What are the differential diagnoses for an 11-year-old girl with markedly elevated lactate dehydrogenase, hypertension, tachycardia, leukopenia, oral mucosal involvement, and a diffuse rash involving the bilateral extremities and chest while sparing the abdomen and back?

Differential Diagnoses for an 11-Year-Old with Markedly Elevated LDH, Hypertension, Tachycardia, Leukopenia, Oral Lesions, and Rash

The most critical diagnosis to rule out immediately is Multisystem Inflammatory Syndrome in Children (MIS-C), given the constellation of persistent fever (implied by tachycardia), mucocutaneous findings (oral lesions and rash), cardiovascular involvement (hypertension, tachycardia), leukopenia, and markedly elevated LDH—this requires urgent echocardiogram, troponin, BNP/NT-proBNP, and SARS-CoV-2 testing (both PCR and serology) within hours of presentation. 1, 2, 3

Primary Differential Diagnoses

1. Multisystem Inflammatory Syndrome in Children (MIS-C)

This is the most urgent consideration given the clinical presentation:

• Key distinguishing features: MIS-C characteristically presents with persistent fever, mucocutaneous findings (oral lesions, rash on extremities and chest), cardiovascular involvement (hypertension, tachycardia suggesting myocardial dysfunction or shock), leukopenia, and markedly elevated inflammatory markers including LDH 1, 3

• Critical laboratory findings in MIS-C: Elevated LDH is expected, along with elevated CRP (typically ≥10 mg/dL), elevated ferritin (500-2,000 ng/dL range), profoundly elevated procalcitonin without bacterial infection, elevated D-dimer, and elevated troponin/BNP indicating cardiac involvement 1

• Timing consideration: MIS-C typically occurs 2-6 weeks after SARS-CoV-2 exposure, so obtain both PCR (positive in only 20-40% of MIS-C cases) and serology (positive in 80-90% of cases) 1, 2, 3

• Immediate workup required: Echocardiogram to assess for left ventricular dysfunction (quantify ejection fraction and end-diastolic volume with z-scores), coronary artery involvement (measure all segments with z-scores), troponin T, BNP/NT-proBNP (highly elevated levels distinguish patients with LV dysfunction), complete blood count, CRP, ESR, complete metabolic panel, D-dimer, ferritin, procalcitonin, and LDH 1

• Rash distribution pattern: The sparing of abdomen and back with involvement of extremities and chest is consistent with the mucocutaneous manifestations of MIS-C, which can present with variable rash patterns 1, 3

2. Acute Lymphoblastic Leukemia (ALL)

The markedly elevated LDH (1200 U/L) combined with leukopenia makes this a critical consideration:

• LDH as a risk marker: In pediatric ALL, LDH >1320 U/L is found in 70% of high-risk patients, and this patient's LDH of 1200 approaches this threshold 4, 5

• Clinical presentation: ALL can present with constitutional symptoms, cytopenias (leukopenia in this case), oral mucosal involvement (from thrombocytopenia or leukemic infiltration), and rash (petechiae, ecchymoses, or leukemia cutis) 4

• Cardiovascular findings: Hypertension and tachycardia could result from anemia, tumor lysis syndrome, or hyperleukocytosis-related complications 4

• Immediate workup: Peripheral blood smear to look for blasts, complete blood count with differential, comprehensive metabolic panel (assess for tumor lysis syndrome with elevated uric acid, potassium, phosphate, and decreased calcium), and bone marrow aspirate/biopsy if blasts are identified 1, 4

3. Systemic Lupus Erythematosus (SLE) or Other Autoimmune Disease

The combination of cytopenias, rash, oral lesions, and multisystem involvement suggests autoimmune disease:

• Clinical features: SLE can present with leukopenia, oral ulcers, photosensitive rash (though distribution here is atypical), hypertension (from renal involvement), and elevated LDH 1

• Laboratory evaluation: ANA, anti-dsDNA, complement levels (C3, C4), anti-Smith antibodies, complete blood count, urinalysis for proteinuria and cellular casts, comprehensive metabolic panel for renal function 1

• Hypertension consideration: If SLE with renal involvement (lupus nephritis), hypertension would be expected and could represent a hypertensive emergency requiring immediate blood pressure management 1

4. Rosai-Dorfman Disease (RDD)

While less common, the clinical presentation has overlapping features:

• Characteristic findings: RDD can present with oral mucosal lesions, skin involvement (red-to-brown macules, papules, or xanthomatous lesions often around orbits or malar region), hypertension (from cardiac involvement), and elevated LDH 1

• Cardiac involvement: RDD rarely involves the heart but when present can cause hypertension and tachycardia from infiltration of cardiac structures 1

• Dermatologic pattern: Skin lesions in RDD can present as papules or plaques, and the distribution described (extremities and chest sparing abdomen and back) could be consistent 1

• Laboratory findings: Elevated LDH is expected, and leukopenia can occur with bone marrow involvement 1

• Diagnostic workup: Tissue biopsy showing characteristic histiocytes with emperipolesis, complete blood count, serum immunoglobulins, ESR, comprehensive metabolic panel, and bone marrow biopsy if cytopenias present 1

5. Severe Infection with Hemolysis or Sepsis

The combination of leukopenia, elevated LDH, and hemodynamic instability suggests severe infection:

• Dengue hemorrhagic fever/shock syndrome: Can present with leukopenia, elevated LDH (mean levels >1,000 IU on day of plasma leakage in severe cases), rash, oral mucosal involvement, hypertension (or hypotension in shock), and hepatic injury 6

• Other severe infections: Bacterial sepsis, viral infections (EBV, CMV), or atypical infections can cause elevated LDH, cytopenias, rash, and cardiovascular instability 6, 7

• Hemolysis: Elevated LDH with leukopenia could indicate hemolytic anemia from autoimmune hemolytic anemia, thrombotic microangiopathy, or infection-related hemolysis 1

• Immediate workup: Blood cultures, complete blood count with peripheral smear, reticulocyte count, haptoglobin, Coombs test, comprehensive metabolic panel, coagulation studies, and lactate level 1, 6

Critical Immediate Actions

Within the first hour of evaluation:

• Obtain SARS-CoV-2 PCR and serology to evaluate for MIS-C 1, 2, 3
• Perform echocardiogram to assess cardiac function and coronary arteries 1
• Draw cardiac biomarkers (troponin, BNP/NT-proBNP) 1
• Complete inflammatory panel: CRP, ESR, ferritin, D-dimer, procalcitonin 1
• Obtain peripheral blood smear to evaluate for blasts or hemolysis 4, 5
• Blood cultures to exclude bacterial sepsis 1

The very high LDH (1200 U/L) is independently associated with severe disease and high mortality risk (26.6% mortality in adults with LDH ≥800 U/L), warranting aggressive investigation and close monitoring. 7

Common Pitfalls to Avoid

• Do not dismiss MIS-C based on negative PCR alone—serology is positive in 80-90% of MIS-C cases while PCR is only positive in 20-40% 1

• Do not delay echocardiogram—cardiac involvement in MIS-C can rapidly progress to cardiogenic shock and requires immediate identification 1, 3

• Do not attribute hypertension solely to pain or anxiety—in this context with multisystem involvement, it may represent malignant hypertension, cardiac dysfunction, or renal involvement requiring specific management 1

• Do not overlook the rash distribution pattern—the specific sparing of abdomen and back while involving extremities and chest provides diagnostic clues and should be carefully documented 1

• Do not wait for lymphadenopathy to consider RDD—extranodal RDD can occur without prominent lymph node involvement 1