Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2

Abstract

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of systemic vasculopathy that often presents during early childhood. Linked to biallelic mutations in ADA2 (previously CECR1), DADA2 was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes, and peripheral vasculopathy that resembles polyarteritis nodosum. However, the wide spectrum of clinical findings and heterogeneity of disease, even among family members with identical mutations, is increasingly recognized. Evidence of systemic inflammation and vasculopathy is not uniformly present in DADA2 patients and some can remain asymptomatic through adulthood. Humoral immunodeficiency characterized by low immunoglobulin levels and increased risk of infection is another common feature of DADA2. Variable cytopenias including pure red cell aplasia that mimics Diamond-Blackfan anemia can also be primary manifestations of DADA2. How defects in a single gene translate into these heterogeneous presentations remains to be answered. In this review, we will summarize lessons learned from the pleiotropic clinical manifestations of DADA2.

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)

“…The prevalence of hypogammaglobinemia in our cohort is similar to the general estimate for all patients. 3 We suspect that humoral immunodeficiency with low immunoglobulin levels likely represents a common clinical feature of DADA2 regardless of the presenting phenotype. DADA2 can also manifest as autoimmunity (systemic lupus erythematosus and antiphospholipid syndrome) and lymphoproliferative disease.…”

“…1,2 Since its initial description in 2014, the clinical spectrum of this condition has expanded considerably, and variable hematologic and immunologic abnormalities have been described in about half the patients with DADA2. 3,4 Primary presentations of the disease include pure red cell aplasia (PRCA) that mimics Diamond-Blackfan anemia and bone marrow failure (BMF) with variable cytopenia, even without vasculitis or systemic inflammation. [5][6][7] The severity of these manifestations can result in transfusion dependency in patients with PRCA or a need for hematopoietic stem cell transplant in those with BMF.…”

ADA2 deficiency in a patient with Noonan syndrome‐like disorder with loose anagen hair: The co‐occurrence of two rare syndromes

“…DADA2 is associated with homozygous mutations in the ADA2 , encoding ADA2 protein, one of the adenosine deaminase group enzymes (Lee, ; Meyts & Aksentijevich, ). Although ADA2 function is yet to be fully elucidated, it has been suggested that ADA2 deficiency results in the increased expression of inflammatory macrophages (reversing the M1/M0 ratio) and has effects on the endothelium.…”

“…It is noteworthy that in half of these patients, symptoms related to immunodeficiency occur prior to symptoms associated with vasculopathy (Schepp et al, ). IgM deficiency, panhypoglobulinemia and lymphopenia especially affecting B lymphocytes, are essential laboratory findings in DADA2 related immune deficiency (Lee, ; Moens et al, ). Immunodeficiency related recurrent herpes simplex virus and sinopulmonary infections have been reported to contribute to morbidity and mortality as was the case in our patient.…”

“…Mutations in ADA2 lead to unprovoked inflammation in various tissues, particularly in vascular system (Lee, ; Moens et al, ). Vascular inflammation is responsible for the majority of the phenotypical features including intermittent fever, rash, PAN‐like symptoms and recurrent strokes as well as hematological and rheumatological features (Lee, ; Moens et al, ). The isolated autoinflammatory disease phenotype has emerged as a phenotype with multisystemic involvement affecting almost all organ systems with variable clinical severity and age of onset after the description of several patients for the last 5 years (Moens et al, ).…”