The DADA2 is a monogenic autoinflammatory disorder with an autosomal recessive inheritance pattern [31, 32]. Since it was first described in 2014, over 600 cases of DADA2 have been reported [31,32,33]. However, the actual frequency of this disorder is believed to be underestimated [34]. Genetic studies have revealed that mutation variants are carried in the population by at least 1 in 236 individuals. This would indicate a prevalence of 35,000 cases in the population [34], which means that DADA2 might be one of the most common autoinflammatory syndromes.

More than 150 variant mutations of the same gene have been described, according to the INFEVERS database (https://infevers.umai-montpellier.fr) [35]. Biallelic mutation are located in the ADA2 gene, previously known as CECR1, located on chromosome 22q11.1 [35]. Most cases are homozygous with missense mutations (substitutions). Deletion, splicing, and nonsense mutations have also been reported in lower frequency [35].

Initial cases were described on Georgian-Jewish, German, and Turkish patients [31, 32]. Today, the majority of patients are Caucasian (> 75%), with emerging reports in India [36] and Brazil [37]. A genetic study showed a higher allelic carrier percentage in Finland, South Asia, and Latino population. The carrier frequency was lower in African, East Asia, and Ashkenazi Jewish populations [34].

Approximately 70% of cases commence in childhood, nevertheless adult onset is also recognized [33, 38]. Moreover, a significant number of adults likely remain undiagnosed [38]. Prevalence was similar between sexes [39].

Adenosine deaminases (ADA) enzymes regulate purine metabolism by converting adenosine to inosine and deoxyadenosine into deoxyinosine [40]. The two isoforms, ADA1 and ADA2, share partial homology but have distinct physiologic roles [41]. ADA1 is intracellular and expressed in every nucleated cell. In contrast, ADA2 is primarily expressed by myeloid cells and secreted to the extracellular space, mainly in inflammatory scenarios [40, 41].

Besides participating in purine metabolism, ADA2 also works as a growth factor, playing a role in the differentiation and activation of immune cells [40]. Furthermore, ADA2 is believed to contribute to the maintenance of vascular integrity [42].

Even though DADA2 pathogenesis is not entirely understood, one of the hallmarks is the polarization of monocyte differentiation towards the macrophage M1 subtype [43]. This results in a pro-inflammatory environment, with increased release of TNF-α, IL-1β, and IL-6, which propagate inflammatory response and endothelial damage [31]. Furthermore, DADA2 upregulates IFN-γ signaling and triggers chronic neutrophile activation with spontaneous NET formation [42, 43]. DADA2 also impair interactions between T and B cells [44].

The first described cases of DADA2 were characterized by a polyarteritis nodosa (PAN)-like cutaneous vasculopathy coupled with early-onset stroke in young children [31, 32]. Further research expanded the clinical spectrum, that is categorized into three groups: (I) inflammatory/vasculitis, (II) hematologic manifestations, and (III) immunodeficiency (Fig. 2) [45]. Patients usually exhibit a dominant clinical phenotype, although overlapping is frequent. Hematological and immunodeficiency manifestations rarely occur in isolation [39, 45].

Deficiency of adenosine deaminase 2 (DADA2) clinical manifestations

Inflammatory/vasculitis phenotype is the most common [33, 37,38,39, 46]. Cutaneous and neurological symptoms are predominant in DADA2 patients, differently from PAN [39]. Cutaneous involvement occurs in about 70–90% of cases, usually with livedo racemosa (47–74%) [33, 39]. PAN-like nodules (23–57%), Raynaud’s phenomena, acral digital gangrene, and erythema nodosum can also appear [33, 37, 39].

Skin biopsy resembles PAN histopathology, with medium-size vasculitis in the deep dermis, with dense transmural infiltrate of neutrophils with karyorrhexis [39, 47]. Fibrinoid necrosis and chronic surrounding inflammation may be present [39]. Leukocytoclastic vasculitis of small vessels, as well as vasculopathy with lymphovascular occlusion and intravascular thrombi, can also be found [31, 32, 36, 39].

The typical neurological manifestation is transient ischemic attack (TIA)/ischemic stroke (41–43%) [33, 39, 46, 48]. Strokes are usually lacunar, affecting mostly basal ganglia, brain stem, internal capsule, and cerebellum [33, 39, 46, 48]. In a 60-patient cohort, the mean age for the first stroke was 6.5 years, with an average of 3 strokes per patient [39]. Additionally, stroke was the disease presenting symptom in several patients, and about half of them experienced their first stroke before reaching five years old [39, 48]. Intracerebral hemorrhage may occur less frequently, typically after an ischemic stroke and/or with the use of aspirin or anticoagulants [31, 32, 39, 48].

