Gianotti-Crosti Syndrome

Gianotti-Crosti syndrome (GCS) is a distinct infectious exanthem with associated lymphadenopathy and acute anicteric hepatitis.[1, 2, 3] Gianotti and Crosti initially described GCS as associated with a hepatitis B virus exanthem, which they termed papular acrodermatitis of childhood. A similar constellation of characteristics was later found to be associated with several infectious agents and immunizations that were called papulovesicular acrolocated syndromes. Subsequent retrospective studies have shown that these 2 entities are indistinguishable from one another, and they are now consolidated under the unifying title of GCS.[4]

Also see Dermatologic Manifestations of Gianotti-Crosti Syndrome.

The most likely explanation for the exanthem is a local type IV hypersensitivity reaction to the offending viral or bacterial antigen within the dermis. This is based on the immunohistochemical characterization of the cutaneous inflammatory infiltrate. Findings on direct immunofluorescence examination of the skin are always negative. Electron microscopy has never revealed virus particles that suggested a reactive process other than an autoimmune phenomenon or direct infection of the skin. Inciting factors include various viral and bacterial infections, as well as recent immunizations. The rarity of Gianotti-Crosti syndrome (GCS) in adults suggests lifelong immunity to a common viral triggering agent. GCS is more common among children with atopic dermatitis, suggesting an immune mechanism. Increased human beta-defensin-4 (hBD-4) activity in the epidermis has been reported, indicating viral antigenemia rather than a type IV hypersensitivity reaction, as a possible cause of GCS in some viral cases.[5] However, more information is needed in order to define the precise mechanism involved. No genetic or familial predisposition is apparent.[6]  An association with oral polio vaccination has been reported.[7]

Associated viral infections are as follows:

• Hepatitis A, B, and C

• Rotavirus

• Epstein-Barr virus[7, 8]

• Rubella virus

• Cytomegalovirus

• Coxsackieviruses A16, B4, and B5

• Adenovirus

• Enterovirus

• Respiratory syncytial virus[9]

• Parainfluenza virus type 1 and type 2[10]

• Parvovirus B19

• Paravaccinia (milker's nodules)

• Human herpesvirus 6

• Echovirus

• Molluscum contagiosum virus

• Human immunodeficiency virus (HIV)

Associated bacterial infections are as follows:

• Group A b-hemolytic streptococci

• Mycobacterium avium-intracellulare

• Mycoplasma pneumoniae

• Bartonella henselae

• Borrelia burgdorferi

• Meningococcemia

Associated immunizations are as follows:

• Polio[7]

• Diphtheria[11]

• Influenza

• Pertussis

• Measles[11]

• Smallpox

• Hepatitis A

• Hepatitis B

• H1N1[12]

Frequency

United States

Because of the benign self-limited nature of Gianotti-Crosti syndrome (GCS), most cases are not reported, and the overall incidence is unknown. Frequency probably parallels the incidence of a precipitating infection in a specific geographic region.

International

The underlying infection correlates with the endemic pathogens of a specific geographic region.

For example, in Japan and Mediterranean countries, GCS is more commonly associated with hepatitis B virus infection. With the advent of more universal hepatitis B immunization, Epstein-Barr virus is now the most common etiologic factor worldwide.[13, 14]

Race

No racial predilection has been noted; however, the underlying infection correlates with the endemic pathogens of a specific geographic region.

Sex

In the pediatric population, GCS affects males and females with equal frequency. However, affected adults have been almost exclusively female, with only 3 documented cases affecting men.[15] Thus, hormonal influences may play a role in GCS.[10]

Age

GCS primarily occurs in children aged 3 months to 15 years, with a peak in children aged 1-6 years. More than 90% of patients are younger than 4 years, with a mean age of diagnosis of 15 months to 2 years.[15]

Prognosis is excellent. Lesions clear within 4-12 weeks. No long-term complications are associated with Gianotti-Crosti syndrome (GCS). The mere presence of a rash does elicit some degree of social morbidity, depending on the age of the affected child. Although typically nonpruritic, some reports document pruritus in the later stages of the rash. The only significant morbidity involves the underlying infectious process, particularly the hepatitis B virus.

