Differential Diagnosis of Hand, Foot, and Mouth Disease
The differential diagnosis for hand, foot, and mouth disease (HFMD) includes erythema multiforme, herpes simplex virus infection, varicella, measles, drug hypersensitivity reactions, and in adults, more serious conditions such as infective endocarditis, secondary syphilis, and meningococcal infection. 1, 2
Primary Differential Considerations in Children
The most common mimics of HFMD in pediatric patients include:
- Erythema multiforme: Distinguished by target lesions and typically more extensive mucosal involvement beyond the oral cavity 2
- Herpes simplex virus (HSV) infection: Presents with grouped vesicles on an erythematous base, typically confined to perioral areas or gingiva, without the characteristic palmar-plantar distribution 2
- Varicella (chickenpox): Features a generalized vesicular rash in various stages of healing, with a centripetal distribution (trunk predominance) rather than acral involvement 2
- Measles: Characterized by Koplik spots, cough, coryza, conjunctivitis, and a maculopapular rash that begins on the face and spreads caudally 2
Additional Considerations in Adults
When evaluating adults with suspected HFMD, the differential broadens significantly:
- Drug hypersensitivity reactions: Can present with oral lesions and palmar-plantar involvement, particularly with certain medications 1
- Infective endocarditis: May present with palmar lesions (Janeway lesions) and requires urgent evaluation 1
- Secondary syphilis: Classically presents with palmar-plantar rash and oral lesions; serologic testing is essential 1
- Meningococcal infection: A life-threatening condition that can present with petechial or purpuric rash involving palms and soles 1
Key Distinguishing Features of HFMD
To differentiate HFMD from these conditions, focus on:
- Distribution pattern: The characteristic triad of oral lesions plus palmar AND plantar involvement is highly specific for HFMD 2, 3
- Lesion morphology: HFMD typically presents with maculopapular or papulovesicular lesions on hands and feet, with painful oral ulcerations 2
- Timing and progression: Initial fever and sore throat followed by rash development after a few days 4
- Age and epidemiology: Most commonly affects children under 5 years, with outbreaks occurring in spring to fall 2
Atypical Presentations Requiring Broader Differential
Recent outbreaks of coxsackievirus A6 have caused more severe and atypical presentations:
- Widespread exanthema: Lesions extending beyond classic distribution to involve legs and other body areas 5, 4
- Adult involvement: More frequent adult cases with severe symptoms 4
- Delayed nail changes: Onychomadesis (nail shedding) occurring up to two months after initial symptoms, which can be confused with other nail dystrophies 6
Diagnostic Approach
Diagnosis is primarily clinical based on the characteristic distribution of lesions. 1 However, when the diagnosis is uncertain:
- Laboratory confirmation: Reverse transcriptase PCR (RT-PCR) of vesicle fluid samples (preferred due to high viral loads) or respiratory/stool specimens can confirm the diagnosis 5, 1
- Consider serious alternatives first: In adults or severe presentations, rule out life-threatening conditions like meningococcal infection or infective endocarditis before settling on HFMD 1
Critical Pitfalls to Avoid
- Don't dismiss adult cases: While HFMD predominantly affects children, adult cases do occur and may present more severely 1, 4
- Don't overlook severe complications: Particularly with enterovirus 71 strains, watch for neurological complications (encephalitis/meningitis, acute flaccid myelitis/paralysis) and cardiopulmonary complications 5, 4, 3
- Don't confuse with serious systemic infections: The palmar-plantar distribution can mimic secondary syphilis or meningococcemia, which require urgent intervention 1