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 must be differentiated from other common diseases that cause rash such as measles, rubella, Kawasaki disease , and mononucleosis. Syphilis must also be differentiated from other genital infections such as chancroid, Condyloma acuminata, genital warts, Herpes simplex, and Herpes zoster.

Differentiating Syphilis from other Diseases

Stage of Syphilis	Differential diagnosis	Findings
Primary	Herpes simplex	Presents as multiple, round, superficial oral and genital ulcers which are painful.
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, gonnorhea, 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. Presenting findings may include fever, rash, and constitutional symptoms.
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.
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.
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 seizures	Neurosyphilitic disease can present with seizures.
Other causes of stroke	Presents as weakness, sensory loss, gait abnormality and cranial nerve damage.
Other causes of meningitis]	Such as bacterial, fungal and viral meningitis. It commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.
Meningococcemia	Rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Psychosis	Presents as hallucinations, delusions, auditory hallucinations, and flat or blunted affect and emotion, poverty of speech (alogia), anhedonia, and lack of motivation.
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 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 stiffnes.
Other causes of lymphadenitis	May present as fever, myalgias, 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.

Syphilis is a curable sexually transmitted disease caused by the Treponema pallidum spirochete. The route of transmission of syphilis is almost always by sexual contact, although there are examples of congenital syphilis via transmission from mother to child in utero. In fact, the disease was dubbed the "Great Imitator" because it was often confused with other diseases, particularly in its tertiary stage. Hence, patients with tertiary syphilis should also be tested for other sexually transmitted diseases such as chlamydia, gonorrhea, trichomoniasis, bacterial vaginosis and HIV infection. Different rash-like conditions may be misdiagnosed with syphilis, including:

• Insect bites - In an insect bite, the insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.

• 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.

• Measles - commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.

• Monkeypox - presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.

• Rubella - commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.

• Atypical measles - symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.

• Coxsackievirus - the most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.

• Acne - typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"

• Molluscum contagiosum - lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.

• 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.

• Toxic erythema - common rash in infants, with clustered and vesicular appearance.

• Rat-bite fever - commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.

• Parvovirus B19 - the rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.

• Cytomegalovirus - common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.

• Scarlet fever - commonly includes 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.

• Rocky Mountain spotted fever - symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.

• 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. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.

• Varicella-zoster virus - commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.

• Chickenpox - commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.

• Meningococcemia - commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.

• Rickettsialpox - first symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.

• Meningitis - commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.

• Impetigo - commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.

• Candidiasis - Symptoms of candidiasis vary depending on the area affected. Most candidial infections result in minimal complications such as redness, itching and discomfort, though complications may be severe or even fatal if left untreated in certain populations. In immunocompetent persons, candidiasis is usually a very localized infection of the skin or mucosal membranes, including the oral cavity (thrush), the pharynx or esophagus, the gastrointestinal tract, the urinary bladder, the fingernails or toenails (onychomycosis), and the genitalia (vagina, penis).

• Chancroid - sexually transmitted infection characterized by painful sores on the genitalia. Chancroid is known to be spread from one to another individual through sexual contact.

• Condyloma acuminata - often occur in clusters and can be very tiny or can spread into large masses in the genital or penis area. In women they occur on the outside and inside of the vagina on the opening (cervix) of the uterus, or around the anus. They are approximately as prevalent in men, but the symptoms may be less obvious. When present, they usually are seen on the tip of the penis. They also may be found on the shaft of the penis, on the scrotum or around the anus. Rarely, genital warts also can develop in the mouth or throat of a person who has had oral sex with an infected person.

• Drug eruptions - cutaneous drug eruptions are the most frequent type of adverse drug reactions and the overwhelming majority of these reactions are thought to be allergic in origin. Common eruptions include: morbilliform rash, urticaria, erythema multiforme and toxic epidermal necrolysis.

• Genital warts - often occur in clusters and can be very tiny or can spread into large masses in the genital or penis area. In women they occur on the outside and inside of the vagina on the opening (cervix) of the uterus, or around the anus. They are approximately as prevalent in men, but the symptoms may be less obvious. When present, they usually are seen on the tip of the penis. They also may be found on the shaft of the penis, on the scrotum or around the anus. Rarely, genital warts also can develop in the mouth or throat of a person who has had oral sex with an infected person.

• Granuloma inguinale - clinically, the disease is commonly characterized as painless, progressive ulcerative lesions without regional lymphadenopathy. The lesions are highly vascular and bleed easily on contact. However, the clinical presentation also can include hypertrophic, necrotic, or sclerotic variants.

• Herpes simplex - Primary orofacial herpes / Herpes simplex type 1 presents itself as multiple, round, superficial oral ulcers 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.. They present with blisters and ulcers in genital area that are similar to orofacial herpes. Herpes infection can recur even after successful initial treatment. The first episode is usually longer (two to four weeks) more painful and severe than the subsequent/recurrent episodes.

• Herpes zoster - or shingles usually starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7–10 days and clears up within 2–4 weeks. Before the rash develops, there is often pain, itching, or tingling in the area where the rash will develop. This may happen anywhere from 1 to 5 days before the rash appears. The pain may be extreme in the affected nerve, where the rash will later develop, and can be characterized as stinging, tingling, aching, numbing, or throbbing, and can be pronounced with quick stabs of intensity. During this phase, herpes zoster is frequently misdiagnosed as other diseases with similar symptoms, including heart attacks and renal colic. Most commonly, the rash occurs in a single stripe around either the left or the right side of the body. In other cases, the rash occurs on one side of the face. In rare cases (usually among people with weakened immune systems), the rash may be more widespread and look similar to a chickenpox rash. Shingles can affect the eye and cause loss of vision.

• Lymphogranuloma venereum - The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis, including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus

• Urethritis - Discharge (milky or pus-like) from the penis, stinging or burning during urination, itching, tingling, burning or irritation inside the penis.

• Yaws - tropical infection of the skin, bones and joints caused by the spirochete bacterium Treponema pertenue. Other treponematosis diseases are bejel (Treponema endemicum), pinta (Treponema carateum), syphilis (Treponema pallidum), and Lyme Disease (Borrelia burgdorferi).

Diseases caused by other species of Treponema

These diseases are caused by other species or subspecies of Treponema:

• Yaws is a tropical disease characterized by an infection of the skin, bones and joints; it is caused by a spirochete bacterium, Treponema pallidum, sp. pertenue, also called Treponema pertenue
• Pinta - caused by Treponema carateum
• Bejel - caused by Treponema endemicum

References

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