Vasculitic DADA2 presentation may also resemble Sneddon Syndrome, with ischemic stroke, livedo racemosa, and biopsy with intravascular thrombi. In addition, DADA2 may present positive antiphospholipid (aPL) antibodies in 27% of patients [48]. Because the treatments for these two conditions are considerably distinct, there should be caution when diagnosing Sneddon Syndrome without performing ADA2 screening.

Other neurologic manifestations include polyneuropathy, mononeuritis multiplex, cranial nerve palsies, spastic paraplegia, sensorineural hearing loss, and posterior reversible encephalopathy syndrome (PRESS) [37, 42, 49]. Ophthalmologic involvement may occur as optic neuritis, uveitis, retinal artery occlusion, and orbital pseudotumor [42, 49].

Vasculopathy may affect other organs, such as intestinal ischemia, hepatomegaly, hepatic fibrosis, portal hypertension, mesenteric and renal aneurysms, testicular pain, cardiomyopathy, inflammatory myositis, and other manifestations [33, 39, 46]. Also, unspecific symptoms such as musculoskeletal manifestations and periodic fever may occur in more than half of patients [39, 46].

Hypogammaglobulinemia with low immunoglobulin M (IgM) is the most common presentation in the immunodeficiency phenotype [31, 50]. Low immunoglobulin G (IgG), generalized lymphadenopathy, and splenomegaly may also occur [51]. Recurrent infections, typically caused by bacteria, herpes zoster, and verrucous warts, have been reported [39, 51]. Immunodeficiency is generally milder when associated with the vasculitic form of disease than the hematologic DADA2 phenotype [39]. Severe presentations, such as combined variable immunodeficiency disease, autoimmune lymphoproliferative syndrome (ALPS), and lymphoma, may occur more rarely [33, 39].

Finally, the hematological phenotype is the least frequent, often more severe, and predominantly affects younger patients [50]. Lymphocytopenia is the most common hematological feature [50]. Anemia is usually multifactorial and may appear in half of the patients [39, 50]. Coombs-positive autoimmune hemolytic anemia has been described [36]. Bone marrow evaluations can reveal lineage hypoplasia, and severe conditions such as Diamond-Blackfan anemia, pure red cell aplasia, and bone marrow failure more rarely occur [50].

While patients with vasculitis/systemic inflammation usually present up to 3% of residual activity of ADA2, patients with hematological manifestation present minimal or absent ADA2 activity [49, 52]. There is a genotype-phenotype correlation, where the vasculitis manifestations are more frequently associated with ADA2 missense mutations, whereas hematological phenotypes have more catalytic mutations, such as nonsense, insertions, and deletion variants [49, 52].

In a comparative study of adult versus child disease-onset, adults presented more cutaneous nodules, ulcers, purpura, peripheral neuropathy, gastrointestinal events, and infections associated with humoral deficiency [38]. Whereas children exhibited more strokes, anemia, and neutropenia [38]. Also, adult-onset disease correlated with ADA2 hypomorphic mutations [38].

Despite the genotype-phenotype correlation, there is evidence that epigenetics and environment influence the clinical presentation. Studies with siblings with same mutations showed differences in severity and age of onset [53, 54].

DADA2 is a potentially fatal disease, with a mortality rate of 8% before 30 years old [55]. Worst outcomes are associated with recurrent stroke, gastrointestinal ischemia, recurrent infections, and hematological phenotype [39].

Diagnosis is established in symptomatic patients who present low plasma ADA2 enzymatic activity or display a compatible genetic sequencing of the ADA2 gene [45]. A recent consensus for managing DADA2 recommends that both methods should be employed when feasible since both have limitations [45].

Normal ADA2 activity rules out the condition; conversely, low ADA2 levels supports the diagnosis [45]. ADA2 activity levels can be assessed using spectrometry or high-performance liquid chromatography assay [45]. The availability of the tests is usually limited to research [45].

Genetic diagnosis is also established by the identification of biallelic pathogenic or likely pathogenic ADA2 variants [56]. ADA2 genetic testing may be found in most commercial sequencing panels for inborn errors of immunity or autoinflammatory syndromes [45].

When ADA2 variants of unknown significance (VUS) are detected, the assessment of ADA2 enzyme activity is recommended [