Syphilis (cutaneous manifestations)

Meet the patient

A 26-year-old man comes back to the sexual health clinic two months after a painless penile ulcer that healed on its own. Today he has a copper-red rash on his palms and soles, faint grey patches on his tongue, and patchy hair loss he calls "moths got at it". He feels well. The ulcer is gone, the rash is new — and the unifying diagnosis is the one he did not expect: secondary syphilis.[1]

The two findings that should trigger serology before he leaves the room are the same two that define the disease for examiners: a painless ulcer that healed by itself, and a rash on the palms and soles. Hold those two images and the four stages slot into place behind them.[1][2]

One spirochaete, four staged faces

Syphilis is one organism read through four clinical chapters, each with its own mucocutaneous signature. The agent is a thin spiral bacterium, T. pallidum subsp. pallidum (6–20 µm long, 0.1–0.2 µm wide), that cannot be cultured on artificial media, penetrates intact mucosa or abraded skin, and disseminates in the bloodstream within hours — before the chancre even appears. Its histological calling card at every stage is obliterative endarteritis: the organism homes in on small vessels and drives an endarteritis and periarteritis that produce every lesion from chancre to gumma.[1]

The staged progression is the spine of the topic — memorise the timeline, because the questions hang off it:[1]

[1]

One-line discriminator: palms and soles → secondary; painless ulcer → primary; nothing but a positive test → latent; a gumma or tabes → tertiary.[1]

The numbers examiners reach for first:[1]

[1]

Etymology for viva gold: lues is Latin for "plague" or "pestilence" — the name 16th-century physicians gave the great pox when they could not yet name its agent, and the source of the synonym lues venerea. "The great imitator" was earned in the 19th-century syphilology clinics, where the polymorphic secondary rash mimicked every inflammatory dermatosis on the ward. Both names outlived their eras because the clinical behaviour they describe is unchanged.[1]

The painless chancre — primary syphilis

The primary chancre is a single, painless, indurated ulcer with a clean base and non-tender regional lymphadenopathy. It appears at the site of inoculation — genital, anal, or oral — after a 9 to 90 day incubation (mean 21 days), is typically 0.5 to 2 cm across, and exudes clear serum rich in treponemes. The painlessness is the feature that separates it from the painful genital ulcers (herpes, chancroid, Behçet's) — and the very reason it is missed.[1]

The chancre heals spontaneously in 3 to 6 weeks without treatment, which is the second half of the trap: the patient feels cured while the spirochaete has already disseminated. Diagnose at the lesion, not the blood, early on — dark-field microscopy of the chancre exudate shows motile spirochaetes, and PCR of a swab is more sensitive still; serology may still be negative in the first week or two.[5]

The classic trap: a painless ulcer does not hurt, so the patient does not present — and when he does, the registrar reaches for herpes antivirals because "syphilis is rare these days". A single painless, clean-based, indurated genital ulcer with rubbery non-tender inguinal nodes is a chancre until serology proves otherwise. Swab it for treponemal PCR before you treat, because the early RPR can still be negative.[1]

The great imitator on the skin — secondary syphilis

Secondary syphilis is systemic dissemination with a polymorphic rash, and its hallmark is involvement of the palms and soles. It appears 2 to 8 weeks after the chancre heals (and may overlap with it), and the rash is so variable — maculopapular, papulosquamous, annular, psoriasiform, lichenoid, pustular, even ulceronecrotic — that no other infection is misdiagnosed as widely.[1][2]

The cutaneous findings, in the order they earn marks:[1]

• Maculopapular rash (the classic sign): copper-red, "ham-coloured" macules and papules beginning on the trunk, spreading to the extremities and the palms and soles. Palmoplantar involvement is the single finding that should trigger serology.
• Condylomata lata: broad, moist, fleshy, grey-white, warty papules and plaques in warm intertriginous folds — perianal, vulval, scrotal, inguinal. Teeming with treponemes and highly infectious.[7]
• Mucous patches: painless grey-white plaques on the oral mucosa, tongue and lips — the "snail-track" ulcers of viva lore.
• Moth-eaten alopecia: patchy, non-scarring loss of scalp and beard hair, like moths have been at it; eyebrows may go too.
• Generalised lymphadenopathy: firm, rubbery, non-tender nodes.[1]

