In an adult male with vesicular lesions on the palms and soles, what are the differential diagnoses besides hand‑foot‑mouth disease?

Differential Diagnosis of Vesicular Lesions on Palms and Soles in Adult Males

The key differential diagnoses for vesicular lesions on palms and soles in an adult male, excluding hand-foot-mouth disease, include: secondary syphilis, palmoplantar pustulosis/pustular psoriasis, drug-induced hand-foot syndrome (chemotherapy-related), Rocky Mountain spotted fever, Stevens-Johnson syndrome/TEN, and varicella-zoster virus infection.

Primary Differential Considerations

Infectious Etiologies

Secondary Syphilis should be high on your differential—this classically presents with a papulosquamous eruption involving palms and soles in adults. The lesions may appear vesicular or pustular. Always obtain RPR/VDRL and treponemal testing.

Rocky Mountain Spotted Fever 1 presents with fever, headache, and a maculopapular rash that becomes petechial and characteristically involves palms and soles by day 5-6 of illness. The rash appears 2-4 days after fever onset in most cases. This is a medical emergency with 5-10% mortality if untreated—start doxycycline immediately if suspected, even before confirmation.

Varicella-Zoster Virus 2 can cause vesicular eruptions in immunocompromised patients, though typically dermatomal. Disseminated VZV may present with atypical vesicular lesions. High-dose IV acyclovir is the treatment of choice in compromised hosts.

Drug-Induced Reactions

Hand-Foot Syndrome (Palmar-Plantar Erythrodysaesthesia) 3 is critical to identify if the patient is on chemotherapy. This occurs with:

• 5-fluorouracil (6-34% incidence)
• Capecitabine (50-60%)
• Doxorubicin (22-29%)
• Multikinase VEGFR inhibitors like sorafenib (10-62%)

The presentation includes dysaesthesia, burning pain, swelling, erythema, and progression to blisters on palms/soles. Hand-Foot Skin Reaction (HFSR) from BRAF/MEK inhibitors presents with well-defined painful hyperkeratosis and calluses at pressure points, sometimes with bullae.

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis 4 presents with painful purpuric macules or flat atypical targets that progress to flaccid bullae and epidermal detachment. Palms and soles can be prominently involved with blistering. This is a dermatologic emergency—look for mucosal involvement, positive Nikolsky sign, and recent medication exposure (typically within 1-4 weeks).

Inflammatory Dermatoses

Palmoplantar Pustulosis 5, 6 presents with sterile pustules on palms and soles, often in adults. This is distinct from chronic plaque psoriasis and may occur without psoriasis elsewhere (only 20% have associated psoriasis). Importantly, TNF antagonists should be avoided 5 as they can paradoxically trigger or worsen palmoplantar pustulosis.

Acropustulosis of Hallopeau 5 causes intense pustular inflammation around terminal phalanges, often severe enough to destroy nail plates. Unlike palmoplantar pustulosis, this condition may respond to TNF antagonists.

Palmoplantar Psoriasis 7 typically presents with erythematous, scaly, fissured hyperkeratotic patches and plaques rather than true vesicles, though pustular variants exist.

Clinical Approach Algorithm

1. Obtain medication history immediately: Chemotherapy agents, immunosuppressants, recent new medications (within 4 weeks)

2. Assess for systemic symptoms:

   • Fever + headache + tick exposure → Consider RMSF, start doxycycline empirically
   • Fever + mucosal involvement + skin tenderness → Consider SJS/TEN, hospitalize immediately
   • Constitutional symptoms in immunocompromised → Consider disseminated VZV

3. Examine lesion morphology carefully:

   • Sterile pustules only → Palmoplantar pustulosis
   • Purpuric macules/flat targets → SJS/TEN
   • Petechial progression → RMSF
   • Hyperkeratotic calluses at pressure points → HFSR from targeted therapy
   • Papulosquamous with systemic features → Secondary syphilis

4. Check for exposure history:

   • Children with recent HFMD (though you're excluding this)
   • Sexual contacts
   • Outdoor/tick exposure
   • Occupational chemical exposures

Critical Pitfalls to Avoid

Do not dismiss palmoplantar involvement as "just eczema" in adults—this distribution pattern is highly specific and demands thorough evaluation. The quality of life impact is disproportionate to body surface area involved 7.

Do not delay treatment for RMSF or SJS/TEN while awaiting confirmatory testing—both have significant mortality risk. RMSF has 5-10% mortality 1, and absence of rash early in disease should not preclude treatment.

Do not start TNF antagonists for palmoplantar pustulosis 5—a pilot study showed no benefit over placebo with etanercept, and these agents can paradoxically induce the condition.

In chemotherapy patients, recognize that HFSR from MEK inhibitors differs clinically and histologically from classic hand-foot syndrome 3—the former shows well-defined hyperkeratosis while the latter shows more diffuse erythema and vesiculation.

Consider atypical presentations: Recent literature 8, 9, 10, 11 documents that adult HFMD (which you're excluding) increasingly presents with atypical features including extensive involvement, bullous lesions, and purpuric patterns—other viral exanthems may similarly present atypically in adults.