Syphilis differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Aysha Anwar, M.B.B.S[3]

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Overview

Syphilis is named as the "Great Imitator" because the symptomatology and physical exam findings of syphilis in different stages mimicks large variety of other diseases. Syphilis must be differentiated from other common diseases that cause rash such as measles, rubella, Kawasaki disease , and mononucleosis. Syphilis also has overlapping symptoms with the other genital infections such as chancroid, condyloma acuminata, genital warts, herpes simplex, and herpes zoster.

Differentiating Syphilis from other Diseases

Syphilis is named as a "great imitator" because symptomatology and physical exam findings of syphilis in different stages mimicks large variety of other diseases.

Stage of Syphilis	Differential diagnosis	Findings
Primary	Herpes simplex(1,2)	Presents as multiple, round, superficial oral and genital ulcers which are painful. Adults with non-typical presentation are more difficult to diagnose. However, prodromal symptoms that occur before the appearance of herpetic lesions helps to differentiate HSV from other conditions with similar symptoms like allergic stomatitis. Genital herpes can be more difficult to diagnose than oral herpes since most genital herpes/HSV-2-infected persons have no classical signs and symptoms.
Granuloma inguinale	Commonly characterized as painless, progressive ulcerative lesions without regional lymphadenopathy. The lesions are highly vascular and bleed easily on contact.
Chancroid	Characterized by painful sores on the genitalia.
Lymphogranuloma venereum	Self-limited genital ulcer or papule with tender inguinal or femoral lymphadenopathy.
Condyloma acuminatum	Presents as warty lesions in the form of clusters and can be very tiny or can spread into large masses in the genital or penile area.
Urethritis	Discharge (milky or pus-like) from the penis, stinging or burning during urination, itching, tingling, burning or irritation inside the penis.
Cystitis	Presents as abnormal urine color (cloudy), blood in the urine, frequent urination or urgent need to urinate, painful or burning urination, pressure in the lower pelvis or back, flank pain, back pain, nausea, vomiting, and chills
Candidiasis	Presents as redness, itching and discomfort of affected area.
Other STIs	Such as Chlamydia, Gonorrhea, and Trichomonas vaginalis
Secondary	HIV	Acute illness present with fever, lymphadenopathy, rash, fatigue, and myalgia. AIDS classically presents with weight loss, night sweats, fatigue, diarrhea, mucosal sores, cough, and cognitive and neurological deficits.
Pityriasis rosea	Pink and flaky oval-shaped rash followed by clusters of smaller, more numerous patches of rash. May be accompanied by headache, fever, nausea and fatigue.
Viral exanthem	Such as measles, mumps, chicken pox, cytomegalovirus, coxsackie virus, rubella. Findings may include fever, rash, and constitutional symptoms.
Scarlet fever	Presenting symptoms include fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy.
Insect bite	Immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.
Mononucleosis	Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.
Rocky mountain spotted fever	Symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Rickettsialpox	Overlapping symptoms with secondary syphilis may include flu-like illness including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area
Yaws	Tropical infection of the skin, bones and joints caused by the spirochete bacterium Treponema pertenue
Stevens-Johnson syndrome	Symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions.
Tertiary	Brain tumour	Findings which may overlap with neurosyphilis include headache,seizures, visual changes and personality changes.
Other causes of seizures	Neurosyphilitic disease can present with seizures and must be differentiated from other causes of seizures.
Other causes of stroke	Presents as weakness, sensory loss, gait abnormality and cranial nerve damage.
Meningococcemia	Rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Multiple sclerosis	May presents as changes in sensation (hypoesthesia), muscle weakness, abnormal muscle spasms, or difficulty in moving, difficulties with coordination and balance (ataxia), problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis, or diplopia), fatigue and acute or chronic pain syndromes, bladder and bowel difficulties, cognitive impairment, or emotional symptomatology (mainly depression).
Other causes of meningitis]	Such as bacterial, fungal and viral meningitis. It commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.
Psychosis	Presents as hallucinations, delusions, auditory hallucinations, and flat or blunted affect and emotion, poverty of speech (alogia), anhedonia, and lack of motivation.
Vasculitides	Cardiovasular syphilis may present as aortitis and aortic aneurysm. Overlapping symptoms with other vasculitis may include back pain, fever, abdominal pain, chest pain, shortness of breath, fatigue, arm and leg weakness, lightheadedness, dizziness, fainting, and headaches.
Other causes of congestive heart failure	Presenting symptoms include dizziness, dyspnea on ordinary exertion or greater shortness of breath with usual activities, fainting, fatigue, hemoptysis or frothy sputum, nocturia or urination during the night, nocturnal cough, orthopnea or sleeping on pillows, palpitations or extra heart beats, paroxysmal nocturnal dyspnea or awakening at night with shortness of breath, shortness of breath, syncope or passing out and weakness.
Other causes of glomerulonephritis	May presents as blood in the urine (dark, rust-colored, or brown urine), foamy urine (due to excess protein in the urine), swelling (edema) of the face, eyes, ankles, feet, legs, or abdomen.
Other causes of arthritis	Gummatous lesions of syphilis in joints may present as joint pains and stiffness.
Other causes of lymphadenitis	May present as fever, myalgia, weight loss, and lymph node enlargement.
Other causes of hepatitis	Common presenting symptoms may include dark urine, fatigue, weight loss, fever usually low-grade, itching, jaundice (yellowing of the skin or eyes), loss of appetite, nausea and vomiting.
Other causes of nephrotic syndrome	Presents as proteinuria, edema, weight gain, fatigue and dyspnea.
Other causes of uveitis	Symptoms of uveitis include eye pain, eye redness, and photophobia. Intermediate, posterior, and panuveitis commonly present with floaters, blurry vision, and impaired vision.