Everyone forgets the biopsy. When the rash is genuinely baffling, a punch biopsy of a secondary lesion shows a plasma-cell-rich infiltrate with obliterative endarteritis — psoriasiform epidermal hyperplasia with a band-like lymphoplasmacytic dermal infiltrate; a Warthin-Starry silver stain highlights the spirochaetes. The histology is not pathognomonic on its own, but paired with serology it closes the case.[8]

Condylomata lata versus condylomata acuminata

This is the bedside comparison examiners love, because the two look alike and the management is entirely different:[7]

[7]

One-line discriminator: broad, moist and fleshy → lata (syphilis); narrow, dry and keratotic → acuminata (HPV).[7]

Extra-genital and atypical presentations

Condylomata lata can appear at extra-genital sites — oral, axillary, interdigital, even umbilical — and the secondary rash can be purely annular, pustular, or rupioid. In HIV co-infection the picture turns aggressive: the uncommon "malignant syphilis" (lues maligna) presents as ulceronecrotic, crusted, nodular lesions with fever and myalgia, mimicking ecthyma, deep mycoses, vasculitis, or pyoderma gangrenosum.[2][7]

Latent and tertiary — when the rash is long gone

Latent syphilis is asymptomatic infection with positive serology and no clinical signs. It splits on the one-year line: early latent (under 1 year, still infectious, relapse possible) and late latent (over 1 year, non-infectious but treponemes persist). It is detected only by screening serology — another reason every antenatal, pre-operative and STI-screening panel includes a treponemal test.[1]

Tertiary syphilis arrives in roughly a third of untreated patients after 3 to 30 years, and its three faces are gummas, cardiovascular disease, and neurosyphilis:[1]

• Cutaneous gummas: noduloulcerative granulomatous nodules that ulcerate with a sticky, necrotic ("gummatous") discharge and heal with "tissue-paper" scars; they may involve mucosa, bones (saddle nose), and viscera.
• Cardiovascular syphilis: aortitis, aortic aneurysm, aortic regurgitation.
• Neurosyphilis: can occur at any stage — meningovascular (stroke, cranial nerve palsies), general paresis (dementia, Argyll Robertson pupil), tabes dorsalis (sensory ataxia, lightning pains, absent reflexes), or asymptomatic CSF abnormalities.[1]

Everyone forgets that neurosyphilis is not confined to tertiary disease. Ocular and otic syphilis (uveitis, optic neuritis, sudden sensorineural hearing loss) and asymptomatic CSF infection can occur in early syphilis and are treated with the neurosyphilis regimen, not the single intramuscular dose. Any headache, visual change, hearing loss or cranial nerve sign in a patient with positive syphilis serology is an indication for CSF examination.[1]

The painless versus painful genital ulcer

Ulcer morphology and the character of the regional nodes localise the diagnosis in a sexually active adult. The single most examinable split is painless versus painful:[1]

[1]

One-line discriminator: painless and indurated → think syphilis; painful and ragged → think chancroid; grouped vesicles → think herpes.[1]

Serology — screen, confirm, monitor for life

Two test types do all the work: non-treponemal tests screen and monitor, treponemal tests confirm and stay positive for life. Know what each measures and what each cannot tell you:[1]

[1]

The prozone — when the screen lies negative

The prozone phenomenon is a false-negative RPR or VDRL caused by antibody excess overwhelming the antigen reagent. Suspect it whenever secondary syphilis is clinically obvious — classic palmoplantar rash, condylomata lata — but the RPR is non-reactive or only weakly reactive. The fix is laboratory: ask the lab to dilute the serum (1:16 or 1:32) and repeat, and the test becomes strongly positive.[1]

The classic trap (prozone in HIV): the prozone is most common in HIV co-infection, in pregnancy, and in very high-titre secondary disease — exactly the settings where the clinical rash is most florid and the false-negative is most dangerous. A negative RPR in a patient who looks like secondary syphilis is not a negative; it is an undiluted sample. Treponemal EIA is usually already positive and clinches the diagnosis.[1]

Biological false positives — confirm before you label the patient

A biological false positive is a positive RPR or VDRL with a negative treponemal test. Always confirm with a treponemal test before telling a patient they have syphilis:[1]

[1]

