What is the differential diagnosis and workup for a 4-year-old female child with leukocytosis (elevated white blood cell count) and eosinophilia?

Severe Leukocytosis with Eosinophilia in a 4-Year-Old: Differential Diagnosis and Workup

A 4-year-old with 70,000 leukocytes and eosinophilia requires urgent evaluation for myeloid/lymphoid neoplasms with tyrosine kinase gene fusions, particularly given that this degree of leukocytosis with eosinophilia is highly suggestive of a clonal hematologic disorder rather than a reactive process. 1

Differential Diagnosis

Primary (Clonal) Causes - Highest Priority

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions (M/LN-eo-TK) are the most critical consideration given the extreme leukocytosis, as these can present with clinical features similar to chronic eosinophilic leukemia, other myeloproliferative neoplasms, or acute leukemia. 1 Key genetic rearrangements include:

• PDGFRA (4q12), PDGFRB (5q32), or ETV6::ABL1 rearrangements - these are particularly important because they respond to tyrosine kinase inhibitors and represent treatable causes. 1
• BCR::ABL1-positive chronic myeloid leukemia (CML) - can present with marked leukocytosis and eosinophilia, with basophilia being an additional clue. 1
• Acute myeloid leukemia with inv(16)/CBFB::MYH11 - characteristically presents with eosinophilia. 1

Chronic myeloid leukemia in blast phase (CML-BP) should be considered, as pediatric patients with de novo CML-BP often present with very high leukocyte counts (>70,000 is common). 1

Secondary (Reactive) Causes - Lower Priority Given Severity

While the American Journal of Hematology notes that secondary causes range from infections and allergies to paraneoplastic phenomena 1, a leukocyte count of 70,000 with eosinophilia is rarely if ever explained by allergic disease alone and mandates investigation for clonal disorders. 2, 3

• Parasitic infections (Strongyloides, hookworm, Ascaris) - though common causes of eosinophilia, they typically do not produce this degree of leukocytosis. 4, 5
• Allergic disorders - account for 80% of eosinophilia cases but are associated with mild elevations, not extreme leukocytosis. 4, 3
• Primary immunodeficiencies - important in children, especially in regions with consanguineous marriages, but typically present with moderate rather than severe leukocytosis. 3

Essential Workup

Immediate Laboratory Studies

Complete blood count with manual differential to determine:

• Absolute eosinophil count and percentage 1
• Presence of basophilia (suggests CML) 1
• Blast percentage and promyelocyte count 1
• Left-shifted myeloid maturation pattern 1

Peripheral blood flow cytometry to define myeloid versus lymphoid phenotype and assess for aberrant immunophenotypes. 1

Peripheral blood molecular genetics:

• BCR::ABL1 fusion transcript testing (quantitative RT-PCR on International Scale) - essential for CML diagnosis. 1
• Tyrosine kinase domain mutation analysis if BCR::ABL1 positive. 1

Bone Marrow Evaluation - Mandatory

Bone marrow aspiration and biopsy with the following studies 1, 6:

• Morphology with blast and promyelocyte percentage 1
• Conventional cytogenetics with minimum 15 metaphases analyzed 1
• FISH for CHIC2 deletion (indicates FIP1L1-PDGFRA fusion) 6
• RT-PCR for tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1, JAK2, ETV6::ABL1) 1, 6
• Reticulin/collagen staining to assess fibrosis 6
• Immunohistochemistry 6

Optical genome mapping (OGM) on peripheral blood should be performed if conventional cytogenetics fail or to identify cryptic rearrangements involving PDGFRA, CHIC2, or GSX2 partners, as correct interpretation is critical for targeted therapy decisions. 1

Additional Essential Studies

Serum tryptase and vitamin B12 levels - elevated in myeloproliferative neoplasms. 6

Comprehensive metabolic panel and liver function tests to assess organ involvement. 6

Cardiac evaluation (ECG, echocardiogram, troponin) - persistent high-grade eosinophilia can cause irreversible cardiac damage, and early assessment is critical for prognosis. 6, 4, 5

HLA typing - initiate donor search immediately given high likelihood of needing allogeneic stem cell transplantation. 1

Secondary Cause Evaluation - Only After Excluding Malignancy

Travel and exposure history focusing on geographic areas endemic for helminths. 6, 4

Stool examination for ova and parasites (three samples) and Strongyloides serology - critical because Strongyloides can cause fatal hyperinfection syndrome if immunosuppression is initiated. 4, 5

Medication review for drug-induced eosinophilia. 4

Critical Pitfalls to Avoid

Failing to test for PDGFRA/PDGFRB rearrangements can lead to missed opportunities for highly effective tyrosine kinase inhibitor therapy. 6

Attributing severe leukocytosis to allergic disease - allergic disorders account for 80% of eosinophilia but cause only mild elevations (typically <1,500 cells/μL), not leukocytosis of 70,000. 4, 3

Not assessing cardiac involvement early can result in irreversible heart failure, as eosinophil-mediated cardiac damage occurs with persistent high-grade eosinophilia. 6

Overlooking Strongyloides infection before initiating immunosuppression can be fatal. 5

Misinterpreting FISH results - rearrangements involving closely positioned genes (PDGFRA, CHIC2, GSX2) require optical genome mapping for accurate characterization. 1

Algorithmic Approach

1. Immediate: CBC with differential, peripheral blood flow cytometry, BCR::ABL1 testing 1
2. Urgent (within 24-48 hours): Bone marrow aspiration/biopsy with comprehensive genetic testing including FISH for CHIC2 deletion and RT-PCR for TK fusions 1, 6
3. Concurrent: Cardiac evaluation, metabolic panel, HLA typing 1, 6
4. If genetic testing negative: Stool studies, Strongyloides serology, detailed exposure history 4, 5
5. If persistent hypereosinophilia >1 month with negative workup: Consider idiopathic hypereosinophilic syndrome, though this represents only 0.3% of childhood eosinophilia cases 3