Clinical Guidance

To date no genotype-phenotype correlations associating ADA2 pathogenic variants with the clinical presentation of DADA2 have been identified. Studies of affected individuals in the two major founder populations in the Middle East and northern Europe could possibly offer insight into some genotype-phenotype correlations. See for more details.

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"

Diagnostic Criteria

Formal diagnostic criteria for adenosine deaminase 2 deficiency (DADA2) have not been established.

Suggestive Findings

Adenosine deaminase 2 deficiency (DADA2) should be suspected in individuals with clinical and laboratory findings of systemic autoinflammatory disease characterized by vasculitis, dysregulation of immune function, and hematologic abnormalities .

Systemic Autoinflammatory Disease

Clinical findings

• Intermittent fevers

• Hepatosplenomegaly (can be evidence of portal hypertension)

• Systemic hypertension

Laboratory findings

• Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes

• Elevated transaminases

Vasculitis

Clinical findings

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"

Differential Diagnosis

Inherited disorders to consider in the differential diagnosis of DADA2 are included in ; disorders without a known genetic component to consider in the differential diagnosis are discussed following . Table 2. Inherited Disorders with Normal ADA2 Enzyme Activity to Consider in the Differential Diagnosis of Adenosine Deaminase 2 Deficiency (DADA2)

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase 2 deficiency (DADA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

• Complete physical examination with emphasis on:

• Blood pressure and other vital signs, as systemic hypertension and/or fever are common.

• Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations.

• Assessment for lymphadenopathy and hepatosplenomegaly.

• Neurologic examination for evidence of prior or recent strokes.

• Ophthalmologic examination for vision loss, diplopia, retinal infarcts, optic nerve damage, uveitis, ptosis, strabismus, and nystagmus

• Electrocardiogram (ECG) for manifestations of portal hypertension, including prolonged QT interval

• Laboratory assessment

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"

Clinical Guidance

Avoid the following:

• Antiplatelet medications including aspirin

• Anticoagulation medications (except in the presence of atrial fibrillation)

• Smoking, which may exacerbate peripheral arterial disease

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"

Surveillance Guidelines

Suggested follow-up evaluations include the following:

• Complete physical examination (performed yearly or sooner if clinically indicated):

• Blood pressure and other vital signs

• Skin examination

• Assessment for presence of lymphadenopathy and hepatosplenomegaly

• Neurologic examination for evidence of prior or recent strokes

• Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage

• ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction.

• Laboratory assessment (performed yearly or sooner if clinically indicated):

• CBC and differential

• ESR and CRP

• Kidney and liver function

• Quantitative serum immunoglobulins

• Lymphocyte phenotyping for evidence of a B-cell maturation defect

• Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations

• Imaging assessment (yearly or if clinically indicated):

• Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement

• Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction

• Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow

• FibroScan® ultrasound examination (if available) to assess hepatic elasticity for evidence of early portal hypertension

• Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension).

Source: GeneReviews — "Adenosine Deaminase 2 Deficiency"