Differentiating secondary syphilis from other diseases

• Secondary siphilis should be differentiated from other diseases causing erythamosquamous rash. the differentials include the following:

Disease	Rash Characteristics	Signs and Symptoms	Associated Conditions	Images
Cutaneous T cell lymphoma/Mycosis fungoides	Premycotic phase: A scaly, red rash in areas of the body that usually are not exposed to the sun. This rash does not cause symptoms and may last for months or years. Patch phase: Thin, erythematous, eczema-like rash. Plaque phase: Small raised bumps (papules) or hardened lesions on the skin, which may be erythematous. Tumor phase: Tumors form on the skin. Infection secondary to ulcers.	Epidermal atrophy or poikiloderma Generalized itching (pruritus) Pain in the affected area of the skin Insomnia Red (erythematous) patches scattered over the skin of the trunk and the extremities Tumor-like lobulated outgrowths form on the skin in the latter phase of the disease Weight loss Lymphadenopathy Malaise and fatigue Anemia May progress to Sezary syndrome (skin involvement plus hematogenous dissemination)	Sezary syndrome
Pityriasis rosea	Pink or salmon in color, which may be scaly; referred to as "herald patch" Oval shape Long axis oriented along the cleavage lines Distributed on the trunk and proximal extremities Squamous marginal collarette and a “fir-tree” or “Christmas tree” distribution on posterior trunk Secondary to viral infections Resolves spontaneously after 6-8 weeks	Preceded by a prodrome of: Sore throat Gastrointestinal disturbance Fever Arthralgia	Infection by any of the following: HHV-6 HHV-7 HHV-8
Pityriasis lichenoides chronica	Recurrent lesions are usually less evenly scattered than in cases of psoriasis Brownish red or orange-brown in color Lesions are capped by a single detachable, opaque, mica-like scale Often leave hypopigmented macules	High fever Malaise Myalgias Paraesthesia Pruritus	Infection by any of the following: Epstein-Barr virus (EBV) Toxoplasma gondii Human immunodeficiency virus (HIV)
Nummular dermatitis	Multiple coin-shaped eczematous lesions Commonly affecting the extremities (lower>upper) and trunk May ooze fluid and become dry and crusty	Often appears after a skin injury, such as a burn, abrasion (from friction), or insect bite Lesions commonly relapse after occasional remission or may persist for long periods Pruritus	Associated with: Dry skin Emotional stress Allergens (rubber chemicals, formaldehyde, neomycin, chrome, mercury, and nickel) Staphylococcus infection Seasonal variation Alcohol Drugs Atopy
Secondary syphilis	Round, coppery, red colored lesions on palms and soles Papules with collarette of scales	Fever Generalized lymphadenopathy Sore throat Patchy hair loss Headache Weight loss Myalgia Fatigue	Associated with: Condylomata lata Corona verinata Positive VDRL test