Neurosyphilis and the CSF — when to do the lumbar puncture

Cerebrospinal fluid examination is required for any neurological, ophthalmic or otic symptom, for treatment failure, for HIV co-infection with RPR at least 1:32 or CD4 at or below 350 per microlitre, and for infants of seropositive mothers. The diagnostic signature is a CSF-VDRL positive (highly specific but insensitive — a negative does not exclude neurosyphilis), a lymphocytic pleocytosis over 5 white cells per microlitre, and an elevated CSF protein over 45 mg per decilitre. A negative CSF-FTA-ABS largely excludes it; a CSF-TPPA index over 70 is a useful adjunct.[1]

Treatment — penicillin by stage, verbatim

Penicillin is the drug, and the stage sets the regimen. These are the doses fellowship vivas reward, reproduced exactly:[1][3]

[1] [3]

A second-line late-latent option where benzathine is unavailable is procaine penicillin G 1.2 MU IM daily plus probenecid 500 mg oral QDS for 17–21 days. Two rules that cost marks when forgotten: tetracyclines and doxycycline are contraindicated in pregnancy and in children under 7 years (bone and tooth discoloration), and ceftriaxone does not adequately treat the fetus — so pregnancy forces penicillin, with desensitisation if need be.[1]

Follow-up — the titre must fall

Follow RPR or VDRL titres at 6 and 12 months for early syphilis, and at 6, 12 and 24 months for late syphilis; the goal is a 4-fold (two-dilution) decline. A persistent or rising titre at 12 months is serological failure — re-treat, and in HIV co-infection or with RPR at least 1:32, perform CSF examination first. Trace and treat sexual contacts within the past 90 days presumptively, even if their serology is negative (they may still be pre-seroconversion).[3]

Jarisch-Herxheimer — the reaction that is not an allergy

The Jarisch-Herxheimer reaction (JHR) is an acute, self-limiting cytokine release within 6 to 12 hours of the first effective dose of any treponemal antibiotic. It affects roughly half to nine-tenths of patients with early syphilis, is triggered by lipoprotein and endotoxin-like fragments shed from killed treponemes, and produces fever of 38–40 °C, rigors, headache, myalgia, tachycardia, hypotension and a transient flare of the rash that resolves within 12 to 24 hours.[6][9]

Management is supportive — antipyretics and fluids — and JHR is NOT a reason to stop penicillin. Pre-treat the patient with paracetamol, warn them in advance (the counselling itself prevents the 2 am phone call and inappropriate cessation), and in pregnancy monitor the fetal heart for 24 hours because JHR can precipitate fetal distress and preterm labour. In neurosyphilis the reaction can transiently worsen meningismus, so observe the first night in a monitored setting.[6][9]

What it is NOT: JHR is not an antibiotic allergy (do not stop penicillin) and not treatment failure (it peaks at 6 to 12 hours and resolves within 24). Many patients and clinicians confuse the two, and inappropriate cessation of penicillin mid-treatment is a common, preventable cause of treatment failure.[6][9]

Congenital syphilis — the Hutchinson triad and the preventable baby

Congenital syphilis is transplacental transmission, and it is almost entirely preventable with antenatal screening and maternal penicillin. T. pallidum crosses the placenta from about 9 weeks gestation; transmission risk tracks the maternal stage — roughly 70 to 100 per cent in primary or secondary disease, 40 per cent in early latent, 10 per cent in late latent — and two-thirds of affected infants are asymptomatic at birth. Universal maternal serology at the first antenatal visit (repeated at 28 weeks and at delivery in high-risk mothers) plus direct neonatal testing is how the diagnosis is made.[4]

Early congenital syphilis (onset under 2 years) is a mucocutaneous and systemic illness: a vesiculobullous or maculopapular rash on the palms, soles and periorificial skin, the snuffles (blood-tinged nasal discharge teeming with treponemes), mucous patches, hepatosplenomegaly, jaundice, anaemia and osteochondritis.[4]

Late congenital syphilis (onset over 2 years) is the residual stigmata — and the Hutchinson triad is the viva answer:[4]

[4]

Add saddle-nose deformity, mulberry molars, frontal bossing, short maxilla, high palatal arch and Clutton joints (painless knee effusions) to round out the stigmata. Recognising any combination of these in a young adult mandates re-testing the mother and the patient for active treponemal infection.[4]

Why antenatal screening matters — and where vertical-transmission programs converge

