Deficiency of adenosine deaminase 2 (DADA2)

INTRODUCTION — Deficiency of adenosine deaminase 2 (DADA2) is a rare, recessively inherited autoinflammatory disease characterized by systemic inflammation, vasculitis, early-onset stroke, cytopenias, and immunodeficiency. Initially recognized as a monogenic form of systemic vasculitis that resembles polyarteritis nodosa (PAN), DADA2 is caused by biallelic pathogenic variants in the adenosine deaminase 2 gene (ADA2; formerly known as CECR1) on chromosome 22q11 [1,2]. The clinical spectrum of DADA2 is broad, and manifestations can vary even among family members with the same genotype [3,4]. DADA2 can also present as bone marrow failure and immunodeficiency, with or without features of inflammation and vasculitis.

Additional topics cover other specific autoinflammatory diseases:

●(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

●(See "Cryopyrin-associated periodic syndromes and related disorders".)

●(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

●(See "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)".)

●(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

●(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

●(See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)

●(See "Autoinflammatory diseases mediated by miscellaneous mechanisms".)

A general discussion of autoinflammatory diseases is available separately, as are topics on classification and genetic diagnosis of inborn errors of immunity:

●(See "The autoinflammatory diseases: An overview".)

●(See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

●(See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

EPIDEMIOLOGY — More than 300 cases of DADA2 have been published in the literature since the first description of this syndrome in 2014. The carrier frequency for deleterious ADA2 variants is estimated to be 1 in 236 persons worldwide based on functional annotation of population variants in Genome Aggregate Database (gnomAD) [5]. Accordingly, disease prevalence is expected to be approximately 1 in 222,000 persons. Carrier frequency and disease prevalence vary significantly among different populations. (See 'Genetics' below.)

Among 48 European children with early-onset vasculitis, 15 (31 percent) were found to have DADA2 [6]. Screening of adult patients with polyarteritis nodosa (PAN) found that 4 out of 108 cases (3.4 percent) possessed biallelic pathogenic ADA2 variants, and several others carried a single pathogenic variant [7]. By contrast, DADA2 was not found among 1107 patients with granulomatosis with polyangiitis or microscopic polyangiitis [7]. (See 'Vasculitis' below.)

In a genomic survey of patients with Diamond-Blackfan anemia (DBA), 9 out of 472 cases (2 percent) possessed biallelic pathogenic ADA2 variants in the absence of the ribosomal protein gene mutations associated with DBA [8]. (See 'Bone marrow failure' below.)

GENETICS — DADA2 is recessively inherited, and approximately half of cases are caused by compound heterozygous pathogenic variants [9]. These pathogenic variants have been described in all exons and functional domains of ADA2. However, as with most monogenic autoinflammatory diseases, DADA2 exhibits incomplete penetrance (not all patients with mutations have clinical disease) [10,11].

Missense ADA2 variants account for most disease-associated mutations, especially in cases with the vasculitis phenotype. Loss-of-function variants (nonsense and insertions/deletions with frameshift) are more commonly found in patients with severe hematologic compromise due to bone marrow failure. Studies characterizing DADA2 variants in vitro reveal a gradient of residual function, with complete or near absence of functional protein correlating with hematologic disease (often without vasculitis), while retention of some functional protein correlates with risk for stroke and other vasculitic manifestations [12,13]. This genotype-phenotype correlation has important therapeutic implications because tumor necrosis factor (TNF) inhibitors effectively ameliorate the vasculitis phenotype but have little efficacy in DADA2 patients with bone marrow failure. (See 'Vasculitis' below and 'Bone marrow failure' below and 'Treatment' below.)