Bowen’s disease	Erythematous, small, scaly plaque, which enlarges erratically over time Scale is usually yellow or white and it is easily detachable without any bleeding Well-defined margins	Pruritus Pain Bleeding lesions	Associated with: Erythroplasia of Queyrat (Bowen's disease of the penis) Squamous cell carcinoma Solar radiation and ultraviolet (UV) exposure Radiotherapy Immunosuppression Arsenic exposure Human papilloma virus (HPV) type 16 Merkel cell polyomavirus Sjögren’s syndrome
Exanthematous pustulosis	Numerous small, primarily non-follicular, sterile pustules, arising within large areas of edematous erythema	Fever Leukocytosis Intracorneal, subcorneal, and/or intraepidermal pustules with papillary dermal edema containing neutrophils and eosinophils	Associated with: Antibiotics (penicillins, sulfonamides, tetracyclines) Carbamazepine Calcium channel blockers (Diltiazem) Hydroxychloroquine
Hypertrophic lichen planus	Classically involves shin and ankles and is characterized by hyperkeratotic plaques and nodules covered by a scale Lesions may transform into hyperkeratotic thickened, elevated, purplish or reddish plaques and nodules	Chronic pruritus Scaling May be asymptomatic	Associated with Hepatitis C virus infection
Sneddon–Wilkinson disease	Flaccid pustules that are often generalized and have a tendency to involve the flexural areas Annular configuration	Pruritus May be asymptomatic	Associated with: Monoclonal gammopathy, usually an IgA paraproteinemia Crohn's disease Osteomyelitis Adalimumab
Small plaque parapsoriasis	Erythematous plaques with fine scaly surface May present with elongated, finger-like patches Symmetrical distribution on the flanks Known as digitate dermatosis	Lesions may be asymptomatic May be mildly pruritic May fade or disappear after sun exposure during the summer season, but typically recur during the winter	May progress to mycosis fungoides
Intertrigo	Red and fleshy looking lesion in skin folds Itching Oozing May be sore	Pruritus Musty odor	Associated with: Infections (Fungal, bacterial, viral) Allergies Diabetes Obesity
Langerhans cell histiocytosis	Scaling and crusting of scalp	Pathological fractures Visceromegaly (hepatomegaly, spleenomegaly) Chronic cough Dyspnea Lymphadenopathy	Associated with: Diabetes insipidus Pancytopenia
Tinea manuum/pedum/capitis	Scaling, flaking, and sometimes blistering of the affected areas Hair loss with a black dot on scalp in case of tinea capitis	Pruritus KOH preparation of the lesions confirms fungal infection	Associated with: Diabetes Immunosupression Intimate contact with infected person May lead to asthma exacerbation
Seborrheic dermatitis	Papulosquamous, scaly, flaky, itchy, and red rash found particularly at sebaceous gland-rich areas of the body	Pruritus	Associated with: AIDS Stress Fungal infection Fatigue Sleep deprivation Change of season Parkinson's disease Biotin deficiency

Syphilitic oral lesions must be differentiated from other mouth lesions such as oral candidiasis and aphthous ulcer