The surge in congenital syphilis is a failure of antenatal screening and treatment, not of biology. The fix is systems-level: universal maternal serology, prompt penicillin treatment of seropositive mothers, and partner notification — the same programme infrastructure that delivers the hepatitis B birth-dose vaccine and other vertical-transmission prevention in resource-limited settings. Strengthening that shared antenatal platform is how both congenital syphilis and perinatal HBV are driven down together.[12]

HIV co-infection — the high-alert dermatology scenario

Syphilis and HIV amplify each other. Syphilis ulceration roughly doubles to quintuples the per-act risk of HIV acquisition, and persons living with HIV have a markedly higher risk of acquiring syphilis at every CD4 stratum — so every new syphilis diagnosis is an HIV testing opportunity, and vice versa.[10]

In HIV co-infection the cutaneous picture is atypical and aggressive: the florid ulceronecrotic malignant syphilis (lues maligna) described above, higher RPR titres (often at least 1:32), a greater risk of early neurosyphilis and ocular syphilis, and the prozone phenomenon from antibody excess. Lower the threshold for CSF examination (RPR at least 1:32 or CD4 at or below 350 per microlitre), follow serology more closely (3, 6, 9, 12 and 24 months), and remember that a normal-looking rash in an HIV-positive patient is syphilis until serology says otherwise.[10]

Pregnancy and penicillin allergy — desensitise, do not substitute

Penicillin is the only agent proven to prevent vertical transmission of syphilis, so a pregnant patient with credible IgE-mediated penicillin allergy must be desensitised — not switched to doxycycline. Doxycycline and tetracycline cause fetal bone and tooth toxicity, and ceftriaxone does not adequately treat the fetus. After a credible history (urticaria, angio-oedema, bronchospasm or anaphylaxis within minutes to hours of a dose), either skin-test to exclude IgE sensitisation or, if positive or unavailable, desensitise before the first therapeutic dose.[11]

The Wendel oral penicillin V desensitisation ladder (4–6 hours, obstetric HDU or ICU, anaphylaxis trolley at the bedside) doubles the dose every 15 minutes from 100 units to a final 800,000 units:[11]

[11]

Once the top dose is tolerated, give the full parenteral regimen — benzathine penicillin G 2.4 million units IM (or aqueous crystalline penicillin G for neurosyphilis) — within 30 minutes, because desensitisation is transient and a missed dose over 24 hours re-establishes sensitisation. In the original Wendel cohort of 15 pregnant women (13 with syphilis) no reaction was life-threatening, and only about a third had mild cutaneous reactions that did not stop therapy. Premedication with antihistamines or steroids does not prevent IgE reactions and is no substitute for the protocol.[11]

The preventable-harm list

• A painless chancre dismissed as "just a sore" that heals spontaneously while the spirochaete disseminates — the preventable progression to secondary and tertiary disease.[1]
• A florid palmoplantar rash with a "negative RPR" that was never diluted — the prozone missed in HIV or pregnancy.[1]
• Penicillin withheld in pregnancy for a non-credible allergy, with doxycycline substituted — a congenitally infected infant.[11]
• A new headache or visual change in a seropositive patient treated with the single IM dose instead of the IV neurosyphilis regimen — undertreated neurosyphilis.[1]
• Jarisch-Herxheimer mistaken for drug allergy and penicillin stopped mid-course — preventable treatment failure.[6][9]
• A seropositive mother not rescreened in the third trimester — a late-gestation congenital infection the 28-week test would have caught.[4]

The mantra

The one line to carry to the ward and the viva: painless ulcer, palmoplantar rash — serology before you discharge.[1]

If you remember nothing else, remember that a painless genital ulcer that heals by itself and any unexplained rash on the palms and soles are syphilis until serology proves otherwise. Screen with RPR or VDRL, confirm with a treponemal test, treat early disease with benzathine penicillin G 2.4 million units IM once — and never let the patient leave the room without the bloods in the pipeline.[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the rash on the palms (answer)

A 28-year-old man has a three-week history of a copper-red maculopapular rash on his palms, soles and trunk, with grey patches on his tongue and patchy scalp hair loss. He recalls a painless penile ulcer two months ago that resolved without treatment. RPR is reported as non-reactive. What is going on, and what is the next step? Model: This is secondary syphilis — the polymorphic palmoplantar rash, snail-track mucous patches and moth-eaten alopecia following a healed chancre are pathognomonic. The negative RPR is the prozone phenomenon (antibody excess in high-titre secondary disease). Ask the laboratory to dilute the serum (1:16 or 1:32) and repeat, and run a treponemal EIA/TPPA, which will be positive. Treat with benzathine penicillin G 2.4 million units IM as a single dose, warn the patient about the Jarisch-Herxheimer reaction in the first 6–12 hours, and offer HIV testing.[1]

