What is the most likely diagnosis in an 11‑year‑old boy with a pulmonary arteriovenous malformation, leukopenia, and thrombocytopenia?

Hereditary Hemorrhagic Telangiectasia (HHT)

The most likely diagnosis in this 11-year-old boy with pulmonary arteriovenous malformation, leukopenia, and thrombocytopenia is Hereditary Hemorrhagic Telangiectasia (HHT) with SMAD4 mutation, which uniquely associates with juvenile polyposis syndrome and can present with cytopenias. 1, 2

Primary Diagnostic Consideration

HHT accounts for 70-90% of all pulmonary arteriovenous malformations and should be systematically evaluated in all patients presenting with PAVMs. 1, 3 The presence of leukopenia and thrombocytopenia in this case points specifically toward a SMAD4 mutation variant, which occurs in 1-2% of HHT patients and associates with juvenile polyposis syndrome. 1, 2

Clinical Features to Assess

Establish the diagnosis by evaluating for the four clinical criteria of HHT: 4

• Recurrent epistaxis - particularly if associated with anemia or requiring repeated evaluation 1
• Mucocutaneous telangiectasias - visible vascular lesions on skin, lips, hands, and oral mucosa 1, 5
• Visceral arteriovenous malformations - pulmonary (already identified), hepatic, cerebral, or gastrointestinal 1, 5
• Family history - autosomal dominant inheritance with age-related penetrance 1, 4

The diagnosis is definite if three criteria are present, possible if two criteria are present, and unlikely if fewer than two criteria exist. 4

Genetic Subtypes and Their Implications

Three main genetic subtypes exist with distinct clinical presentations: 1, 2, 5

• HHT Type 1 (ENG mutation) - characteristically presents with cerebral and pulmonary AVMs 1, 2
• HHT Type 2 (ACVRL1/ALK1 mutation) - typically presents with pulmonary hypertension and hepatic AVMs 1, 2
• SMAD4 mutation - occurs in 1-2% of HHT patients and uniquely associates with juvenile polyposis syndrome, which can cause gastrointestinal bleeding and potentially contribute to cytopenias 1, 2

The combination of PAVM with leukopenia and thrombocytopenia strongly suggests SMAD4-associated HHT with juvenile polyposis syndrome, as this is the only HHT variant associated with hematologic abnormalities through chronic gastrointestinal blood loss or bone marrow involvement from polyposis-related complications. 1, 2

Immediate Risk Assessment

This child faces serious complications that require urgent evaluation: 1, 3, 2

• Stroke risk: 3.2-55% in patients with untreated PAVMs due to paradoxical emboli bypassing pulmonary filtration 1, 3, 2
• Brain abscess risk: 0-25% from bacterial emboli entering systemic circulation 1, 3, 2
• Hemorrhage risk: Massive hemoptysis or hemothorax occurs in 0-2% but represents a life-threatening emergency 2

Diagnostic Workup

Proceed with the following algorithmic approach: 1, 3

1. Confirm PAVM characteristics - Obtain CT chest with IV contrast to determine number, size, location, and distribution of PAVMs 1, 3

2. Screen for right-to-left shunt - Perform transthoracic contrast echocardiography with 98-99% sensitivity for detecting intrapulmonary shunts 1, 3

3. Assess oxygenation - Measure positional oxygen saturation (supine and upright) as 65-83% of PAVMs are in lower lobes causing orthodeoxia and platypnea 3, 2

4. Genetic testing - Obtain molecular testing for ENG, ACVRL1/ALK1, and particularly SMAD4 mutations to establish genetic subtype and guide family screening 5, 4, 6

5. Screen for juvenile polyposis - If SMAD4 mutation confirmed, perform colonoscopy to evaluate for gastrointestinal polyps that may explain cytopenias 1, 2

6. Evaluate for other visceral AVMs - Screen for hepatic and cerebral AVMs based on genetic subtype 1, 5

Treatment Approach

Percutaneous transcatheter embolization is the first-line treatment for this patient's PAVM regardless of feeding artery size, given the significant risk of paradoxical embolic complications including stroke and brain abscess. 3, 2

The American College of Cardiology recommends transcatheter occlusion for all PAVMs detected by CT or catheter angiography due to paradoxical embolism risk, even when feeding arteries are small. 3, 2 Treatment should not be delayed while completing the diagnostic workup for HHT, as neurological complications represent the most serious morbidity and mortality risk. 2

Critical Management Points

• Antibiotic prophylaxis - Provide before all dental and invasive procedures to prevent bacteremia and brain abscess 7
• Avoid activities with Valsalva - Counsel against scuba diving, high-altitude exposure, and contact sports that increase risk of hemorrhage 8
• Long-term surveillance - Perform follow-up CT angiography at 6-12 months post-embolization, then every 3-5 years to detect recanalization or new lesions 3

Family Implications

Given the autosomal dominant inheritance pattern, all first-degree relatives require screening for HHT and PAVMs. 1, 5, 4 Children of affected individuals should be considered at risk even if asymptomatic, as HHT demonstrates age-related penetrance. 4, 6