Spirochetal STI (Treponema pallidum) with characteristic primary chancre, secondary mucocutaneous disease, latent phase, and tertiary complications.
Also known as: syphilis, Treponema pallidum, lues, neurosyphilis, congenital syphilis
Overview
Systemic infection caused by Treponema pallidum subspecies pallidum, a microaerophilic spiral bacterium transmitted by sexual contact, vertical transmission, and rarely transfusion. Disease progresses through primary, secondary, latent, and tertiary stages over years if untreated.
Epidemiology
US rates have risen sharply over the past decade — 207,000 cases of all stages in 2022 (CDC), highest since 1950s. Disproportionate increase in MSM, women of reproductive age, and congenital syphilis (alarming resurgence; >3,700 congenital cases in 2022). HIV coinfection common (~50% in MSM with syphilis).
Try two board-style Syphilis questions
Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.
Question 1Infectious DiseaseMedium
A 28-year-old man presents with a diffuse maculopapular rash involving his palms and soles, along with mucous patches in his mouth and condylomata lata in the perianal region. He had a painless genital ulcer six weeks ago that resolved on its own. RPR is reactive at 1:64 and confirmatory treponemal testing is positive. Which of the following is the most likely long-term complication if he remains untreated?
AAcute glomerulonephritis
BMyocardial infarction
CHemolytic anemia
DHutchinson teeth
ETabes dorsalis
Reveal answer & full explanation
Correct answer: E — Tabes dorsalis
AAcute glomerulonephritis
BMyocardial infarction
CHemolytic anemia
DHutchinson teeth
ETabes dorsalis✓
Why Tabes dorsalis is correct
This presentation is secondary syphilis, characterized by a palmar/plantar maculopapular rash, mucous patches, and condylomata lata, occurring 4-10 weeks after the primary chancre.
Without treatment, roughly one-third of patients progress to tertiary syphilis years to decades later.
Tertiary manifestations include neurosyphilis (tabes dorsalis, general paresis, Argyll Robertson pupils), cardiovascular syphilis (ascending aortic aneurysm), and gummatous disease.
Tabes dorsalis results from demyelination of the dorsal columns and dorsal roots and is among the most recognizable late complications.
Why the others are wrong
Acute glomerulonephritis — a rare immune-complex phenomenon seen mainly during secondary syphilis, not a long-term sequela.
Myocardial infarction — not a characteristic sequela; cardiovascular syphilis causes aortitis with ascending aortic aneurysm and aortic regurgitation, and when the aortitis narrows the coronary ostia it usually causes angina, with infarction only rarely.
Hemolytic anemia — paroxysmal cold hemoglobinuria (the Donath-Landsteiner antibody) was historically linked to late and congenital syphilis, but it is a rare association, and most cases now follow viral infections in children.
Hutchinson teeth — a classic late stigma of congenital syphilis from treponemal damage to the developing permanent incisors; this man acquired syphilis as an adult with fully formed permanent teeth, so it is not a complication of untreated acquired disease (the trap is confusing congenital stigmata with tertiary syphilis).
Additional high-yield points
Penicillin G remains the treatment of choice across all stages of syphilis.
Question 2Infectious DiseaseEasy
A 35-year-old man presents with a painless, indurated genital ulcer and non-tender bilateral inguinal lymphadenopathy. He first noticed the lesion about 3 weeks after unprotected intercourse with a new partner. Which of the following is the most likely diagnosis?
