Dermatologic Manifestations of Gianotti-Crosti Syndrome

Practice Essentials

Gianotti-Crosti syndrome (GCS) is a self-limited childhood exanthem that manifests in a characteristic acral distribution. It is rarely associated with systemic findings. Other descriptive designations, papular acrodermatitis of childhood (PAC) and papulovesicular acrolocated syndrome (PAS), described indistinguishable clinical entities. PAC is the term most commonly used today.

The original cases, described by Gianotti in 1955, were associated with hepatitis B virus infection, although other viral infections and vaccinations currently account for most cases.^[1]   In the United States, the agent that has been reported most frequently in association with Gianotti-Crosti syndrome is Epstein-Barr virus (EBV).

The pathophysiologic process underlying Gianotti-Crosti syndrome remains unknown, although it is believed to represent an immunologic response to transient viremia or bacteremia, possibly a delayed-type hypersensitivity response. Children with a history of atopic dermatitis are at increased risk for developing GCS.^[2]

The most common presentation is an acute, symmetric, exanthematous, asymptomatic cutaneous eruption that develops over several days, although pruritis is not uncommon. The eruption typically lasts at least 10 days but can last longer than 6 weeks in more than 50% of patients. Complete resolution typically takes more than 2 months.  Pruritus accompanies the eruption in 23% of patients. Systemic findings related to the primary viral syndrome or underlying bacterial infection may include malaise, fever, diarrhea, lymphadenopathy, and upper respiratory symptoms.^[3]

Recurrences are rare, although a recurrent case associated with influenza virus vaccination has been reported.^[4]  Chronic cases lasting more than 12 months have been reported.^[3]

Diagnostic criteria for Gianotti-Crosti syndrome have been proposed.  All of the following positive clinical features must be present^{[5, 6]} :

• Monomorphous, flat-topped, pink-brown papules or papulovesicles 1-10 mm in diameter
• At least three of the following four sites involved: cheeks, buttocks, extensor surfaces of forearms, extensor surfaces of legs
• Symmetric eruption
• Duration of at least 10 days

In addition, extensive truncal lesions and scaling are absent, alternative diagnoses based on clinical judgment have been excluded, and histopathologic findings are compatible, if skin biopsy is performed.

Treatment is primarily supportive. Topical steroids are generally not effective, although anecdotal responses have been reported. Systemic treatment with antihistamines has been moderately helpful in relieving pruritus. Some children may require symptomatic care for the associated viral or bacterial infection.  Follow-up appointments are required to monitor the lesions and address parental concerns.

Discussion with the parents regarding the benign, self-limited course is advisable. If a particular viral or bacterial infection is suspected as the etiology, the course of the associated infection should also be discussed.

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Pathophysiology

Although the original reports of Gianotti-Crosti syndrome (papular acrodermatitis of childhood) were attributed to acute infection with the hepatitis B virus, more recent studies have demonstrated that Gianotti-Crosti syndrome is more commonly associated with a number of other infectious agents, both viral and bacterial. In the United States, the agent that has been reported most frequently in association with Gianotti-Crosti syndrome is Epstein-Barr virus (EBV).

The pathophysiologic process underlying Gianotti-Crosti syndrome remains unknown, although it is believed to represent an immunologic response to transient viremia or bacteremia, possibly a delayed-type hypersensitivity response.^[2] Deposition of circulating immune complexes in the dermis may play a role. Several studies have failed to demonstrate deposition of viral particles or bacteria within the dermis.

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Etiology

Gianotti-Crosti syndrome has been associated with the following infectious agents:

• Hepatitis B virus, most commonly ayw strain^[7]
• Epstein-Barr virus (probably the most common etiology)^{[7, 8, 9, 10, 11]} : Gianotti-Crosti syndrome has been associated with both primary infection and with endogenous reactivation of EBV.^[12]
• Respiratory syncytial virus^[13]
• Coxsackieviruses,^{[14, 15, 10]} echoviruses, and other enteroviruses^[13]
• Parainfluenza virus^[10]
• Parvovirus B19^[16]
• Poxvirus^[16]
• Cytomegalovirus^{[14, 7, 17, 18]}
• Influenza virus, type A^[19]
• Human herpesvirus 6, both primary infection and reactivation of latent infection^[20]
• Herpes simplex virus-1^[21]
• Rotavirus^[22]
• Hepatitis C virus^[17]
• Human immunodeficiency virus^[17]
• Group A beta-hemolytic streptococci
• Neisseria meningitidis^[23]
• Mycoplasma pneumoniae^[24]
• Bartonella henselae
• Borrelia burgdorferi
• SARS-COV-2 (COVID-19)^{[25, 26]}

Gianotti-Crosti syndrome has also been reported to occur after vaccination for the following:

