RAG deficiency with ALPS features successfully treated with TCRαβ/CD19 cell depleted haploidentical stem cell transplant

Westermann-Clark, Emma; Grossi, Alice; Fioredda, Francesca; Giardino, Stefano; Cappelli, Enrico; Terranova, Paola; Palmisani, Elena; Farmer, Jocelyn R.; Foldvari, Zsofia; Yamazaki, Yasuhiro; Faraci, Maura; Lanino, Edoardo; Notarangelo, Luigi D.; Dufour, Carlo; Ceccherini, Isabella; Walter, Jolán E.; Miano, Maurizio

doi:10.1016/j.clim.2017.10.012

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…Patients ID15, ID39, ID94, and ID97 are homozygous for the deleterious RAG1, LRBA, NCF1, and IL7R gene variants, respectively, in three of which, except for ID97, the parents demonstrated being heterozygotes. These cases are consistent with the autosomal recessive inheritance of the corresponding diseases and with the clinical features of the patients [36,37].…”

Section: Pathogenic or Likely Pathogenic Variants Detectedsupporting

confidence: 87%

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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Inborn errors of immunity (IEI) include a large group of inherited diseases sharing either poor, dysregulated, or absent and/or acquired function in one or more components of the immune system. Next-generation sequencing (NGS) has driven a rapid increase in the recognition of such defects, though the wide heterogeneity of genetically diverse but phenotypically overlapping diseases has often prevented the molecular characterization of the most complex patients. Two hundred and seventy-two patients were submitted to three successive NGS-based gene panels composed of 58, 146, and 312 genes. Along with pathogenic and likely pathogenic causative gene variants, accounting for the corresponding disorders (37/272 patients, 13.6%), a number of either rare (probably) damaging variants in genes unrelated to patients’ phenotype, variants of unknown significance (VUS) in genes consistent with their clinics, or apparently inconsistent benign, likely benign, or VUS variants were also detected. Finally, a remarkable amount of yet unreported variants of unknown significance were also found, often recurring in our dataset. The NGS approach demonstrated an expected IEI diagnostic rate. However, defining the appropriate list of genes for these panels may not be straightforward, and the application of unbiased approaches should be taken into consideration, especially when patients show atypical clinical pictures.

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Section: Pathogenic or Likely Pathogenic Variants Detectedsupporting

confidence: 87%

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Grossi

Miano

Lanciotti

et al. 2021

Genes

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“…Moreover, patients with hypomorphic RAG mutations may initially be given other diagnoses, including idiopathic CD4 + lymphopenia, common variable immunodeficiency, IgA deficiency, selective deficiency of polysaccharide‐specific antibodies, hyper‐IgM syndrome, and autoimmune lymphoproliferative syndrome . Although at least in some of these cases, the clinical and laboratory data were clearly suggestive of a combined immunodeficiency, the fact remains that these clinical examples have taught us how diverse is the clinical and immunological phenotype associated with hypomorphic RAG mutations.…”

Section: Spectrum Of Clinical Manifestations Caused By Rag Gene Defectsmentioning

confidence: 99%

RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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Summary Mutations of the Recombinase Activating Genes (RAG) in humans underlie a broad spectrum of clinical and immunological phenotypes that reflect different degrees of impairment of T and B cell development and alterations of mechanisms of central and peripheral tolerance. Recent studies have shown that this phenotypic heterogeneity correlates, albeit imperfectly, with different levels of recombination activity of the mutant RAG proteins. Furthermore, studies in patients and in newly developed animal models carrying hypomorphic RAG mutations have disclosed various mechanisms underlying immune dysregulation in this condition. Careful annotation of clinical outcome and immune reconstitution in RAG-deficient patients who have received hematopoietic stem cell transplantation has shown that progress has been made in the treatment of this disease, but new approaches remain to be tested to improve stem cell engraftment and durable immune reconstitution. Finally, initial attempts have been made to treat RAG deficiency with gene therapy.

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“…In this study, twenty-four genetic disorders with ALPS-like characteristics have been identified in the literature: PRKCD, MAGT1, XIAP, SH2D1A, RASGRP1, TNFRSF9, ITK, STK4, CTLA4, LRBA, CD25, CD122, DEF6, TET2, TPP2, IL12RB1, ADA2 and TNFAIP3 deficiencies, PIK3CD, STAT3, STAT1 and CARD11 gain of function, PIK3R1 loss of function and RALD (caused by somatic gain of function mutations in NRAS and KRAS genes). Furthermore, other genetic defects as IKZF1 ( 75 ) , NFKB1 ( 102 ), RAG1 ( 103 ) or NFKB2 ( 104 ) deficiencies have been associated with autoimmune and lymphoproliferative features in several patients cohorts.…”

Section: Discussionmentioning

confidence: 99%

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

et al. 2021

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Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP, SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare in other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life.

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RAG deficiency with ALPS features successfully treated with TCRαβ/CD19 cell depleted haploidentical stem cell transplant

Cited by 13 publications

References 11 publications

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

RAG gene defects at the verge of immunodeficiency and immune dysregulation

Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management

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