ALymphogranuloma venereum
BGranuloma inguinale
CPrimary syphilis
DGenital herpes
EChancroid
Reveal answer & full explanation
Correct answer: C — Primary syphilis
ALymphogranuloma venereum
BGranuloma inguinale
CPrimary syphilis✓
DGenital herpes
EChancroid
Why Primary syphilis is correct
Primary syphilis presents with a painless indurated chancre and non-tender regional lymphadenopathy
The chancre appears a median of about 3 weeks (range 10-90 days) after exposure, matching this timeline
Confirm with a nontreponemal test (RPR or VDRL) plus a treponemal test (FTA-ABS or TP-PA); darkfield microscopy or PCR of chancre exudate is also diagnostic, and nontreponemal tests can still be nonreactive this early
Why the others are wrong
Genital herpes — causes painful grouped vesicles and shallow ulcers, not a single painless indurated chancre
Lymphogranuloma venereum — produces a transient painless ulcer followed by painful suppurative inguinal buboes and is caused by Chlamydia trachomatis L serovars, not Treponema
Chancroid — causes painful, soft, ragged ulcers with tender suppurative adenopathy (Haemophilus ducreyi), the opposite of the painless indurated chancre
Granuloma inguinale — also causes a painless genital ulcer, but Klebsiella granulomatis produces a beefy red, friable, highly vascular ulcer that bleeds easily, with subcutaneous granulomas (pseudobuboes) rather than true lymphadenopathy; it is rare in the US
Additional high-yield points
Treatment is benzathine penicillin G 2.4 million units IM x 1
Non-pregnant penicillin-allergic patients can receive doxycycline x 14 days
Repeat RPR at 6 and 12 months to confirm treatment response
That's 2. Get 7,700+ more.
Unlock the full FirstPassPA bank: 7,700+ board-style questions, flashcards, and an AI tutor that explains every answer. Your 7-day free trial includes everything, and there's no credit card required.
You've read your 2 free diagnosis previews. Create your free account to unlock the full Syphilis outline — plus all 514 diagnoses, 7,700+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
T. pallidum penetrates intact mucous membranes or microabrasions, replicates locally, then disseminates hematogenously and lymphatically within hours. Cannot be cultured in vitro. Tissue damage results from intense host inflammatory response. CNS invasion occurs early; clinical neurosyphilis can present at any stage.
Clinical presentation
Symptoms
Primary (median ~3 weeks, range 10-90 days after exposure): single painless indurated ulcer (chancre) with raised borders, clean base; heals spontaneously in 3-6 weeks
Secondary (4-10 weeks after chancre): diffuse maculopapular rash including palms and soles, mucous patches, condyloma lata (moist gray-white papules in intertriginous areas), patchy 'moth-eaten' alopecia, generalized lymphadenopathy, low-grade fever, headache, hepatitis, glomerulonephritis
Latent: asymptomatic but seropositive — early latent (<1 year) versus late latent (≥1 year or unknown duration)
Tertiary (years-decades): cardiovascular syphilis (aortitis, aortic aneurysm), gummatous lesions (granulomas of skin/bone/viscera), neurosyphilis at any stage (meningitis, meningovascular, general paresis, tabes dorsalis, Argyll Robertson pupils)
Signs / physical exam
Painless genital, anal, or oral ulcer with raised indurated borders
Palmar/plantar maculopapular rash (highly characteristic in secondary)
Generalized lymphadenopathy
Late: ascending aortic aneurysm, dorsal column dysfunction with sensory ataxia and lancinating pains, dementia, small accommodating but non-reactive pupils (Argyll Robertson — 'prostitute's pupil')
Early congenital (before age 2; many affected newborns look normal at birth): hepatosplenomegaly, jaundice, snuffles (rhinitis), maculopapular or bullous rash including palms and soles, osteochondritis/periostitis with pseudoparalysis, nonimmune hydrops, lymphadenopathy
Painless genital ulcer that heals on its own → 6-8 weeks later, generalized rash including the palms and soles with mucous patches — classic primary and secondary syphilis.
Drug eruption — Recent drug exposure; eosinophilia
Lichen planus — Pruritic violaceous polygonal papules with Wickham striae
Diagnostic workup
Diagnostic criteria
Positive serology with confirmation by reciprocal test; clinical staging based on examination, sexual history, and timing.