The most common pathogenic variant associated with DADA2, p.Gly47Arg (G47R), is found in the majority of patients from Turkey, Israel, and South Asia. Persons with homozygous G47R mutations typically exhibit the vasculitis phenotype that resembles polyarteritis nodosa (PAN) [14,15]. In Europeans, the most common DADA2-associated variant is p.Arg169Gln (R169Q). This variant likely originated in Northern Europe, with the highest carrier frequency (1 in 160) found in Finland. Patients with homozygous R169Q display variable features of vasculitis, severe hematologic defects, and/or immunodeficiency [4,16].

PATHOGENESIS — ADA2 is one of two enzymes that catalyze conversion of adenosine to inosine. The major intracellular enzyme responsible for this function is adenosine deaminase 1 (ADA1). Deficiency of ADA1 leads to an accumulation of toxic metabolic products that impair lymphocyte viability and presents as T-negative, B-negative, natural killer (NK) negative severe combined immunodeficiency (SCID) (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis"). By contrast, ADA2 is an extracellular protein produced preferentially by monocytes, macrophages, and dendritic cells, although ADA1 may also be present extracellularly due to cell turnover and lysis of erythrocytes [17,18].

It is unknown whether DADA2 reflects loss of enzymatic activity or another mechanism, in particular because the adenosine deaminase activity of ADA2 is 100-fold weaker than that of ADA1 due to lower affinity for adenosine [17]. The accumulation of toxic metabolites deoxyadenosine and deoxyadenosine triphosphate seen in ADA-SCID is not observed in DADA2, suggesting nonredundant physiologic roles of ADA1 and ADA2.

ADA2 promotes T cell proliferation independent of its enzymatic activity and also augments the differentiation of monocytes to macrophages [19,20]. Correspondingly, monocytes from DADA2 patients exhibit impaired expansion into immunomodulatory M2 macrophages [1]. These observations suggest disease driven by an intrinsic defect in monocyte/macrophage biology. Alternately, inflammation may arise through failure to degrade extracellular adenosine at the tissue level, triggering neutrophils to release immunostimulatory neutrophil extracellular traps (NETs) that subsequently stimulate macrophages to produce tumor necrosis factor (TNF) [21].

TNF has a critical role in driving the systemic inflammation and vasculitis in DADA2, as reflected in the efficacy of TNF inhibition in the prevention of recurrent stroke [22]. Type I interferons also may play a role, as suggested by the detection of an interferon signature by gene expression profiling of peripheral blood [23-25]. In vitro studies suggest that ADA2 could serve as a direct regulator of interferon production by modulating adenosine levels or as a lysosomal nuclease that regulates interferon production induced by endogenous nucleic acids [26,27]. However, the clinical phenotype of DADA2 is largely distinct from that of type I interferonopathies (see "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)"). It remains to be seen whether excess interferon production is observed across the different phenotypes of DADA2 and whether these antiviral cytokines contribute to the pathophysiology of DADA2.

CLINICAL MANIFESTATIONS

Phenotypes — DADA2 was initially identified as a monogenic form of systemic vasculitis that affects medium- and small-sized vessels (figure 1). This vasculitis phenotype accounts for most cases in the literature and remains the more common presentation of DADA2. A second phenotype characterized by bone marrow failure was recognized later. While the overlapping feature of vasculitis and cytopenia are seen in some patients, these two phenotypes differ in genotype (see 'Genetics' above) and treatment response (see 'Treatment' below). Immunodeficiency is another feature of DADA2, but whether it constitutes a distinct clinical phenotype is unclear [28,29]. Impaired humoral immunity and recurrent infection are seen in DADA2 with both vasculitis and hematologic phenotypes [1,12].

Age at presentation — Most patients exhibit first disease manifestations during childhood, with an average age of onset of five to seven years; approximately 25 percent of patients are diagnosed before one year of age and 77 percent by age 10 years [30,31]. Patients with DADA2 who have pure red cell aplasia and bone marrow failure tend to present during early infancy, whereas delayed presentation is common in patients with vasculitis and systemic inflammation [12]. With growing awareness of DADA2 and greater availability of diagnostic tests, new cases are increasingly recognized in adults, with diagnosis as late as the seventh decade of life [14,32,33]. It is not clear what factors precipitate disease onset [10,11].