Stem 2 — the pregnant woman with a penicillin history (answer)

A 24-year-old woman at 18 weeks gestation has a reactive RPR at 1:64 with a positive treponemal EIA. She reports "penicillin allergy" as a child with a rash. How do you treat her? Model: This is early latent syphilis in pregnancy. Penicillin is the only agent proven to prevent vertical transmission — doxycycline is contraindicated (fetal bone and tooth toxicity) and ceftriaxone under-treats the fetus. Clarify the allergy: a vague childhood rash is not a contraindication, but if the history is credible IgE-mediated (urticaria, angio-oedema, bronchospasm), skin-test and, if positive, formally desensitise on the obstetric HDU using the Wendel oral penicillin V ladder, then give benzathine penicillin G 2.4 million units IM. Monitor the fetal heart for 24 hours for Jarisch-Herxheimer, which can precipitate fetal distress.[11]

Stem 3 — the seropositive patient with a headache (answer)

A 35-year-old man with newly diagnosed early syphilis (RPR 1:128) and HIV co-infection (CD4 280) develops headache and photophobia three days after his benzathine penicillin injection. What do you do? Model: This is possible neurosyphilis and the single IM dose was inadequate. Perform CSF examination — CSF-VDRL (specific but insensitive), cell count and differential (lymphocytic pleocytosis over 5 per microlitre), protein (over 45 mg per decilitre), and CSF-FTA-ABS or TPPA index. If neurosyphilis is confirmed, switch to aqueous crystalline penicillin G 18–24 million units per day IV (3–4 MU q4h) for 10–14 days. The threshold for CSF examination in HIV co-infection is low: RPR at least 1:32 or CD4 at or below 350 per microlitre is enough to justify the lumbar puncture.[1]

References

1. [1]Lautenschlager S. Cutaneous manifestations of syphilis : recognition and management Am J Clin Dermatol, 2006.PMID 17007540
2. [2]Balagula Y, Mattei PL, Wisco OJ, et al. The great imitator revisited: the spectrum of atypical cutaneous manifestations of secondary syphilis Int J Dermatol, 2014.PMID 25312512
3. [3]Bond SM, Blain MLM Diagnosis and Treatment of Secondary Syphilis in Women J Midwifery Womens Health, 2021.PMID 34101969
4. [4]Newton J, Silence C, Boetes J, et al. Mucocutaneous manifestations of congenital syphilis in the neonate: A review of a surging disease Pediatr Dermatol, 2023.PMID 36583308
5. [5]Junejo MH, Collery M, Whitlock G, et al. Treponema pallidum PCR testing for diagnosis of mucocutaneous ulcers suspicious for syphilis Sex Transm Infect, 2022.PMID 34785619
6. [6]Nair BR, Murugan S Jarisch-Herxheimer reaction in syphilis Indian J Sex Transm Dis AIDS, 2022.PMID 36743098
7. [7]Barei F, Murgia G, Ramoni S, et al. Secondary syphilis with extra-genital condyloma lata: A case report and review of the literature Int J STD AIDS, 2022.PMID 36113077
8. [8]Lapenda I, Tauana A, Pereira A, et al. Histologic Features of Secondary Syphilis: A Systematic Review and Meta-Analysis Am J Dermatopathol, 2026.PMID 41849752
9. [9]Marinella MA. Jarisch-Herxheimer reaction West J Med, 1996.PMID 8909178
10. [10]Wu MY, Gong HZ, Hu KR, Zheng HY, Wan X, Li J. Effect of syphilis infection on HIV acquisition: a systematic review and meta-analysis Sex Transm Infect, 2021.PMID 33219164
11. [11]Wendel GD Jr, Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin allergy and desensitization in serious infections during pregnancy N Engl J Med, 1985.PMID 3921835
12. [12]Boisson A, Goel V, Yotebieng M, et al. Implementation Approaches for Introducing and Overcoming Barriers to Hepatitis B Birth-Dose Vaccine in sub-Saharan Africa Glob Health Sci Pract, 2022.PMID 35294378