Labs
Two-step serology — order BOTH a treponemal and non-treponemal test:
• Non-treponemal: RPR or VDRL (titers correlate with disease activity; used to monitor response). Can have false positives (pregnancy, HIV, autoimmune disease, IV drug use, viral infections)
• Treponemal: FTA-ABS, TP-PA, or EIA (positive for life; cannot use to monitor treatment)
Dark-field microscopy of chancre fluid (specialty labs only)
Direct PCR available in some centers
Lumbar puncture for neurosyphilis: CSF VDRL specific but insensitive; reactive CSF treponemal sensitive but nonspecific; CSF pleocytosis and elevated protein suggest disease
HIV testing in all syphilis cases; screen for other STIs
Seronegative window: early primary syphilis can be nonreactive on serology, and RPR/VDRL (only about 50-80% sensitive in primary syphilis) often lags the treponemal test, so a nonreactive RPR does not exclude a chancre; most patients are reactive on both tests within a few weeks of chancre onset. Confirm with darkfield or PCR of lesion exudate when available and treat a typical chancre presumptively
Imaging
Echo or CT chest if cardiovascular syphilis suspected
MRI brain/spine for neurosyphilis evaluation
Skeletal X-rays in congenital syphilis (metaphyseal lucencies, periostitis)
CDC 2021 syphilis treatment by stage (penicillin-based regimens).
Treatment
First-line
Primary, secondary, and early latent syphilis (<1 year duration):
• Benzathine penicillin G 2.4 million units IM × 1 dose
Late latent (≥1 year or unknown duration) and tertiary syphilis without neurologic involvement:
• Benzathine penicillin G 2.4 million units IM weekly × 3 weeks (total 7.2 million units)
Neurosyphilis, ocular syphilis, otosyphilis:
• Aqueous crystalline penicillin G 18-24 million units/day IV × 10-14 days (3-4 million units q4h or continuous infusion)
• Alternative: procaine penicillin G 2.4 million units IM daily + probenecid 500 mg PO QID × 10-14 days
Congenital syphilis: aqueous crystalline penicillin G 50,000 units/kg IV q12h (first 7 days of life) then q8h × 10 days total
Second-line / adjunct
Penicillin allergy: doxycycline 100 mg PO BID × 14 days (early) or 28 days (late) — NOT for pregnancy or neurosyphilis
Ceftriaxone 1-2 g IM/IV daily × 10-14 days — alternative in penicillin allergy or neurosyphilis if desensitization not feasible
Pregnancy: penicillin is the ONLY recommended therapy. Desensitize if allergic (doxycycline is teratogenic; tetracyclines and erythromycin do not adequately treat fetus)
Jarisch-Herxheimer reaction (fever, chills, headache, myalgia within hours of first penicillin dose) — common in secondary syphilis; supportive care; counsel patients in advance
Rash involving palms and soles is short list: secondary syphilis, RMSF, Coxsackie hand-foot-mouth, drug eruption.
Pregnancy + penicillin allergy = desensitize. NEVER substitute doxycycline.
Monitor non-treponemal titers (RPR/VDRL): a 4-fold drop (e.g., 1:32 to 1:8) confirms treatment response; expect it within 12 months for primary/secondary syphilis (titers at 6 and 12 months) and within 24 months for latent syphilis (titers at 6, 12, and 24 months).
Test all syphilis patients for HIV and screen for other STIs at all exposed sites.
Screening: test every pregnant patient at the first prenatal visit (USPSTF, reaffirmed 2025), with repeat testing at 28 weeks and at delivery for those at risk or in high-prevalence areas (CDC); ACOG (2024) now recommends universal third-trimester and delivery screening. USPSTF (2022) recommends screening nonpregnant adolescents and adults at increased risk.
USPSTF 2022 — Screening for Syphilis Infection in Nonpregnant Adolescents and Adults: Recommendation Statement
CDC 2024 — Papp JR, Park IU, Fakile Y, et al. CDC Laboratory Recommendations for Syphilis Testing, United States, 2024. MMWR Recomm Rep 2024;73(1):1-32
ACOG 2024 — Screening for Syphilis in Pregnancy. ACOG Practice Advisory, April 2024
USPSTF 2025 — US Preventive Services Task Force. Screening for Syphilis Infection During Pregnancy: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA 2025;333(22):2006-2012
Practice Infectious Disease questions on FirstPassPA
Turn this outline into retention. 7,700+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.