Vasculitis — Vessel wall inflammation leading to stenosis, aneurysm formation, and perforation drive the organ-specific manifestations of DADA2 (figure 1). Vasculitis may affect the skin, cranial nerves, peripheral nerves, digits, kidneys, intestine, and even testes, with pathologic features that are indistinguishable from polyarteritis nodosa (PAN) [1,2,6,34].

●Neurologic – Inflammation of blood vessels most characteristically involves the central nervous system (CNS), resulting in recurrent strokes that are either ischemic or hemorrhagic, often beginning in early childhood [1]. Stroke is reported in approximately one-third of DADA2 patients and may be the initial presenting feature [30,31,35]. The risk for stroke appears to be greater in patients diagnosed with DADA2 during childhood rather than adulthood [36]. The incidence of cerebral vascular events is likely underestimated due to silent infarcts and mild cases with transient symptoms (ie, transient ischemic attack). Neuropathy of cranial and peripheral nerves is common and distinguishes DADA2 from childhood PAN [6]. Neurosensory hearing loss, vision loss, central retinal artery occlusion, optic nerve atrophy, and uveitis have all been described in patients with DADA2 [1].

●Skin – Common skin manifestations include livedo racemosa (considered to reflect vasculopathy), subcutaneous nodules, and erythematous papules (picture 1); ulcerations and skin necrosis are seen in some patients. Severe skin vasculitis is more common in adults with DADA2 [36].

●Musculoskeletal – Musculoskeletal complications are observed in approximately half of patients, and arthritis can affect small and large joints. A plethora of visceral organ involvement including infarction of bowels, kidneys, spleen and pancreas; upper and lower gastrointestinal tract bleeding; diffuse alveolar hemorrhage; and cardiac inflammation have been reported in DADA2 (image 1).

Systemic inflammation — Features of systemic inflammation are common in patients with the DADA2 vasculitis phenotype and sometimes appear before localized manifestations of vascular inflammation. Patients exhibit constitutive symptoms, lymphadenopathy, elevated transaminases, and elevation of inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Children may exhibit poor growth. Presentation with fever, lymphadenopathy, and hepatosplenomegaly can resemble autoimmune lymphoproliferative syndrome (ALPS), multicentric Castleman disease, or other autoinflammatory syndromes [37-39]. Macrophage activation syndrome has also been reported in rare cases [3,12]. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis" and "HHV-8-negative/idiopathic multicentric Castleman disease" and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)

Bone marrow failure — Patients may exhibit anemia, neutropenia, and lymphopenia, in some cases with transfusion-dependent pure red cell aplasia resembling Diamond-Blackfan anemia (DBA) [40-43]. Patients with pure red cell aplasia or bone marrow failure represent a minority of patients with DADA2 and typically present during early childhood. Autoimmune cytopenias are less common, but Evans syndrome and idiopathic thrombocytopenic purpura have been reported as presenting features of DADA2 [40,44]. Bone marrow biopsy of DADA2 patients typically shows diminished erythroid, myeloid, and/or lymphoid development. Lymphoid aggregates in the bone marrow are often seen, but their significance is unclear [42,45]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

Immunodeficiency — Approximately half of patients with DADA2 exhibit low levels of immunoglobulin, including immunoglobulin M (IgM), immunoglobulin A (IgA), and immunoglobulin G (IgG) [1,12,29]. In some cases, progressive decline in immunoglobulins is reminiscent of common variable immunodeficiency (CVID) [29]. Upper and lower respiratory infections are the most common manifestations of immunodeficiency in patients with DADA2, although chronic Epstein-Barr virus infection and recurrent cutaneous herpes (not usually associated with isolated humoral immunodeficiency) have been documented [29,46,47]. Infection with opportunistic pathogens such as fungi and mycobacteria also have been reported, although some of these cases are confounded by concurrent neutropenia and lymphopenia in the setting of bone marrow failure [12,40,45]. In some patients, recurrent infection is the sole presenting feature [28,29]. Immunologic characterization reveals defective B cell development in the bone marrow at the pro-B to pre-B cell stage as well as impaired memory B cell class switching [29,48,49]. Expanded immunophenotyping further shows impaired differentiation of memory T cells with features of accelerated exhaustion/senescence, impaired survival, and granzyme production [49].

