Adenosine Deaminase 2 Deficiency L95.5

Deficiency of adenosine deaminase 2 (DADA2) was first described as a monogenic form of systemic vasculitis that is very similar to polyarteritis nodosa (PAN). The phenotypic spectrum of DADA2 has greatly expanded in recent years to include pure erythroaplasia, bone marrow failure, lymphoproliferative disorders and human immunodeficiency. ADA2 mutations can also be associated with Sneddon syndrome.

DADA2 (vasculitis, autoinflammation, immunodeficiency and hematologic defect syndrome/VAIHS) is a rare, autosomal recessive multisystem disorder with onset in childhood caused by biallelic pathogenic variants (according to ACMG guidelines) in the ADA2 gene (OMIM: 615688, formerly CER1). ADA2 deficiency leads to vasculitic and vasculopathic manifestations in different organs, hematologic disorders and immune dysregulation (Schmidt MF et al. 2025).

To date, more than 400 cases have been published (Lee PY et . al. 2o23); the estimated prevalence of the disease is 1/ 222,000. According to this estimate, DADA2 is considered a rare disease by the US Food and Drug Administration (FDA).

DADA2 is caused by biallelic pathogenic variants in the ADA2 gene (formerly known as CECR1) on chromosome 22q11.3. While the first series of cases mainly affected infants, cases of DADA2 in adults are increasingly being reported. The exact function of ADA2 has not yet been clarified. The polarization of the monocyte phenotype, the regulation of the formation of extracellular neutrophil traps and the modulation of innate immunity are being discussed.

DADA2 has a broad spectrum of clinical manifestations ranging from fatal systemic vasculitis with multiple strokes, especially in pediatric patients, to limited skin disease in middle-aged patients.

Leading symptoms include: intermittent fever, strokes, flash-like vascular markings in the skin (livedo racemosa), cerebrovascular events (typically in childhood or early adulthood), peripheral neuropathies, retinal artery occlusions, hearing loss, possible skin necrosis, increased acne, and other symptoms. skin necrosis, increased acute phase proteins and erythrocyte sedimentation rate, arthralgias, myalgias, arthritides, hepatosplenomegaly, hypogammaglobulinemia. While mild hypogammaglobulinemia is common, generalized variable immunodeficiency and recurrent infections can also be symptoms of DADA2 (Schmidt MF et al. 2025; Zhou Q et al. 2014).

Elevated acute phase proteins.

As a recessive disorder, DADA2 is genetically diagnosed based on biallelic pathogenic or likely pathogenic ADA2 variants, which are determined according to the guidelines of the American College of Medical Genetics and Genomics. Targeted sequencing of ADA2 is commercially available. ADA2 is included in most commercial sequencing panels developed for the evaluation of congenital immunodeficiencies and/or autoinflammatory syndromes. All exons of ADA2 should be sequenced, as pathogenic or likely pathogenic variants have been described in each exon. Individuals with monoallelic pathogenic or likely pathogenic ADA2 variants are considered carriers. Individuals with monoallelic or biallelic ADA2 variants of unknown significance (VUS) should have their ADA2 enzyme activity measured.

In patients with an inflammatory or vasculitic phenotype, retrospective studies consistently show a clear positive effect of tumor necrosis factor inhibitors (TNFi). Treatment with TNFi significantly reduces the risk of ischemic and hemorrhagic strokes and other vasculitic organ lesions.

Treatment also reduces the overall inflammatory burden of the disease. Soluble TNF receptors (etanercept) and monoclonal antibodies against TNF (adalimumab, infliximab and golimumab) appear to be effective. The use of glucocorticoids, disease-modifying antirheumatic drugs (DMARDs) and biologics targeting interleukin (IL)-1 and IL-6 has been described in patients with DADA2, but the long-term efficacy of these approaches appears to be limited based on descriptions of refractory and relapsing disease.

In patients with an inflammatory or vasculitic phenotype in combination with bone marrow failure and/or immunodeficiency, the additional risk of infection due to chronic immunosuppression should be considered.

With the exception of mild anemia as a result of chronic inflammation, the hematologic features of DADA2 do not respond to TNFi and glucocorticoids. Allogeneic HSCT is a curative option for patients with pure red cell aplasia, bone marrow failure or refractory immunologic cytopenias. Allogeneic HSCT is also effective in severe immunodeficiency or vascular involvement that does not respond to immunomodulators.

