Deficiency of adenosine deaminase 2 (DADA2)

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic pathogenic variants in the ADA2 gene, which lead to functional deficiency of the adenosine deaminase 2 enzyme. The condition may present with overlapping clinical features of vasculitic autoinflammation, cytopaenias and immunodeficiency, and can demonstrate considerable phenotypic variation.

The clinical spectrum of DADA2 is broad and can be divided into vasculitic, haematological and immunodeficiency features. Symptoms typically commence in childhood, although an adult-onset phenotype is also increasingly recognised.

Even within families, there is variable expressivity of clinical features in terms of age of onset, frequency and severity of manifestations that does not necessarily correlate with the level of ADA2 activity.

Vasculitic autoinflammatory symptoms include:

• recurrent fever;
• raised inflammatory markers;
• cutaneous vasculitis, including ulcers and livedo reticularis;
• ischaemic stroke;
• aneurysms;
• intracranial haemorrhage;
• neuropathy;
• polyarteritis nodosa, specifically neurological; and
• abdominal pain and hepatic disease.

Haematological features include:

• variable cytopaenias (haemolytic anaemia, thrombocytopaenia, neutropaenia or pancytopaenia). which may be immune-mediated or due to bone marrow failure;
• lymphoproliferation;
• splenomegaly; and
• lymphoma.

Immunodeficiency features include:

• hypogammaglobulinaemia;
• common variable immunodeficiency;
• recurrent and/or opportunistic infections, including:
  • bacterial respiratory, gastrointestinal and urinary infections; and
  • viral skin/mucosal infections, such as cold sores (HSV) and warts (human HPV); and
• lymphopenia.

DADA2 is caused by biallelic pathogenic variants in the ADA2 gene (formerly known as CECR1), which codes for the enzyme adenosine deaminase 2. This is an extracellular enzyme that metabolises adenosine to maintain immune homeostasis, neutrophil-mediated inflammation and endothelial integrity.

Loss-of-function variants include missense, nonsense, frameshift, splice and copy number variants, and result in low or absent levels of the ADA2 enzyme (<20% of expected). Some heterozygous variants have been associated with disease, but further case evidence is required to assign pathogenicity to those variants.

There are a few more frequently encountered variants, some of which have arisen due to isolated populations (founder variants). These include:

• ADA2 c.139G>A, p.G47R, reported in Israeli, Georgian-Jewish and Turkish populations;
• ADA2 c.506G>A, p.Arg169Gln, reported in persons of Finnish or Dutch ancestry; and
• ADA2 c.1078A>G p.Thr360Ala; reported in persons of Italian ancestry.

DADA2 can be diagnosed following clinical evaluation, the gathering of a family history and genomic testing.

In laboratory tests, findings may include low ADA2 enzymatic activity in the blood (typically <20% compared to control). Very low levels (<10%) with compatible clinical features is highly suggestive of a DADA2 diagnosis.

Other laboratory features that may be present include:

• elevated inflammatory markers – for example, C-reactive protein, erythrocyte sedimentation rate;
• hypogammaglobulinaemia; and
• lymphopaenia.

Diagnostic imaging should also be undertaken in patients with suspected DADA2. These may include visceral vascular functioning tests, such as transient elastography of the liver (fibroscan), magnetic resonance angiography, and bone marrow aspiration and trephine.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘ and/or ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

DADA2 may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

DADA2 is caused by biallelic pathogenic variants in the ADA2 gene. It is inherited in an autosomal recessive pattern.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise. Some carriers may be variably affected by milder disease via a dominant negative mechanism, although further cases are required to define this fully.

• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
• Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease). The condition also shows variable expressivity, with considerable range in severity within families.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

DADA2 is a rare, complex condition and is best managed by a tertiary autoinflammatory service with specialist multidisciplinary input.

For patients with inflammatory and vasculitic features, tumour necrosis factor inhibitors (TNFi) are the first-line treatment and have been demonstrated to lower the risk of stroke and other end-organ ischaemia. Etanercept (soluble TNF receptor inhibitor) and adalimumab (monoclonal antibody against TNF) are licensed for DADA2 patients in the UK.

Corticosteroids and disease-modifying anti-rheumatic drugs, or DMARDs, have also been used to treat DADA2, but may have limited long-term efficacy. Other supportive treatments should be considered as required, such as immunoglobulin replacement therapy and prophylactic antibiotics.

Allogeneic haematopoietic stem cell transplantation (HSCT) is potentially curative of the inflammatory and/or bone marrow aspects of the condition. Better outcomes are found where HSCT is undertaken prior to the onset of significant organ damage or infections.

DADA2 may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Further information about management can be found in the resources section below.

For clinicians

• GeneReviews: Adenosine deaminase 2 deficiency
• NHS England: Etanercept and adalimumab for the treatment of deficiency of adenosine deaminase type 2 (aged 5 years and older)
• OMIM: 615688 Vasculitis, autoinflammation, immunodeficiency, and hematolgic defects syndrome

References:

• Ehlers L and Meyts I. ‘Getting to know adenosine deaminase 2 deficiency inside and out‘. The Journal of Allergy and Clinical Immunology 2025: volume 155, issue 5, pages 1,451–1,463. DOI: 10.1016/j.jaci.2025.01.040
• Lee PY, Davidson BA, Abraham RS and others. ‘Evaluation and management of deficiency of adenosine deaminase 2: An international consensus statement‘. Journal of the American Medical Association Network Open 2023: volume 6, issue 5, page e2315894. DOI: 10.1001/jamanetworkopen.2023.15894
• Wouters M, Ehlers L, Van Eynde W and others. ‘Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers‘. Journal of Experimental Medicine 2025: volume 222, issue 11, page e20250499. DOI: 10.1084/jem.20250499

For patients

• Autoinflammatory UK
• National Organization for Rare Diseases: Vasculitis due to ADA2 deficiency