ADA2 deficiency (DADA2) associated with Evans syndrome and a severe <i>ADA2</i> genotype

Ferriani, Mariana Paes Leme; Valera, Elvis Terci; Sousa, Graziella Ribeiro de; Sandrin-Garcia, Paula; Moura, Romero Marinho de; Hershfield, Michel S; Carvalho, Luciana

doi:10.1093/rheumatology/keab011

Cited by 7 publications

(9 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ). In addition to expected bone marrow examination findings of erythroid hyperplasia (with reticulocytosis), features of erythroid hypoplasia or dysplasia (with reticulocytopenia) have also been described in these patients ( 46 , 49 , 50 ). Direct antiglobulin test was also positive in absence of overt hemolysis and PRCA in few patients ( 50 , 52 ).…”

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 86%

“…To date, more than a dozen such patients of DADA2 have been reported accompanied with predominant autoimmune cytopenia. In most of these patients the clues for etiological diagnosis have ranged from vasculopathic ulcers ( 30 ), stroke ( 1 ), low IgG/IgM or hypogammaglobulinemia ( 32 , 44 – 48 ), recurrent infections ( 18 , 49 ) including the vaccine pathogens ( 46 ). Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ).…”

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 99%

“…In most of these patients the clues for etiological diagnosis have ranged from vasculopathic ulcers ( 30 ), stroke ( 1 ), low IgG/IgM or hypogammaglobulinemia ( 32 , 44 – 48 ), recurrent infections ( 18 , 49 ) including the vaccine pathogens ( 46 ). Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ). In addition to expected bone marrow examination findings of erythroid hyperplasia (with reticulocytosis), features of erythroid hypoplasia or dysplasia (with reticulocytopenia) have also been described in these patients ( 46 , 49 , 50 ).…”

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 99%

See 2 more Smart Citations

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

et al. 2022

View full text Add to dashboard Cite

Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.

show abstract

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 86%

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 99%

Section: Spectrum Of Clinical Manifestationsmentioning

confidence: 99%

See 1 more Smart Citation

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

et al. 2022

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Patients may display humoral immunode ciency of variable severity characterized by low immunoglobulin levels and increased risk of infection [1, 2, 4] . Hematologic disorders are present in some patients as pure red cell aplasia (PRCA) that mimics Diamond-Blackfan anemia, lymphopenia, neutropenia, thrombocytopenia, or pancytopenia and bone marrow failure (BMF) [5, 8,[18][19][20][21][22] .Adenosine deaminase 2 (ADA2) is an extracellular enzyme mainly secreted by myeloid cells, i.e., monocytes, macrophages, dendritic cells [15,23,24] , and is a dimeric enzyme with four domains, including signal peptide, catalytic domain, putative receptor binding domain, and dimerization domain [10,23,25] . It is clear that biallelic homozygous or compound heterozygous mutations in the ADA2 gene leading to decreased ADA2 activity are responsible for the disease [1, 2] .…”

mentioning

confidence: 99%

A cohort study on deficiency of ADA2 from China

Han²,

Wu³

et al. 2022

Preprint

View full text Add to dashboard Cite

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function mutations in ADA2, characterized by systemic inflammation, vasculitis, immunodeficiency, and/or hematologic abnormalities. Methods: A retrospective analysis of patients with DADA2 diagnosed by whole exome sequencing at 17 rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype and treatment responses were analyzed.Results Thirty patients with DADA2 were enrolled in this cohort between January 2015 and December 2021. Median age at onset was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects in the cohort died from DADA2-related complications. The patients presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient with pure red cell aplasia (PRCA) and bone marrow failure (BMF) with variable cytopenia was observed in our cohort. Twenty-three (76.7%) patients received TNF inhibitors and all achieved clinical remission. Homozygous variants and compound heterozygous variants were identified in 5 and 25 patients, respective. Two patients received hematopoietic stem cell transplantation (HSCT), and both got remission. Among 39 unique variants in our cohort, six is novel.Conclusion: In order to establish the diagnosis early and prevent devastating clinical outcomes, genetic screening and/ or testing of adenosine deaminase enzymatic activity should be performed in patients with suspected clinical features. TNF inhibitors can be first line drug for patients with vasculitic DADA2. HSCT is an alternative choice for patients with refractory to TNF inhibitors or hematological disorders.

show abstract

A Cohort Study on Deficiency of ADA2 from China

Han

et al. 2023

J Clin Immunol

View full text Add to dashboard Cite

Purpose Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. Methods A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. Results Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. Conclusion To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

show abstract

ADA2 deficiency (DADA2) associated with Evans syndrome and a severe ADA2 genotype

Cited by 7 publications

References 7 publications

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

A cohort study on deficiency of ADA2 from China

A Cohort Study on Deficiency of ADA2 from China

Contact Info

Product

Resources

About