What are the top differential diagnoses for a 16-year-old sexually active female with a 3-day history of a maculopapular (maculopapular rash) erythematous (redness of the skin) rash on her palms and the back of her hands, which is slightly painful but not pruritic (itchy), with one additional lesion on the top of her right foot, and no recent fever or illness?

Top Differential Diagnoses

Secondary syphilis is the most critical diagnosis to rule out immediately in this sexually active adolescent with a painful maculopapular rash on palms and hands, given the high-risk population and characteristic distribution. 1, 2

Primary Differential: Secondary Syphilis

Secondary syphilis must be at the top of your differential given:

• Sexual activity in a 16-year-old (high-risk behavior) 2
• Palmar involvement is classic for secondary syphilis, along with soles 1, 3
• Maculopapular rash is the typical presentation 2
• Slightly painful rather than pruritic distinguishes it from many viral exanthems 2
• Scattered distribution (palms, hands, one foot lesion) fits the diffuse pattern of secondary syphilis 2

Immediate action required: Order RPR/VDRL and treponemal-specific testing (FTA-ABS or TP-PA) today. 2

Secondary Differential: Rocky Mountain Spotted Fever (RMSF)

RMSF remains a critical consideration despite no reported outdoor exposure because:

• Rash on palms indicates advanced disease with high mortality risk 1, 3
• Tick exposure history is absent in 40% of cases 3
• Classic triad (fever, rash, tick bite) is present in only a minority at presentation 1, 3
• However, the 3-day timeline is early for RMSF (rash typically appears day 5-6) 1, 3
• Absence of fever argues against RMSF but does not exclude it 3

Critical pitfall: Up to 20% of RMSF cases lack rash entirely, and absence of fever does not exclude early disease. 1, 3

If any systemic symptoms develop (fever, headache, myalgias), start doxycycline immediately without waiting for confirmation, as 50% of deaths occur within 9 days. 3

Tertiary Differential: Drug Reaction

Drug hypersensitivity can cause maculopapular rash on palms and soles: 1

• Obtain detailed medication history including over-the-counter drugs, supplements, and any new medications in the past 2-4 weeks 1
• Drug reactions typically are pruritic rather than painful, making this less likely 1

Less Likely Differentials

Viral exanthems (enterovirus, EBV, parvovirus B19):

• Typically pruritic rather than painful 4, 3
• Usually accompanied by systemic symptoms (fever, malaise) 4
• Less commonly involve palms specifically 3

Kawasaki disease:

• Excluded by absence of fever (requires ≥5 days of fever for diagnosis) 5
• Requires ≥4 of 5 principal criteria including conjunctivitis, oral changes, cervical lymphadenopathy 5
• Palmar erythema in Kawasaki is typically accompanied by firm, painful induration and subsequent desquamation 5

Dyshidrotic eczema:

• Presents with vesicular "tapioca pudding" lesions, not maculopapular 6
• Intensely pruritic, not painful 6

Diagnostic Algorithm

Immediate laboratory workup:

1. RPR/VDRL and treponemal-specific testing (FTA-ABS or TP-PA) 2
2. Complete blood count with differential to assess for thrombocytopenia or bandemia 3
3. Comprehensive metabolic panel to evaluate for hyponatremia or hepatic transaminase elevations 3

Clinical red flags requiring immediate escalation:

• Development of fever, headache, or altered mental status → start empiric doxycycline immediately for presumed RMSF 3
• Rapidly progressive rash or systemic toxicity → hospitalize and add ceftriaxone to cover meningococcemia 3
• Petechial or purpuric evolution → immediate admission for life-threatening infection 3

If initial workup is negative:

• Consider skin biopsy with immunohistochemical staining if syphilis serology is equivocal 2
• Reassess medication history for drug reaction 1
• Monitor closely for evolution of symptoms over 48-72 hours 3

Critical Clinical Pitfalls to Avoid

Do not dismiss this as a benign viral exanthem based on:

• Absence of fever (secondary syphilis may be asymptomatic systemically) 2
• Young age (syphilis rates are rising in adolescents) 2
• Patient denial of sexual activity (obtain confidential history separately from parents) 2

Rash on palms and soles is never pathognomonic for a single condition—always consider secondary syphilis, RMSF, meningococcemia, bacterial endocarditis, and drug reactions in your differential. 1, 3

In sexually active adolescents, secondary syphilis should be considered first-line until proven otherwise with negative serology. 2