DIAGNOSIS

Approach — The diagnosis of DADA2 should be suspected in children and young adults who present with polyarteritis nodosa (PAN) like vasculitis and ischemic or hemorrhagic stroke, especially in the presence of livedo, systemic inflammation, cytopenias, and hypogammaglobulinemia (see 'Clinical manifestations' above). It is confirmed by genetic studies that identify biallelic deleterious ADA2 variants or by a biochemical assay that demonstrates near-absent levels of ADA2 activity in the plasma or serum. The choice of testing for DADA2 is based on urgency and availability. Our practice is to measure plasma ADA2 activity to rule in or rule out DADA2 and then to arrange genetic studies to confirm the diagnosis. An alternate approach is to screen with genetic panels containing multiple immune dysregulatory inborn errors of metabolism genes. Given the recessive pattern of inheritance and incomplete penetrance, as well as reports of symptomatic carriers, we screen all siblings of patients with confirmed DADA2 as well as any other family members with clinical features of the disease.

Genetic testing — The ADA2 gene is included in many commercially available sequencing panels for periodic fever syndromes and primary immunodeficiencies. Most disease-associated ADA2 variants are captured by targeted next-generation sequencing or by whole-exome sequencing. However, large deletions and complex chromosomal rearrangements can be missed by standard sequencing technology, and dedicated studies to analyze copy number variants such as multiplex ligation-dependent probe amplification may be necessary to resolve these cases [11,50]. (See "Genomic disorders: An overview" and "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

Biochemical assays — Measurement of ADA2 enzymatic activity can rapidly diagnose DADA2 on the basis of absent or near-absent activity in patient serum or plasma. ADA2 enzyme testing is useful to identify patients with DADA2 who do not have identifiable ADA2 variants, who have one deleterious variant, or who carry variants of unknown significance. Spectrophotometric assays that detect the conversion of adenosine to inosine and mass spectrometry quantification of inosine (and the downstream product hypoxanthine) have been described [51,52]. These assays require the use of a specific ADA1 inhibitor, typically erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), to distinguish the enzymatic activity of ADA2 from that of the more potent enzyme. Patients with DADA2 exhibit minimal or no residual activity, while persons heterozygous for a deleterious variant exhibit intermediate levels of enzymatic activity between patients with DADA2 and controls [1,9,17]. These tests are not available but are routinely performed as a service by several research laboratories.

DIFFERENTIAL DIAGNOSIS

Stroke or peripheral vasculitis — DADA2 presenting as stroke or peripheral vasculitis engages a differential diagnosis that includes other forms of vasculitis such as Sneddon syndrome and polyarteritis nodosa (PAN):

●Sneddon syndrome is a rare thrombotic vasculopathy characterized by ischemic strokes and livedo racemosa that affect females between 20 to 40 years of age [53]. Several cases of DADA2 were previously diagnosed as Sneddon syndrome; low IgM levels favor the diagnosis of DADA2 [54].

●Compared with classic PAN, patients with DADA2 typically are younger (mean age of onset four to five years versus nine years of age), more frequently have neurologic involvement, and commonly have ancillary manifestations of DADA2 such as hypogammaglobulinemia and/or cytopenias [6,9,15]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Vasculitis in children: Incidence and classification", section on 'Polyarteritis nodosa' and "Vasculitis in children: Evaluation overview".)