Disease	Presentation	Risk Factors	Diagnosis	Affected Organ Systems	Important features	Picture
Diseases predominantly affecting the oral cavity
Oral Candidiasis	Dysphagia or odynophagia White patches on the mouth and tongue	Newborn babies Denture users Poorly controlled diabetes As a side effect of medication, most commonly having taken antibiotics. Inhaled corticosteroids for the treatment of lung conditions (e.g, asthma or COPD) may also result in oral candidiasis which may be reduced by regularly rinsing the mouth with water after taking the medication. People with poor nutrition, specifically vitamin A, iron and folate deficiencies. People with an immune deficiency (e.g. as a result of AIDS/HIV or chemotherapy treatment). Women undergoing hormonal changes, like pregnancy or those on birth control pills. Organ transplantation patients	Clinical diagnosis Confirmatory tests rarely needed	Localized candidiasis Oral and esophageal candidasis Candida vulvovaginitis Chronic mucocutaneous candidiasis Invasive candidasis Candidaemia Candida endocarditis Candida osteoarticular disease	Oral candidiaisis is a benign self limiting disease unless accompanied by immunosuppression.	Tongue infected with oral candidiasis - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=11717223.jpg
Herpes simplex oral lesions	Fever Sore throat Painful ulcers	Stress Recent URTI Female sex	Physical examination Viral culture Tzanck smear	Orofacial Infection Anogenital Infection Ocular Infection Herpes Encephalitis Neonatal Herpes Herpetic Whitlow Herpes Gladiatorum	The symptoms of primary HSV infection generally resolve within two weeks	Oral herpes simplex infection - By James Heilman, MD - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=19051042.jpg
Aphthous ulcers	Painful, red spot or bump that develops into an open ulcer	Being a female Between the ages of 10-40 Family history of aphthous ulcers	Physical examination Diagnosis of exclusion	Oral cavity	Self-limiting , Pain decreases in 7 to 10 days, with complete healing in 1 to 3 weeks	By Ebarruda - Own work, CC BY-SA 3.0, httpscommons.wikimedia.orgwindex.phpcurid=7903358
Squamous cell carcinoma	Non healing ulcer, nodule, indurated plaque or mass May involve skin, lips, inside the mouth, throat or esophagus	Chronic sun or UV exposure Fair skin Elderly age (>45 yrs) Male sex Smoking	Physical exam Biopsy	Oral Cavity Floor of mouth Lateral tongue Throat Esophagus	Malignant Can spread to TMJ Some times associated with leukoplakia
Leukoplakia	White leathery spots on the mucous membranes of the tongue and inside of the mouth Lateral borders of tongue	Atypical Tobacco use Chronic irritation Immunodeficiency Bloodroot (sanguinaria)	Physical exam Diagnosis of exclusion Biopsy	Vulvar lesions occur independent of oral lesions	Associated with HIV Persistant white spots Benign but can progress to carcinoma after almost 10 years Oral proliferative verrucous leukoplakia is an aggressive sub type with multiple lesions and higher conversion to warts or carcinoma
Melanoma	A lesion with ABCD Asymmetry Border irregularity Color variation Diameter changes Bleeding from the lesion	UV radiations Genetic predisposition Old age Male gender Family or personal history of melanoma Multiple benign or atypical nevi	ABCD characteristics Bleeding or ulceration may show malignancy Serum LDH may be elevated in case of malignancy Biopsy	Can metastasize All UV radiation or sun exposed areas can be effected independently 1-2 to hundreds of granules	Neural crest cell derivative Development begins with disruption of nevus growth control Progression involves MAPK/ERK pathway N-RAS or BRAF oncogene also involved
Fordyce spots	Rice-like granules or spots Small, painless, raised, pale, red or white 1 to 3 mm in diameter	Greasy skin types Some rheumatic disorders Hereditary nonpolyposis colorectal cancer Lower gingiva (gums) Vestibular mucosa	Physical exam Small keratin-filled pseudocysts May be seen on incidental mucosal biopsy Biopsy not done for them primarily	Oral cavity Vermilion border of the lips Oral mucosa of the upper lip Buccal mucosa in the commissural region often bilaterally Genitals	Benign neoplasms with sebaceous features Visible sebaceous glands No surrounding mucosal change Several adjacent glands may coalesce into a larger cauliflower-like cluster
