Last reviewed: 29 Oct 2021
Last updated: 29 Jul 2021



History and exam

Key diagnostic factors

  • presence of risk factors
  • anogenital ulcer
  • lymphadenopathy
  • diffuse rash
  • constitutional symptoms
  • fatigue
  • rhinitis (congenital syphilis)
  • hepatosplenomegaly (congenital syphilis)
  • patchy alopecia
  • condylomata lata
  • memory impairment, altered mood, confusion, or dementia
  • visual changes
  • Argyll-Robertson pupils
  • loss of sense of vibration, proprioception, and position sense
  • ataxia
  • loss of anal and bladder sphincter control
  • positive Romberg's sign
  • diastolic murmur
  • rubbery lesions/nodules with a necrotic centre
  • miscarriage, stillbirth, or neonatal death (congenital syphilis)
  • premature labour and intrauterine growth retardation (congenital syphilis)
  • neonatal skin rash (congenital syphilis)
  • tibial bowing (congenital syphilis)
  • craniofacial malformation (congenital syphilis)
  • tooth abnormalities (congenital syphilis)
  • necrotising funisitis (congenital syphilis)

Other diagnostic factors

  • mouth ulcer
  • asymptomatic with positive serology (latent syphilis)
  • tremor
  • headache
  • meningismus
  • eye pain
  • hearing loss
  • seizures
  • peripheral oedema
  • jaundice
  • peripheral neuropathy
  • areflexia
  • angina
  • dyspnoea
  • organomegaly
  • skin or visceral organ perforation or collapse of structure
  • neonatal neurological abnormalities (congenital syphilis)

Risk factors

  • sexual contact with an infected person
  • men who have sex with men (MSM)
  • illicit drug use
  • commercial sex workers
  • multiple sexual partners
  • people with HIV or other STIs
  • syphilis during pregnancy (risk for congenital syphilis)

Diagnostic investigations

1st investigations to order

  • dark-field microscopy of swab from lesion
  • serum treponemal enzyme immunoassay (EIA)
  • serum Treponema pallidum particle agglutination (TPPA)
  • serum Treponema pallidum haemagglutination (TPHA)
  • serum fluorescent treponemal antibody absorption (FTA-ABS) test
  • immunocapture assay
  • line immunoassay (LIA) serological test
  • serum rapid plasma reagin (RPR) test
  • serum Venereal Disease Research Laboratory (VDRL) test

Investigations to consider

  • lumbar puncture, cerebrospinal fluid (CSF) analysis
  • chest x-ray
  • echocardiogram
  • computed tomography brain
  • magnetic resonance imaging brain
  • HIV test
  • fetal ultrasound scan
  • full blood count
  • cranial ultrasound
  • long-bone x-rays
  • liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and bilirubin
  • evoked auditory potentials
  • audiometry

Emerging tests

  • Treponema pallidum polymerase chain reaction (PCR) (sample taken directly from ulcerative lesions)
  • point of care (POC) testing with either treponemal or combination treponemal/non-treponemal antibody

Treatment algorithm



Juan C. Salazar, MD, MPH, FAAP

Professor and Chair

Department of Pediatrics

University of Connecticut School of Medicine




JCS is the author of references cited in this topic.

Jairo M. Montezuma-Rusca, MD, MPH

Assistant Professor of Medicine

Assistant Professor of Pediatrics

Department of Medicine

University of Connecticut School of Medicine




JMM-R declares that he has no competing interests.

Adriana R. Cruz, MD

Research Associate





AC declares that she has no conflicting interests.


Dr Juan C. Salazar, Dr Jairo M. Montezuma-Rusca, and Dr Adriana Cruz would like to gratefully acknowledge Nicholas Bennett, Patrick French and Nooshin Barmania, previous contributors to this topic.


PF is an author of a reference cited in this topic. NB and NB declare that they have no competing interests.

Peer reviewers

Robert A. Larsen, MD

Associate Professor of Medicine

University of Southern California

Keck School of Medicine

Los Angeles



RAL declares that he has no competing interests.

William Rodriguez, MD

Assistant Professor of Medicine

Harvard Medical School

Director of Research

Global Health Delivery Project

Harvard School of Public Health




WR declares that he has no competing interests.

Jennifer Handforth, MB ChB, MRCPCH, DTM&H

Consultant Paediatrician

Croydon University Hospital




JH declares that she has no competing interests.

Use of this content is subject to our disclaimer