In a 31‑year‑old man with left thalamic intracerebral hemorrhage, string‑and‑bead appearance of the left posterior cerebral artery on digital subtraction angiography, and low adenosine deaminase‑2 activity, what diagnosis is suggested?

Deficiency of Adenosine Deaminase 2 (DADA2)

This clinical presentation is highly suggestive of Deficiency of Adenosine Deaminase 2 (DADA2), a monogenic autoinflammatory vasculopathy that requires immediate initiation of TNF inhibitor therapy.

Diagnostic Confirmation

The combination of findings in this patient establishes the diagnosis:

• Low ADA2 enzyme activity is the diagnostic hallmark of DADA2, confirmed by functional enzymatic assay 1, 2
• String-and-bead appearance on DSA indicates medium-vessel vasculitis affecting the left PCA, consistent with the polyarteritis nodosa (PAN)-like vasculopathy characteristic of DADA2 3, 2
• Left thalamic hemorrhage represents the stroke manifestation—both ischemic and hemorrhagic strokes are cardinal features of DADA2, with a predilection for deep gray matter structures (thalamus, basal ganglia) and brainstem 4
• Young age (31 years) without comorbidities fits the typical DADA2 presentation, as this is an early-onset disease often manifesting in childhood or young adulthood 1, 5

Pathophysiology and Clinical Spectrum

DADA2 results from biallelic loss-of-function mutations in the ADA2 gene (chromosome 22q11), causing a systemic autoinflammatory disorder 1, 2. The disease affects multiple organ systems:

• Vasculopathy: Small- and medium-vessel vasculitis mimicking PAN, with recurrent strokes (77.5% of neurological cases), livedoid rash, and systemic inflammation 4, 2
• Neurological manifestations: Present in 50.3% of patients, with lacunar strokes being most common and showing remarkable predilection for brainstem (37.3%) and deep gray matter (41.6%) 4
• Hematological abnormalities: Cytopenias, bone marrow failure, lymphopenia, and hypogammaglobulinemia 1, 5
• Immunodeficiency: Variable hypogammaglobulinemia and decreased B cells 5

Critical Management Recommendation

The American College of Rheumatology/Vasculitis Foundation strongly recommends treatment with TNF inhibitors over glucocorticoids alone for patients with DADA2 6. This is a strong recommendation based on compelling evidence that TNF inhibitors prevent strokes, which have an 80% mortality rate when untreated 6.

• First-line therapy: Initiate adalimumab or another TNF-α inhibitor immediately 6, 3, 2
• Avoid conventional immunosuppression: Unlike classic PAN, cyclophosphamide is NOT the treatment of choice for DADA2 6
• Monitor for recurrence: Multiple stroke episodes occur in 35.9% of patients with neurological manifestations 4

Diagnostic Workup to Complete

Beyond the confirmed low ADA2 activity, obtain:

• Genetic testing: ADA2 gene sequencing to identify specific mutations and confirm diagnosis 1, 2
• Hematological evaluation: Complete blood count, immunoglobulin levels, lymphocyte subsets to assess for cytopenias and immunodeficiency 5
• Systemic vasculitis screening: Assess for skin lesions (livedo reticularis/racemosa), gastrointestinal involvement, renal function, and hypertension 3, 2
• Repeat vascular imaging: Follow-up DSA or MRA to monitor vascular changes after TNF inhibitor initiation 4

Critical Pitfalls to Avoid

• Do not treat as classic PAN: DADA2 requires TNF inhibitors, not cyclophosphamide-based regimens used for idiopathic PAN 6
• Do not delay genetic confirmation: While low ADA2 activity is diagnostic, genetic testing provides prognostic information and confirms inheritance pattern for family counseling 1
• Do not overlook hemorrhagic risk: Both ischemic AND hemorrhagic strokes occur in DADA2; carefully weigh antithrombotic therapy risks 6
• Screen for systemic manifestations: This is not isolated CNS vasculitis—evaluate for bone marrow failure, immunodeficiency, and multi-organ involvement that may require additional interventions 5

Prognosis and Long-term Considerations

• Hematopoietic stem cell transplant may be required for refractory cytopenias, severe vasculopathy, or immunodeficiency not controlled by TNF inhibitors 1
• Lifelong monitoring is essential, as DADA2 is a chronic condition with risk of recurrent strokes and progressive organ damage 4
• Early TNF inhibitor therapy dramatically improves outcomes and prevents life-threatening complications 6, 3