MPOX is an orthopoxvirus whose infection has been declared a Public Health Emergency of International Concern in 2022 and 2024. It proved to be a virus with markedly heterogeneous and varied clinical presentation. We performed a systematic PubMed review of articles reporting cases of different clinical manifestations of MPOX until October 2024. The infection has mainly affected men who have sex with men. After 4 to 10 days of incubation, it presents with mucocutaneus lesions and systemic symptoms. Some anatomical sites have shown clinical particularities. Genital edema is a potentially serious complication. The ocular and ear/nose/throat area are other infrequent sites with specific manifestations. MPOX whitlow affects the third finger of the dominant hand and may be associated with extensive inflammation and proximal lymphangitis. Bacterial superinfection is a common complication in the genital area with good response to antibiotic treatment. Immunosuppressed patients may develop severe inflammation and necrosis resulting in poor prognosis. Some authors propose ulceronecrotic MPOX as a defining condition of AIDS. The involvement of women has been exceptional in the current outbreak and has predominantly affected the vulva. Some patients such as healthcare workers, atopics, and people who get tattoos are at risk of developing specific lesions via nonsexual routes. Other atypical manifestations include maculopapular rash and inguinal patch. MPOX is a highly relevant and ongoing infection that can present with multiple atypical manifestations, and the knowledge of which is of great importance to the clinician. We present a unique systematic review of atypical presentations of this infection that may be associated with significant morbidity and mortality, especially in the immunocompromised population.