Burning mouth syndrome	Burning or tingling on the lips, tongue, or entire mouth	Nutritional deficiencies Chronic anxiety or depression Diabetes type 2 Menopause Oral thrush or dry mouth, or damaged nerves transmitting taste Female gender Menopause	Presentation Physical exam	Oral cavity	Pain typically is low in the morning and builds up over the day Low dosages of benzodiazepines, tricyclic antidepressants or anticonvulsants may be effective
Torus palatinus	Bony growth on midline of the hard palate Nodular mass covered with normal mucosa	Genetic predisposition Autosomal dominant	Physical exam Types Flat tori Spindle tori Nodular tori Lobular tori	Hard palate	More common in Asian and Inuit populations Twice more common in females Repeated trauma can cause bleeding Surgery may be required in symptomatic
Diseases involving oral cavity and other organ systems
Behcet's disease	Painful mouth sores Acne like skin lesions Headache, fever, poor balance, disorientation Abdominal pain, diarrhea or bleeding Uveitis Joint swelling and joint pain Genital sores wit pain and scaring Aneurysms	Over active immune system	Physical examination	Mouth Genitals GIT Eye Joints Skin Vascular system Brain	Outbreaks of exaggerated inflammation Affects smaller blood vessels
Crohn's disease	Chronic, episodic diarrhea or constipation Abdominal pain Vomiting Weight loss or weight gain	Smoking Whites and European Jews Hormonal contraception Diets high in microparticles, sweet, fatty or refined foods Industrialized country	Typical history and symptoms Skip lesions on biopsy Anti-Saccharomyces cerevisiae antibodies (ASCA) Anti-neutrophil cytoplasmic antibodies (ANCA)	Eyes Joints Skin	May lead to Obstructions Abscesses Free perforation Hemorrhage
Agranulocytosis	Fever or chills Frequent infections Unusual redness, pain, or swelling around a wound Mouth ulcers Abdominal pain Burning sensation when urinating Sore throat	Medications Cytotoxic chemotherapy Hematologic malignancies Autoimmune disorders	Neutropenia <100 cells per micro litre Eosinopenia Basopenia	Oral cavity Skin GIT Urinary system Conjunctiva	Immunocompromization Types Drug-induced Malignant Autoimmune
Syphilis	Chancre Regional lymphadenopathy	Multiple sexual partners Illicit drug use Unprotected sex Men who have sex with men Residence in highly prevalent areas HIV infection Presence of other STIs Previous history of STIs Intravenous drug use	Darkfield microscopy Non treponemal tests like VDRL and RPR test) Treponemal testsFTA-ABS tests, (TP-PA) assay, enzyme immunoassays, and chemiluminescence immunoassays)	Oral cavity Penis Cervix Labia Anal canal Rectum CNS CVS	Primary syphilis Chancre Secondary syphilis Condylomata lata Latent syphilis Asymptomatic Tertiary syphilis Gummas Neurosyphilis
Coxsackie virus	Fever Sores in the mouth Rash with blisters Aches	Pregnancy immunodeficiency	History and Physical exam Throat swabs Swabs from the lesion Tzanck test	Oral cavity Skin	Symptomatic treatment
Chicken pox	Conjunctival symptoms Catarrhal symptoms Characteristic spots on the trunk appearing in two or three waves Itching	Pregnancy Premature infants born to susceptible mothers All infants born at less than 28 weeks gestation or who weigh =1000 grams Immunocompromised	History and physical exam PCR to detect VZV in skin lesions (vesicles, scabs, maculopapular lesions)	Oral cavity Skin	Sodium bicarbonate in baths or antihistamines for itching Paracetamol (acetaminophen) for fever Prednisolone is contraindicated
Measles	Fever Rash Cough Coryza (runny nose) Conjunctivitis (pink eye) Malaise Koplick spots in mouth	Unvaccinated individuals Crowded and/or unsanitary conditions Traveling to less developed and developing countries Immunocompromized Winter and spring seasons Born after 1956 and never fully vaccinated Health care workers	History and examination PCR for Measles-specific IgM antibody PCR for Measles RNA	Oral cavity Skin Respiratory tract Eyes Throat	Caused by Morbillivirus Primary site of infection is the respiratory epithelium of the nasopharynx Transmitted in respiratory secretions, via aerosol droplets containing virus particles