimmunity, has recently been reported 6, 20–22 and is due to hypomorphic mutations that support significant, residual levels of recombination activity. Some of the features reported in these patients overlap with those seen in patients with common variable immunodeficiency (CVID) and may lead to misdiagnosis and insufficient treatment, based on immunoglobulin replacement rather than curative hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency

Abolhassani

Wang

Aghamohammadi

et al. 2014

Journal of Allergy and Clinical Immunology

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Background RAG1 deficiency presents a varied spectrum of combined immunodeficiency, ranging from a T−B−NK+type of disease to a T+B+NK+ phenotype. Objective To assess the genetic background of common variable immunodeficiency (CVID) patients. Methods A patient diagnosed with CVID, who was born in a consanguineous family and thus would be expected to show an autosomal recessive inheritance, was subjected to clinical evaluation, immunological assays, homozygosity gene mapping, exome sequencing, Sanger sequencing and functional analysis. Results The 14-year-old patient, who suffered from liver granuloma, extranodal marginal zone B cell lymphoma and autoimmune neutropenia, is presented with a clinical picture resembling CVID. Genetic analysis of this patient showed a homozygous hypomorphic RAG1 mutation (c.1073 G>A, p.C358Y) with a residual functional capacity of 48% of wild-type protein. Conclusion Our finding broadens the range of disorders associated with RAG1 mutations and may have important therapeutic implications.

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“…Inflammatory complications are increasingly reported for RAG deficient patients with CID-G/AI phenotype and late diagnosis. 9–11 Allograft rejection and fatal post-transplant complications are more common among SCID patients with RAG variants than in other forms of SCID, especially if harboring infections. 12–14 In a recent multicenter study, hematopoietic stem cell transplantation (HSCT) was offered in 61% of cases, less frequently than in variants of SCID.…”

Section: Discussionmentioning

confidence: 99%

“…1 CID-G/AI patients may also fail to engraft stem cells or die from other post-transplant complications. 1, 9, 11, 15 …”

Section: Discussionmentioning

confidence: 99%

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Lawless

Geier²,

Farmer

et al. 2018

Journal of Allergy and Clinical Immunology

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

Cited by 28 publications

References 31 publications

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

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