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

Abstract

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.

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

“…DADA2 has been reported in more than 170 patients, however, the actual number of affected individuals is suspected to be higher (Moens et al, ). 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, ).…”

“…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, ).…”

ADA2 deficiency due to a novel structural variation in 22q11.1

“…ADA2 enzymatic activity was absent in the patient's circulating monocytes and plasma whereas parents showed a level lower than healthy donors (HD) (Figure A). The patient consistently responded to anti‐tumor necrosis factor treatment (etanercept) …”

“…Deficiency of the adenosine deaminase 2 ( ADA2 ) gene (OMIM#607575) (DADA2) (OMIM#615688) is a rare recessive autoinflammatory disease caused by bi‐allelic loss‐of‐function ADA2 mutations , showing a wide range of clinical manifestations, including cerebral stroke events and several kind of immune dysregulation . Interestingly, patients with typical DADA2 and complete enzymatic impairment, may present with only one or no ADA2 mutation, thus, suggesting involvement of null alleles …”

“…Indeed, deletions of variable lengths have already been observed to encompass the ADA2 locus and to associate with DADA2 symptoms, although breakpoints are uncharacterized yet . Noteworthy, a timely identification of the ADA2 enzymatic defect in the presence of a clinical phenotype clearly consistent with DADA2 should lead to a careful search for CNVs at the ADA2 locus, especially in genetically undefined patients often at risk for acute events …”