What are the primary differential diagnoses to consider in a 15-month-old female with hand, foot, and mouth disease (HFMD)?

Differential Diagnoses for a 15-Month-Old Female with Hand, Foot, and Mouth Disease

The primary differential diagnoses to consider in a 15-month-old with suspected HFMD include herpetic gingivostomatitis (herpes simplex virus), herpangina, varicella (chickenpox), enteroviral infections without HFMD, Kawasaki disease, and less commonly, erythema multiforme or drug reactions. 1, 2

Key Clinical Distinctions

Herpetic Gingivostomatitis (Herpes Simplex Virus)

• Most important differential in this age group with oral lesions 3
• Presents with painful oral vesicles and ulcers, but typically lacks the characteristic hand and foot involvement of HFMD 3
• Oral lesions in HSV tend to be more severe, with prominent gingivitis and bleeding gums
• Fever may be higher and more prolonged than typical HFMD
• Look for perioral vesicles and crusting around the lips, which is more characteristic of HSV than HFMD 4

Herpangina

• Caused by the same enterovirus family as HFMD 5
• Key distinction: oral lesions are confined to the posterior pharynx, soft palate, and tonsillar pillars without hand/foot involvement 3
• Vesicles and ulcers do not appear on the anterior mouth, tongue, or buccal mucosa as commonly seen in HFMD 5
• Fever pattern and duration are similar to HFMD

Varicella (Chickenpox)

• Distribution pattern is the key differentiator 2
• Varicella presents with widely distributed lesions across the trunk, face, and scalp in various stages (macules, papules, vesicles, crusts) 2
• HFMD lesions are concentrated on hands, feet, and mouth rather than being centripetal 2
• Varicella lesions are typically more pruritic than HFMD lesions
• Check vaccination history—vaccinated children may have modified disease

Atypical Enteroviral Infections

• Widespread exanthema beyond classic HFMD distribution can occur, particularly with Coxsackievirus A6 1, 4
• May involve legs, arms, trunk, and buttocks in addition to classic sites 1, 4
• Peri-oral rash is specifically associated with CV-A6 infections 4
• Up to 87.6% of confirmed HFMD cases have skin lesions on sites other than hands, feet, and mouth 4

Kawasaki Disease

• Critical not to miss due to cardiac complications 6
• Key distinguishing features:
  • Persistent high fever (≥5 days) versus HFMD fever that typically resolves in 3-4 days 2
  • Diffuse erythema rather than vesicular lesions 2
  • Conjunctival injection, strawberry tongue, cervical lymphadenopathy, and extremity changes (erythema and edema) 6
  • HFMD presents with vesicular lesions, not diffuse erythema 2

Erythema Multiforme

• Target lesions with central clearing, typically on extensor surfaces 6
• May have oral involvement but lacks the characteristic vesicular pattern of HFMD 3
• Often preceded by HSV infection or medication exposure
• Lesions are typically larger and more polymorphic than HFMD

Drug Reactions

• Consider if recent medication exposure (antibiotics, anticonvulsants) 6
• Rash pattern is usually more diffuse and maculopapular rather than vesicular 6
• Timing correlates with medication initiation (typically 7-14 days)

Diagnostic Approach

History Elements to Clarify

• Timing and progression: HFMD typically shows fever first, followed by oral lesions, then hand/foot rash 1-2 days later 2
• Sick contacts or daycare exposures: HFMD spreads through respiratory secretions and direct contact 7
• Recent medications: to exclude drug reactions 6
• Vaccination status: particularly varicella vaccine
• Geographic considerations: EV-A71 outbreaks are more common in Asia with higher complication rates 1, 5

Physical Examination Focus

• Oral cavity: HFMD lesions appear on tongue, gums, and buccal mucosa; herpangina is posterior only; HSV causes severe gingivitis 3, 5
• Lesion morphology: vesicles on erythematous base (HFMD) versus target lesions (erythema multiforme) versus crops of lesions in different stages (varicella) 2, 4
• Distribution pattern: hands, feet, mouth, and buttocks suggest HFMD; widespread trunk involvement suggests varicella 2, 4
• Peri-oral involvement: suggests CV-A6 variant of HFMD 4

Laboratory Testing When Indicated

• RT-PCR of vesicle fluid is the gold standard for confirming HFMD and identifying specific enterovirus serotype 1
• Respiratory samples or stool specimens can also be tested 1
• Laboratory testing is typically not necessary for classic presentations but should be considered for:
  • Atypical presentations requiring definitive diagnosis
  • Severe cases with neurological symptoms 5, 8
  • Outbreak investigations 5

Red Flags Requiring Immediate Evaluation

Watch for warning signs of severe complications, particularly with EV-A71 infections 2, 5, 8:

• Persistent high fever beyond 3-4 days
• Lethargy or altered mental status
• Severe headache or stiff neck (meningitis/encephalitis)
• Unusual irritability
• Respiratory distress
• Vomiting without oral intake

These complications occur in approximately 1% of cases, with a case fatality rate of 0.03%, predominantly with EV-A71 5

Common Pitfalls to Avoid

• Do not dismiss minimal skin findings: Fatal HFMD cases have been reported with only punctate vesicles visible with magnification 8
• Do not rely solely on classic hand/foot/mouth distribution: 87.6% of confirmed cases have lesions beyond these sites 4
• Do not assume all vesicular rashes in toddlers are HFMD: Herpes simplex and varicella require different management considerations 3
• Do not overlook Kawasaki disease: The persistent fever pattern and lack of vesicles are key distinguishing features 2