●Some cases have striking resemblance to Behçet syndrome, and monoallelic ADA2 variants have been reported in a cohort of patients with Behçet disease [55,56].

●Although autoimmunity is generally uncommon in DADA2, manifestations of antiphospholipid syndrome and systemic lupus erythematous including the characteristic interferon signature seen in lupus have been described [24,57].

Pure red cell aplasia — DADA2 presenting as pure red cell aplasia can resemble Diamond-Blackfan anemia (DBA) [43]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

Immunodeficiency — The humoral immunodeficiency manifesting as variable hypogammaglobulinemia and impaired B cell switch response can resemble common variable immunodeficiency (CVID). In one patient with severe bone marrow failure and opportunistic infection, GATA binding protein 2 (GATA2) deficiency was suspected before the pathogenic variants in ADA2 were found [45]. Patients with CVID have low IgG and one other low immunoglobulin (A or M), by definition, whereas patients with GATA2 have a natural killer (NK) cell abnormality characterized by near absence of CD56bright cells. (See "Common variable immunodeficiency in children" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

TREATMENT

Phenotype-based treatment — Disease phenotype is an important consideration for the treatment of DADA2. Tumor necrosis factor (TNF) inhibition is associated with lower risk of stroke and decreased inflammatory manifestations in patients with vasculitis but does not appear to be effective in patients with bone marrow failure.

Vasculitis and systemic inflammation — For patients with DADA2 who have vasculitis and/or systemic inflammation, we suggest treatment with TNF inhibitors. Clinical improvement has been reported with the use of etanercept, adalimumab, infliximab, and golimumab, as well as biosimilars [1,6,14,22]. Observational data show that the use of TNF inhibitors is associated with a significantly lower risk for additional strokes and decreased inflammatory burden of the disease [14,22,58]. We continue treatment with TNF inhibitors indefinitely. At least one death has occurred due to gastrointestinal hemorrhage several months after discontinuation of TNF inhibitors [14].

The efficacy of TNF inhibition is illustrated in these example:

●In a series from the United States, 15 patients with DADA2 and a history of strokes were begun on TNF inhibitor therapy with etanercept (0.8 to 1.2 mg per kg body weight, maximum of 50 mg weekly), adalimumab (40 mg every one to two weeks), infliximab (4 to 5 mg/kg every six weeks), or golimumab (50 mg weekly). In the 2077 patient-months before initiation of treatment, patients had 55 strokes. In 733 patient-months on therapy, no further strokes were observed [22].

●In a series from the United Kingdom, 27 patients received anti-TNF treatment for a median of 32 months. The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months compared with 0.00 per 100 patient-months posttreatment. General improvement of systemic vasculitis was reflected by a reduction in Pediatric Vasculitis Activity Score (PVAS), with a median score of 20/63 pretreatment versus 2/63 posttreatment [58].

Glucocorticoids, disease-modifying antirheumatic drugs, and other biologic agents such as tocilizumab (monoclonal interleukin [IL] 6 receptor antagonist) may partially ameliorate systemic inflammation, but these agents are less effective in preventing strokes [59,60]. We typically avoid anticoagulation in DADA2 patients because of concerns that it may precipitate or worsen hemorrhagic stroke.

Asymptomatic or no vasculitis — Whether patients discovered to have DADA2 but who have not yet had stroke or other symptoms of vasculitis (eg, discovered by screening of family members) should be treated with TNF inhibitors remains a difficult dilemma. We suggest treating all such patients, even if asymptomatic, because of the potentially devastating and even life-threatening consequences of a first cerebrovascular event. (See 'Vasculitis and systemic inflammation' above.)

Symptomatic carriers — Some persons present with features of DADA2 but are found to have only a single deleterious ADA2 variant and an intermediate level of ADA2 enzymatic activity [6,61]. Periodic fever, oral ulcers, skin rash, arthritis, and systemic inflammation have been reported in these symptomatic carriers. Optimal management of heterozygous ADA2 deficiency is uncertain due to the lack of systematic studies. The decision may be influenced by the severity of symptoms in relatives with the same pathogenic variant as well as the preference of the patient/caregivers. In these cases, we seek to balance the active disease features and risk of future disease-related clinical events with the risk and cost of indefinite immunosuppression.

