• Prodrome: Fever, malaise, fatigue, and myalgia; may cause respiratory and/or gastrointestinal symptoms, such as cough, vomiting, and diarrhea; many children are asymptomatic; often there is no prodrome or systemic symptoms; may be very mild and often missed before the exanthem blossoms.
  
• Skin: Generalized, blanchable, pink to red erythematous macules and papules; less often vesicular, pustular, or petechial variants.

• Prodrome: Fever and headaches with coryza, pruritus (15%-30%); may see onset of blood dyscrasia, such as reticulocytopenia, anemia, leukopenia, and/or thrombocytopenia.
  
• Skin: ~1 week after prodrome, bright pink to red malar patches with circumoral pallor on cheeks; a few days later maculopapular, lacy dermatitis develops on arms and legs spreading to trunk, less on adults or adolescents (or absent); rash may wax and wane for 1 to 4 weeks, may worsen with intense physical activity, hot showers, and sun exposure.
  
• Musculoskeletal: Rare arthralgia (<10% of children); adolescents and adults have more prominent arthritis.

Rare presentations

• Skin: Gianotti-Crosti syndrome, papular-purpuric “gloves and socks” syndrome, vesicular eruption; transient aplastic crisis causing pallor weakness and lethargy in patients with pre-existing hematological disorders ( ie sickle cell anemia); immunocompromised patients (eg, HIV infection, chemotherapy, transplant patients on immunosuppressive therapy) are at risk for bone marrow suppression and complications of chronic infection.

Enteroviruses are RNA viruses from the Picornaviridae family (includes poliovirus, coxsackievirus, echovirus, and enterovirus). Highly contagious via fecal-oral route, respiratory droplets; infect epithelial cells before infecting cells of other organs; neonates can be infected from mother during or around birth.

• Hand-Foot-and-Mouth Disease (HFMD): Before 2008, most commonly Coxsackievirus A16 but Coxsackievirus A and B groups as well as Enterovirus 71 and Echovirus 4 implicated; over the last decade, Coxsackie A6 imported from Southeast Asia has triggered epidemic outbreaks.
  
• Herpangina: Coxsackievirus A group more often than B group and echoviruses.
  
• Exanthem and others: Multiple, cutaneous and noncutaneous disease resulting from many other enteroviruses, including Coxsackievirus A16, B4, Echovirus 9, and others.

• Traditional HFMD: Brief low-grade fever (<50%) and malaise with rare cough or diarrhea followed by painful gray-white <1-cm vesicles on oral/buccal mucosa, and tongue; erode or ulcerate; 3- to 8-mm elongated gray-white vesicles and pustules on erythematous bases usually on the palms and soles; also on the buttocks and perineum; rarely becomes generalized.
  
• The “new” HFMD: Also may be present with preceding low-grade fever, loose stools, malaise (systemic symptoms <25%) followed by widespread symmetric clusters of 2 to 3 mm round vesicles that crust over and heal in 2 to 3 weeks. Most common sites of involvement include the perioral area (often sparing the oral mucosa), distal half of the arms and legs, and diaper area. When the exanthem blossoms most patients are afebrile, eating and drinking normally, and feeling well. Epidemics in daycare centers and schools are common; children with eczema (if atopic then referred to as eczema coxsackium) or other skin conditions develop more skin lesions than other patients.
  
• Herpangina: Fever (common), abdominal pain and vomiting; painful, tiny vesicles on soft palate, uvula, anterior pillars of throat (fauces), and pharynx (sometimes buccal mucosa), turn into punched out erosions with minimal peripheral erythema and/or yellow-gray coating.
  
• Eruptive pseudoangiomatosis: 2- to 4-mm cherry red papules (usually <10) scattered on the body (Coxsackie B, Echovirus 25 and 32).
  
• Exanthem:
  
  
  
  • Generalized erythematous macules and papules (most common pattern).
    
  • Generalized vesicles: Coxsackie A4.
    
  • Generalized pustular eruption mimicking acute generalized exanthematous pustulosis (AGEP): Coxsackie B4, Enterovirus.
    
  • Multiple petechiae mimicking meningococcemia: Echovirus 9.
    
  • Purpuric eruption: Coxsackie B1.

• Other: Hemorrhagic conjunctivitis (Coxsackie A24, Enterovirus D70); petechiae and purpuric dermatitis (Echovirus 9, Coxsackie A9); urticaria (Coxsackie A9); viral meningitis in infants <1 year of age; acute encephalitis (Coxsackie A9, B2, B5; Echovirus 6, 9); acute paralysis and brainstem encephalitis; pleurodynia, including fever and muscle spasms of the chest or abdomen (Coxsackie B group); respiratory disease; myopericarditis.