Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation

Hsu, Amy P.; West, Robert R.; Calvo, Katherine R.; Cuéllar-Rodríguez, Jennifer; Parta, Mark; Kelly, Susan J.; Ganson, Nancy J.; Hershfield, Michael S.; Holland, Steven M.; Hickstein, Dennis D.

doi:10.1016/j.jaci.2016.03.016

Cited by 43 publications

(42 citation statements)

References 9 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%

“…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%

“…Given that myeloid cells are the major source of ADA2, the rationale for HSCT as a definitive cure for DADA2 is clear. Soon after the initial description of the disease, several single case reports described successful HSCT in DADA2 patients with a predominant hematological phenotype . Up until now HSCT has been reported in 14 patients, and showed remission of immunological, hematological, and vascular manifestations.…”

Section: Treatmentmentioning

confidence: 99%

“…91 A patient clinically diagnosed with a MonoMac syndrome, with monocytopenia and neutropenia resembling GATA2 deficiency and invasive Fusarium proliferatum infection was identified by whole exome sequencing to have biallelic DADA2associated mutations. 95 At present, the origin of these hematological manifestations is unclear. When performed, bone marrow biopsies showed reticular fibrosis as well as characteristic lymphocyte aggregates.…”

Section: Hematological Manifestationsmentioning

confidence: 99%

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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: Hematological Manifestationsmentioning

confidence: 96%

Section: Treatmentmentioning

confidence: 99%

Section: Hematological Manifestationsmentioning

confidence: 99%

See 2 more Smart Citations

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

Moens

Hershfield

Arts

et al. 2018

Immunological Reviews

View full text Add to dashboard Cite

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“…It was only reported in about half of the cases, even though B cell deficiency seems to be a more common trait of the disease than previously anticipated. Also, almost all of the patients who had an immunologic evaluation were pediatric patients, apart from our index patient who was 32 years old and 3 others . However, there are no immunologic data available on other adult DADA2 patients.…”

Section: Discussionmentioning

confidence: 96%

Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood

Schepp

Proietti

Frede

et al. 2017

Arthritis & Rheumatology

113

109

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Taken together, our findings indicate that DADA2 presents not only with vasculopathy but also with an immunodeficiency of the B cell compartment. Therefore, patients with antibody deficiency should be screened for DADA2. Anti-tumor necrosis factor treatment might improve immunologic features over time and might be considered in patients without vascular manifestations but with elevated inflammation markers. Conservative management has so far proven to be the choice for our less severely affected adolescent and adult DADA2 patients; however, in patients with severe cytopenias and bone marrow failure, hematopoietic stem cell transplantation should be considered.

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Dysregulation in B‐cell responses and T follicular helper cell function in ADA2 deficiency patients

et al. 2020

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Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B‐ and T‐cell responses in 14 DADA2 patients to address if ADA2 mutation affects B‐ and T‐cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21low B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B‐cell proliferation and differentiation. Moreover, CD4+ and CD8+ T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL‐21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B‐cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.

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Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: Successful hematopoietic stem cell transplantation

Cited by 43 publications

References 9 publications

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

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

Screening of 181 Patients With Antibody Deficiency for Deficiency of Adenosine Deaminase 2 Sheds New Light on the Disease in Adulthood

Dysregulation in B‐cell responses and T follicular helper cell function in ADA2 deficiency patients

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