The immunodeficiency phenotype of DADA2 includes abnormalities in the B-cell, T-cell and NK-cell compartments. In patients with recurrent infections, the use of prophylactic antibiotics should be considered. In patients with humoral immunodeficiency and recurrent infections, the administration of intravenous immunoglobulins (IVIG) should be considered.

Vaccination is essential for patients with DADA2 due to the prevalence of underlying immunodeficiency and the use of immunosuppressive drugs. Routine inactivated (non-live) vaccines and boosters are recommended for patients not receiving IVIG. Non-live annual influenza and SARS-CoV-2 vaccinations should be considered for all patients according to local regulations.

Treatment of prehospital individuals with DADA2 is controversial. Given the unpredictability of the disease, the lack of reliable biomarkers to estimate disease onset, and the possibility of life-threatening stroke or other emergencies as the first symptom, TNFi therapy should be considered in these individuals.

Some carriers may exhibit symptoms of DADA2. Mild subclinical immunologic abnormalities associated with DADA2 have been described in carriers. However, according to the accumulated clinical experience of a consensus committee, most carriers (i.e. parents and siblings of patients with DADA2) are healthy and symptom-free (Lee PY et al. 2023).

The mortality rate for DADA2 is estimated at around 8% before the age of 30. The actual figure could be considerably higher due to misdiagnosis and underdiagnosis.

Deficiency of ADA2(DADA2) is the first molecularly described monogenic vasculitis syndrome. Over 60 disease-associated mutations have been identified in all domains of ADA2, affecting catalytic activity, protein dimerization and secretion. Vasculopathies ranging from livedo reticularis to polyarteritis nodosa (PAN) and life-threatening ischemic and/or hemorrhagic strokes dominate the clinical features of DADA2 (Meyts I et al. 2018).

A mutation in the ADA2 gene can also cause Sneddon syndrome (182410), which occurs later in life.

Zhou et al (2014) reported 9 patients from 8 unrelated families who presented with early-onset recurrent ischemic apoplexy and recurrent fever between the ages of 5 months and 4 years. Imaging showed that the strokes occurred in the nuclei of the deep brain and brain stem, suggesting small vessel occlusion. All patients had various neurological manifestations of stroke, including paraplegia, ataxia, hemiparesis, headache, ophthalmoplegia, aphasia, altered mental status, and cranial nerve dysfunction. One patient had central retinal artery occlusion, and another had left optic nerve atrophy. Acute-phase proteins were markedly elevated during febrile episodes. All patients had skin involvement: livedo racemosa and signs of leukocytoclastic vasculitis. Other features were hepatosplenomegaly with abnormal liver enzymes, hypogammaglobulinemia, pancytopenia, and leukopenia. 5 patients developed antiphospholipid antibodies after some time.

Navon Elkan et al (2014) reported 19 individuals of Georgian Jewish descent with polyarteritis nodosa vasculopathy. Despite the homogeneous background, there was inter- and intrafamilial variability. Fifteen of the patients were diagnosed with the disease before the age of 10 years, six of whom were diagnosed in infancy. Four patients with onset in infancy suffered from severe systemic reactions, including ischemia and necrosis of the fingers and toes, recurrent fever, coronary aneurysms, necrotizing vasculitis of the intestine, renal aneurysms and stenoses, and abdominal pain. Several patients had hypertension.

Skin: livedo racemosa, leukocytoclastic vasculitis, panniculitis. Neurologic signs and symptoms involved both the central nervous system, manifesting as facial paralysis and infarcts, and the peripheral nervous system (neuropathy). At the mildest end of the spectrum, one patient developed ulcers crura which first appeared at the age of 59 years.

Laboratory: leukocytosis, thrombocytosis, an elevated C-reactive protein, elevated ESR; less commonly, anemia.

1. Lee PY (2018) Vasculopathy, immunodeficiency, and bone marrow failure: the intriguing syndrome caused by deficiency of adenosine deaminase 2. Front Pediat 6: 282.
2. Meyts I et al. (2018) Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol 38:569-578.
3. Navon Elkan P et al. (2014) Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. New Eng J Med 370: 921-931.
4. Van Eyck L et al. (2014) Mutant ADA2 in vasculopathies. (Letter) New Eng J Med 371: 478-479.
5. Van Eyck L et al. (2014) Mutant ADA2 in vasculopathies. (Letter) New Eng J Med 371: 480.
6. Zhou Q et al. (2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. New Eng J Med 370: 911-920.