Bone marrow failure and immunodeficiency — For patients with DADA2 who have treatment-refractory bone marrow failure, we suggest hematopoietic cell transplantation (HCT) rather than TNF inhibitors and supportive care. TNF inhibitors are generally ineffective for severe hematologic manifestation of DADA2 but may ameliorate concurrent features of inflammation in some patients with bone marrow failure [12,15,58]. In addition, the use of TNF inhibitors in patients with bone marrow failure syndrome and/or immunodeficiency may further increase the risk for infection. Intravenous immune globulin, granulocyte colony-stimulating factor (G-CSF), glucocorticoids, and other immunosuppressive agents also have proven largely ineffective for severe hematologic manifestations. Fresh-frozen plasma contains ADA2, but sustained treatment is not feasible given the short half-life of the protein [22]. Restoration of ADA2 production by HCT is potentially curative for patients, and reduced-intensity conditioning appears to be effective [16,62]. In a cohort of 14 patients that underwent HCT, all patients were alive and well, hematologic and inflammatory features of the disease all showed significant improvement, and no new vascular events were reported during a median follow-up of 18 months [16]. In a series of 30 DADA2 patients, HCT corrected the hematologic phenotype in all patients, although one patient died from infection, six required a second HCT due to graft failure, and six patients developed graft-versus-host disease by one year after transplant [63]. Gene therapy and enzyme replacement therapy are promising options that are undergoing preclinical evaluation.

PROGNOSIS — DADA2 carries an overall mortality rate of approximately 8 percent among known cases [12,64]. The risk may be higher in patients with the bone marrow failure phenotype, of whom half died from infection.

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Deficiency of adenosine deaminase 2 (DADA2) should be suspected in children and young adults who present with polyarteritis nodosa (PAN) like vasculitis and ischemic or hemorrhagic stroke, especially in the presence of livedo, systemic inflammation, cytopenias, and/or hypogammaglobulinemia. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of DADA2 is confirmed by identification of biallelic deleterious ADA2 variants or by near-absent ADA2 enzymatic activity in the peripheral blood. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis for DADA2 presenting as stroke or peripheral vasculitis includes other forms of vasculitis such as Sneddon syndrome and PAN. DADA2 presenting as pure red cell aplasia can resemble Diamond-Blackfan anemia (DBA). Immunodeficiency in DADA2 can mimic common variable immunodeficiency (CVID) or GATA binding protein 2 (GATA2) deficiency. (See 'Differential diagnosis' above.)

●Treatment – Disease phenotype is an important consideration for the treatment of DADA2 (see 'Treatment' above):

•For patients with DADA2 who have vasculitis and/or systemic inflammation, we recommend treatment with tumor necrosis factor (TNF) inhibitors rather than supportive care (Grade 1B). Observational data show that the use of TNF inhibitors, including etanercept, adalimumab, infliximab, and golimumab, as well as biosimilars, is associated with a significantly lower risk for additional strokes and decreased inflammatory burden of the disease. (See 'Vasculitis and systemic inflammation' above.)

•For patients with confirmed DADA2 who are asymptomatic or who have not yet had stroke or other symptoms of vasculitis (eg, discovered by screening of family members), we suggest treatment with a TNF inhibitor because of the potentially devastating and even life-threatening consequences of a first cerebrovascular event (Grade 2C). (See 'Asymptomatic or no vasculitis' above.)

•For patients with treatment-refractory bone marrow failure, we suggest hematopoietic cell transplantation (HCT) rather than TNF inhibitors and supportive care (Grade 2C). (See 'Bone marrow failure and immunodeficiency' above.)