What is the most likely explanation for a rash involving palms and soles in a three-week old infant?

A rash that involves the palms and soles in a three-week old infant is most commonly associated with congenital syphilis. This condition can present in neonates with various signs, including a rash that frequently appears on the trunk, face, palms, and soles. The rash may resemble a generalized inflammatory skin reaction known as "mucous membrane lesions," often described as "copper-colored" or "scaly."

In congenital syphilis, other systemic manifestations can also occur, such as nasal discharge, bone abnormalities, and hematological issues like thrombocytopenia or anemia. Immediate recognition and treatment are essential to prevent long-term complications associated with untreated congenital syphilis.

While other congenital infections may cause rashes in infants, the triad of syphilis-related skin manifestations—with the particularly notable involvement of the palms and soles—makes congenital syphilis the most plausible diagnosis in this case. Congenital rubella may involve a rash, but it typically does not localize specifically to the palms and soles. Similarly, congenital toxoplasmosis and cytomegalovirus infection present with different clinical features and do not classically produce a rash involving these areas in newborns.