ADA2 deficiency: Clonal lymphoproliferation in a subset of patients

Trotta, Luca; Martelius, Timi; Siitonen, Timo; Hautala, Timo; Hämäläinen, Sari; Juntti, Hanna; Taskinen, Mervi; Ilander, Mette; Andersson, Emma; Zavialov, Andrey V.; Kaustio, Meri; Keski‐Filppula, Riikka; Hershfield, Michael S.; Mustjoki, Satu; Tapiainen, Terhi; Seppänen, Mikko; Saarela, Janna

doi:10.1016/j.jaci.2018.01.012

Cited by 74 publications

(86 citation statements)

References 17 publications

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“…At present, the origin of these hematological manifestations is unclear. When performed, bone marrow biopsies showed reticular fibrosis as well as characteristic lymphocyte aggregates . In the patient with severe neutropenia reported by Cipe et al, the bone marrow analysis displayed normal myeloid development.…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 86%

“…Thus, other factors, epigenetic or environmental, may influence disease expressivity. In this way, it was observed that bacterial infections provoked inflammatory and vasculitis flares . Observations in a cohort of patients showed disease presentation following CMV primo‐infection and a flare after live measles vaccine (unpublished in‐house observation).…”

Section: The Ada2 Genementioning

confidence: 95%

“…When performed, bone marrow biopsies showed reticular fibrosis as well as characteristic lymphocyte aggregates. 1,80,89,90,95 In the patient with severe neutropenia reported by Cipe et al 91…”

Section: Hematological Manifestationsmentioning

confidence: 96%

“…Another group recently reported a T cell large granular leukemia (T‐LGL) in two patients presenting lymphoproliferation at 8y and 31y, respectively. These patients also showed somatic gain‐of‐function mutations in STAT3 in the CD8 T cells, however, not restricted to the T‐LGL clones . A homozygous p.G47R mutation has been reported in a Jewish patient diagnosed with HHV‐8‐negative multicentric Castleman's disease, a condition of generalized polyclonal lymphoproliferation, systemic inflammation, and multiple‐organ system failure resulting from hypercytokinemia .…”

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 97%

“…In this way, it was observed that bacterial infections provoked inflammatory and vasculitis flares. 89 Observations in a cohort of patients showed disease presentation following CMV primo-infection and a flare after live measles vaccine (unpublished in-house observation). Heterozygous carriers of diseasecausing mutations are typically unaffected and have ADA2 enzyme activity within the "carrier" range.…”

Section: The Ada 2 G Enementioning

confidence: 98%

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Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

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Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small‐ and medium‐size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro‐inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti‐TNF therapy with etanercept and that is the first‐line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients’ refractory to anti‐cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine‐tune and steer future therapeutic strategies.

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Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 86%

Section: The Ada2 Genementioning

confidence: 95%

Section: Hematological Manifestationsmentioning

confidence: 96%

Section: Human Ada2 Deficiency: An Expanding Clinical Phenotypementioning

confidence: 97%

Section: The Ada 2 G Enementioning

confidence: 98%

See 3 more Smart Citations

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

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Evaluation and Management of Deficiency of Adenosine Deaminase 2

Lee,

Davidson,

Abraham

et al. 2023

JAMA Netw Open

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ImportanceDeficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management.ObjectiveTo review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2.Evidence ReviewThe DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence.FindingsThe DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined.Conclusions and RelevanceDADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

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