The rash of Gianotti-Crosti syndrome (GCS) usually has sudden onset and may be associated with an acute infectious illness or immunization. Epstein-Barr virus (EBV) is the most common inciting cause of GCS. The rash is usually present for 2-4 weeks but can last as long as 4 months.[7] Although often asymptomatic, it may be mildly pruritic. Recurrent episodes have been rarely reported.[16]

Children with Gianotti-Crosti syndrome (GCS) generally appear healthy; however, multiple papules may erupt on the face, buttocks, and extensor surface of the extremities; papules are symmetrically distributed, discrete, and flesh-toned–to–erythematous-to-brown and flat-topped. New lesions can continue to appear for 8-11 weeks.[6] See the images below.

Multiple erythematous flat-topped papules on the cheeks of an 18-month-old boy with Gianotti-Crosti syndrome.

Arm of a 3-year-old boy with Gianotti-Crosti syndrome demonstrating well-defined erythematous lichenoid papules on the arm and forearm.

Thigh of the 3-year-old boy with Gianotti-Crosti syndrome.

The trunk is strikingly spared, although a transient eruption can occur. The mucous membrane is not involved.[5]  Individual papules are monomorphous and range in size from 1-5 mm. They may be hemorrhagic or edematous to the point of forming vesicles. They may coalesce into larger plaques. The face may be the only area of involvement. One report that highlighted this clinical presentation showed that all children with an exclusively facial eruption had Epstein-Barr virus.[17]

Hepatosplenomegaly and axillary or inguinal adenopathy are inconsistent findings.

In general, no laboratory studies are needed in patients with Gianotti-Crosti syndrome (GCS). Jaundice or hepatomegaly should prompt a search for the hepatitis B virus and elevated levels of liver enzymes. However, elevated levels of liver enzymes are most likely related to Epstein-Barr virus infection.

A skin biopsy may be performed to rule out other diseases in the differential diagnosis.

Skin biopsy findings are nonspecific and are more helpful in ruling out other diseases. The epidermis shows focal spongiosis, parakeratosis, mild acanthosis, and psoriasiform epidermal hyperplasia.[5]  The upper dermis has a moderately intense perivascular infiltrate of lymphocytes and histiocytes with occasional scattered eosinophils.[19] Extravasated erythrocytes can be found in the papillary dermis.[15]

Gianotti-Crosti syndrome (GCS) is a benign self-limited condition that requires no treatment. Topical steroids are generally not effective, although anecdotal responses have been reported. Systemic treatment with antihistamines has been moderately helpful in relieving pruritus.

Also see Dermatologic Manifestations of Gianotti-Crosti Syndrome.

Consultation with a dermatologist or a pediatric dermatologist should be sought in confusing cases.

Consultation with a pediatric gastroenterologist should be sought for the rare cases associated with the hepatitis B virus.

Activity is limited only by symptoms. The infectious period ends when the exanthem appears; therefore, the patient may participate in daycare or school at this time.

No specific follow-up is necessary for uncomplicated cases of Gianotti-Crosti syndrome (GCS); however, transaminase elevations, if present, should be monitored until normalization.

GCS associated with hepatitis B infection has an increased incidence of a carrier state compared with hepatitis B infection alone. In this instance, some suggest monitoring the surface antigen as an indicator of potential infectivity.

No medical therapy is necessary. Topical corticosteroids and oral antihistamines might provide some symptomatic relief of pruritus.

Class Summary

These agents may provide relief when pruritus is present.

Triamcinolone topical (Aristocort)

The antipruritic effect of this cream is fairly marginal but may be somewhat effective. It treats inflammatory dermatoses that are responsive to steroids. Triamcinolone topical decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Class Summary

These agents may provide some relief when pruritus is present. They are used to treat minor allergic reactions and anaphylaxis and may be used to pretreat patients with prior documentation of minor allergic reactions. These agents may control itching by blocking effects of endogenously released histamine.

Hydroxyzine (Atarax, Vistaril)

Hydroxyzine offers a mild degree of relief from pruritus. It antagonizes H1 receptors in the periphery. Hydroxyzine may suppress histamine activity in the subcortical region of the CNS.