Syphilis is caused by the infection of syphilis spirochetes, and the course of the disease is divided into four stages: the first stage, the second stage, the latent stage and the third stage. Among them, the second stage is the most infectious stage. Syphilis is also known as the “great imitator” because it often has a variety of skin and body atypical manifestations. Since it is difficult to diagnose syphilis clinically from its appearance alone, laboratory testing is required to confirm the diagnosis. If neurosyphilis is suspected, a lumbar puncture of the cerebrospinal fluid is feasible. The most common form of syphilis is a hard, non-painful, non-itchy, well-defined, rubbery skin ulcer (hard chancre), which often develops 21 days after infection. If the ulcers are secondary to bacterial infection, the lesions may be painful. In addition, some cases may present with enlarged proximal lymph nodes. Figure: Presentation of a stage I syphilis hard chancre. (Photo credit: CDC/Drs Gavin Hart and NJ Fiumara) Stage II syphilis results from the multiplication and spread of the syphilis spirochete to the skin and other tissues. This stage most commonly presents as a generalized, desquamative papular rash about 1 cm in size that can be pink, reddish-brown, or dark purple in color. Although the rash does not usually cause pruritus, the presence of pruritus does not exclude a diagnosis of syphilis. Other common clinical manifestations include patchy hair loss, fever, generalized weakness, pharyngitis, and ocular symptoms. The lesions on the palms of the hands and feet may assist in the differential diagnosis of stage II syphilis and other scaly papulopustular disorders such as psoriasis, pityriasis rosea, nodular disease, and lichen planus. Lichen planus, a manifestation of stage II syphilis, is a painless, white or gray lesion that appears on the genital area and may be easily confused with condyloma acuminata. Stage II syphilis lesions are highly contagious. Figure: Reddish-brown, scaly “coin-like” papular lesions on the palm of the hand. (Photo credit: CDC/Susan Lindsley) A patient with stage II syphilis presents with generalized lymphadenopathy accompanied by plaque lesions on the tongue mucosa. (Image credit: CDC/Susan Lindsley) Latent syphilis refers to patients with no clinical manifestations of syphilis (early latency is defined as infection within 1 year and late latency is defined as infection beyond 1 year, which is the US diagnostic criteria). This stage of infection can last for several years in untreated patients. Stage III syphilis, or late syphilis stage, involves the virus in the skin or internal organs. Of these, the respiratory tract, gastrointestinal tract, and bones are the most common sites of involvement. Syphilis tumors may be solitary or multiple. The characteristic symptoms/signs of this stage may be fever, jaundice, anemia, and nocturnal bone pain. Figure: Testicular syphilitic dendritic swelling. (Photo credit: CDC/Susan Lindsley, USA and Brian Hill, New Zealand) Neurosyphilis refers to syphilis spirochete infection of the central nervous system. Syphilis spirochetes are detectable in the CNS in 40% of people with early syphilis infection. Neurosyphilis may be asymptomatic in the early stages or present as syphilitic meningitis (acute or subacute aseptic attacks) and in the later stages as meningoencephalic syphilis, generalized local palsy, or spinal consumption with poor balance and flashing pain in the lower extremities. Syphilitic meningitis is more common in early syphilis; meningeal cerebrovascular syphilis can cause occlusive endarteritis and perivasculitis; spinal consumption causes demyelination of the posterior spinal cord bundle, resulting in ataxia and loss of pain, proprioception, and deep tendon reflexes, leading to broad-bottomed gait and instability; optic atrophy can occur in 20% of patients; and extensive atrophy of the affected side. Congenital syphilis can be asymptomatic, but if left untreated, it can lead to a variety of complications and even death. The cut-off point between early and late congenital syphilis is 2 years of age. In advanced stages, keratoconjunctivitis causes interstitial keratitis, leading to diffuse interstitial clouding and blindness. Other congenital syphilis complications include deafness, paroxysmal cold hemoglobinuria, mulberry molars, Hutchinson’s teeth, hemorrhagic rhinitis, hepatosplenomegaly, glomerulonephritis, and edema. Diagram showing advanced interstitial keratitis in congenital syphilis resulting in diffuse interstitial clouding and blindness. (Image credit: US CDC/Susan Lindsley)