Adenosine Deaminase 2 deficiency

Other Names: Vasculitis due to DADA2; Vasculitis due to ADA2 deficiency; Polyarteritis nodosa, childhood-onset; ADA2 deficiency; Childhood-onset polyarteritis nodosa; DADA2

Adenosine Deaminase 2 deficiency is an inherited disorder causing inflammation in the body, especially in the tissues that make up the blood vessels (vasculitis). Adenosine deaminase 2 (ADA2) deficiency is a disorder characterized by abnormal inflammation of various tissues. Signs and symptoms can begin anytime from early childhood to adulthood. The severity of the disorder also varies, even among affected individuals in the same family. Inflammation is a normal immune system response to injury and foreign invaders (such as bacteria). However, ADA2 deficiency causes abnormal, unprovoked inflammation that can damage the body's tissues and organs, particularly blood vessels. (Inflammation of blood vessels is known as vasculitis.) Other tissues affected by abnormal inflammation can include the skin, gastrointestinal system, liver, kidneys, and nervous system. Depending on the severity and location of the inflammation, the disorder can cause disability or be life-threatening.

Epidemiology

More than 160 individuals with ADA2 deficiency have been described in the medical literature. However, researchers suspect that many more people may be affected, and ADA2 deficiency may not be a rare disease. They are working to determine whether this condition could underlie other, more common forms of vasculitis and stroke whose causes are currently unknown.

Cause

ADA2 deficiency is caused by mutations in the ADA2 gene. This gene provides instructions for making an enzyme called adenosine deaminase 2. Studies suggest that this enzyme plays an essential role in the growth and development of certain immune system cells, including macrophages, which are a type of white blood cell that plays a critical role in inflammation. Some macrophages are pro-inflammatory, meaning they promote inflammation, while others are anti-inflammatory, meaning they reduce inflammation.

Mutations in the ADA2 gene severely reduce or eliminate the activity of adenosine deaminase 2. Researchers do not fully understand how a shortage (deficiency) of this enzyme's activity leads to vasculitis and immune system abnormalities. They speculate that the enzyme deficiency may disrupt the balance between pro-inflammatory and anti-inflammatory macrophages in various tissues, leading to a buildup of pro-inflammatory macrophages and abnormal inflammation.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Signs and symptoms that can occur with ADA2 deficiency include fevers that are intermittent, meaning they come and go; areas of net-like, mottled skin discoloration called livedo racemosa; an enlarged liver and spleen (hepatosplenomegaly); and recurrent strokes affecting structures deep in the brain that can start in the first few years of life. In some people, ADA2 deficiency causes additional immune system abnormalities that increase the risk of bacterial and viral infections.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

5%-29% of people have these symptoms

• Anemia(Low number of red blood cells or hemoglobin)
• Decreased circulating antibody level
• Hypertension
• Leukocytosis(Elevated white blood count)
• Lupus anticoagulant
• Optic atrophy

1%-4% of people have these symptoms

• Elevated hepatic transaminase(High liver enzymes)
• Esophageal varix(Enlarged vein in esophagus)
• Hepatomegaly(Enlarged liver)
• Leukopenia(Decreased blood leukocyte number)
• Pancytopenia(Low blood cell count)
• Portal hypertension
• Splenomegaly(Increased spleen size)
• Stroke
• Thrombocytosis(Increased number of platelets in blood)
• Urticarial plaque

Diagnosis

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 Onset. Usually in early childhood (i.e., age <10 years) Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash Neurologic. Early-onset lacunar and/or hemorrhagic strokes Laboratory findings. Absence of antineutrophilic cytoplasmic antibodies (ANCA)

Imaging findings

• MRI
• Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter
• Hemorrhagic stroke and intracranial bleeding
• Angiography. Aneurysm or stenosis in medium-sized arteries

Dysregulation of Immune Function

Clinical findings Immunodeficiency Lymphoproliferative disease including lymphadenopathy Laboratory findings

Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity Impaired production of transitional and switched memory B cells Low vaccine responses noted in some cases Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported . Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data]

Hematologic Abnormalities Hematologic disorders typically occur early in life; however, in rare instances bone marrow failure may initially appear as late as adulthood (i.e., 5th and 6th decades):

• Lymphopenia
• Neutropenia
• Pure red cell aplasia
• Thrombocytopenia
• Pancytopenia

Bone marrow biopsy may reveal hypo/hypercellularity, grade I myelofibrosis, lymphocyte infiltrate (predominantly CD8+), and mild reticulin fibrosis, further suggesting a defect in cell differentiation. In one individual the bone marrow showed a reduced number of CD138+ plasma cells.

The diagnosis of DADA2 is established in a proband with suggestive clinical and laboratory findings and biallelic loss-of-function ADA2 pathogenic variants identified by molecular testing and/or low (<5% of normal) or undetectable ADA2 catalytic activity in plasma or serum.

Differential diagnosis This includes common variable immunodeficiency,bone marrow failure and idiopathic aplastic anemia.

Treatment

Anti-tumor necrosis factor (TNF) agents (also known as "biologics") including etanercept, adalimumab, golimumab, infliximab, and certolizumab are the drugs of choice to prevent and eliminate manifestations of autoinflammatory disease / vasculitis.

Some individuals with low serum immunoglobulins and frequent infections may require treatment with intravenous immunoglobulin as well as antibiotics and antivirals in conjunction with anti-TNF agents.

Thalidomide is a potential treatment for TNF blockade when biologics are not available. Thalidomide is known to inhibit TNF production in dendritic cells and to exert an inhibitory effect on monocytes.

Steroids and general immunosuppressive therapies (e.g., azathioprine, cyclosporine, cyclophosphamide, methotrexate, mycophenolate mofetil, and tacrolimus) have had variable success. Anti-IL-6 therapy was successfully used in a patient with DADA2 whose manifestations mimicked multicentric Castleman disease.

Hematopoietic stem cell transplantation (HSCT) can be curative in individuals in whom bone marrow failure and/or immune dysregulation predominate, and who fail to respond to TNF inhibitor treatment. Successful HSCT returns plasma ADA2 activity to normal levels.

NIH genetic and rare disease info

• NIH info on Adenosine Deaminase 2 deficiency

Adenosine Deaminase 2 deficiency is a rare disease.

Adenosine Deaminase 2 deficiency Resources
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