vasculitis due to ADA2 deficiency

Vasculitis due to ADA2 deficiency, also called DADA2, is a very rare inherited disease in which harmful changes in the ADA2 gene lower the activity of the adenosine deaminase 2 enzyme. This loss upsets the immune system and leads to ongoing inflammation of small and medium blood vessels throughout the body. The severity and specific features can vary considerably from person to person. Some individuals develop fever, skin rash, or strokes in early childhood, while others first notice symptoms later in life. Because fewer than one in a million people are affected, many doctors may not recognize it, so genetic testing can be important for a clear diagnosis.

Severity and symptoms vary widely between individuals. Early warning signs often include recurrent fevers, livedo-type skin mottling, painful mouth ulcers, or frequent ear and sinus infections that do not respond as expected to routine treatment. Some children present abruptly with ischemic or hemorrhagic strokes that can cause sudden weakness, speech difficulties, or other neurological deficits. Over time, the disease can involve many organ systems. Neurologic complications such as strokes or peripheral neuropathy are among the most serious concerns. The immune system may be underactive as well as overactive, leading to low immunoglobulin levels, repeated infections, and lymphadenopathy. Hematologic features can include low white blood cell counts or broader cytopenias. Many individuals develop hepatosplenomegaly, abdominal pain, or portal hypertension as the liver and spleen become enlarged and inflamed. Joint pain and muscle aches, purplish skin rashes, urticarial plaques, or cutaneous polyarteritis nodosa reflect ongoing vascular inflammation. Not all individuals experience all features, and the same family may include siblings with very different symptom patterns. Episodes can wax and wane, adding to diagnostic complexity.

DADA2 results from pathogenic variants in the ADA2 gene. The ADA2 enzyme normally breaks down adenosine outside cells and helps regulate immune and vascular health. When both copies of the gene are not working, inflammatory pathways remain overactive and blood vessels become prone to damage and clotting. The condition is inherited in an autosomal recessive pattern. A child must receive one altered ADA2 gene from each parent in order to be affected. Parents who each carry a single variant are usually healthy carriers but have a twenty-five percent chance, with every pregnancy, of having a child with DADA2. This condition is more common when parents share a common ancestor because relatives are more likely to carry the same rare variant. Carrier testing and genetic counseling are recommended for family members who may wish to understand their own risk or future reproductive options. Even within the same family, the severity and specific symptoms can vary considerably, a phenomenon called variable expressivity.

Currently, management focuses on supportive care and symptom control tailored to each individual’s presentation. Anti-inflammatory and immune-modifying medications are used to calm vascular inflammation, prevent additional strokes, and reduce systemic symptoms, and the specific regimen is chosen by the treating rheumatologist or immunologist based on disease activity. Treatment of low immunoglobulin levels, infections, or cytopenias may involve immunology or hematology teams. Because DADA2 can affect the nervous system, liver, skin, and blood simultaneously, care is best coordinated through a multidisciplinary team that may include neurology, rheumatology, immunology, hematology, dermatology, and gastroenterology specialists. Long-term management includes regular surveillance to detect emerging complications early. This typically involves periodic neurologic assessments, laboratory monitoring of inflammatory markers and blood counts, and imaging studies to follow organ size and vascular integrity. Genetic counseling supports families in understanding inheritance and planning for the future, and connection with experienced centers can help ensure access to evolving treatment strategies. Patients should discuss specific therapies and monitoring schedules with their healthcare team to determine the most appropriate plan.

Outcomes vary depending on which organ systems are involved, how early the condition is recognized, and how effectively inflammation is controlled. Some individuals remain stable for long periods with minimal symptoms, while others experience recurrent strokes or progressive organ involvement that can significantly affect quality of life. Early detection, close monitoring, and timely intervention appear to reduce the risk of severe complications. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialist centers and patient support groups, and participation in disease registries can help researchers learn which treatments and monitoring approaches lead to the best long-term results.

Clinical trials are underway exploring new treatment approaches for DADA2. Individuals interested in research participation can search ClinicalTrials.gov or consult their care team about eligibility.