• Hepatitis A virus^{[27, 28]}
• Hepatitis B virus^{[29, 30, 31]}
• Measles, mumps, rubella viruses (MMR)^{[8, 32]}
• Measles virus^[29]
• Influenza virus^[33]
• H1N1 influenza A virus^{[34, 35, 36]}
• Oral poliovirus vaccine^[37]
• Japanese encephalitis virus^[38]
• Diphtheria, tetanus and pertussis (DTaP) and varicella virus^[39]
• Diphtheria, tetanus and pertussis^[40]
• Diphtheria^[10]
• BCG, poliovirus, diphtheria, tetanus, and pertussis^[14]
• COVID-19^[41]

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Epidemiology

United States and international statistics

In the United States, Gianotti-Crosti syndrome (papular acrodermatitis of childhood) occurs sporadically in the clinical setting, with no apparent genetic or familial predisposition. It appears to be uncommon and may go unrecognized because of its generally benign and self-limited course. Gianotti-Crosti syndrome is more commonly seen in the spring and summer, possibly as a result of a concomitant increase in viral illness seen in the general population.

The distribution of Gianotti-Crosti syndrome is worldwide, with cases reported in Great Britain, France, Germany, Spain, Russia, Turkey, India, Hong Kong, China, and Japan. In one series of 20,000 patients younger than 5 years seen over a 5-year period in Bordeaux, France, 26 patients with features consistent with Gianotti-Crosti syndrome were identified, yielding an annual incidence of 0.13%.^[14]

Age-, sex-, and race-related demographics

The onset of the eruption typically occurs in children aged 3 months to 15 years, with an average age of 2 years and a peak incidence at 1-6 years.^[3]  Adult cases are rare but have been reported mainly in women aged 17-65 years.^{[24, 42, 43, 44, 33, 45, 46, 47]}  Cases in immunocompromised adults with HIV-infection or following bone marrow transplantation have also been reported.^[18]

In children, males and females are equally affected. Reported cases in adults have been seen almost exclusively in females.

No racial predilection is apparent for Gianotti-Crosti syndrome.

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Prognosis

The prognosis is excellent. This syndrome is generally a benign, self-limited condition. The eruption usually starts to resolve after 6-8 weeks.

In the original cases of hepatitis B virus-associated disease, anicteric hepatitis developed in a proportion of patients. Anicteric hepatitis may also be seen in cases associated with other viral illnesses such as EBV.

In extremely rare cases, chronic liver disease has followed the initial phase of infection with hepatitis B virus.

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History

Children with Gianotti-Crosti syndrome (papular acrodermatitis of childhood) usually present with an acute, symmetric, exanthematous, asymptomatic cutaneous eruption that develops over several days. The eruption typically lasts at least 10 days but can last longer than 6 weeks in more than 50% of patients. Complete resolution typically takes more than 2 months. Recurrences are rare, although a recurrent case associated with influenza virus vaccination has been reported.^[4] Pruritus accompanies the eruption in 23% of patients.

Other symptoms related to the primary viral syndrome or underlying bacterial infection may include mild constitutional symptoms such as low-grade fever and malaise, pharyngitis and/or mucosal lesions, or symptoms of an upper respiratory tract infection. When associated with a hepatitis B virus, EBV, or CMV infection, an anicteric acute hepatitis may be present.

A case control study of 29 children with Gianotti-Crosti syndrome from Bologna, Italy demonstrated a higher prevalence of atopic dermatitis in patients versus controls (24.1% vs 6.8%). They also found that patients were more likely than controls to have elevated levels of total and specific immunoglobulin E and a family history of atopy.^[48]

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Physical Examination

The cutaneous eruption of Gianotti-Crosti syndrome (papular acrodermatitis of childhood) is characterized by monomorphous pale, pink-to-flesh–colored or erythematous 1- to 10-mm papules or papulovesicles localized symmetrically and acrally over the extensor surfaces of the extremities, the buttocks, and the face. (See the images below.) The number of lesions ranges from few to many.

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Characteristic erythematous papules of Gianotti-Crosti syndrome appear on the face of this child. The child does not have a toxic appearance.

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Characteristic erythematous papules of Gianotti-Crosti syndrome can be seen on the extremities, as is the case in this young child.

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A 9-year-old girl who recently returned from a trip to Europe with her family. She developed a low-grade fever, malaise, and some lymphadenopathy. An ....

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A mildly pruritic eruption characterized by erythematous papules localized to the face, arms, legs, and buttocks.

The trunk, knees, elbows, palms, and soles are rarely involved, and in general, extensive involvement of the trunk is not consistent with a diagnosis of Gianotti-Crosti syndrome. Individual papules may coalesce to form larger plaques. Uncommonly, the eruption may develop a petechial or purpuric appearance. Partial involvement of only the face or the extremities is not uncommon, especially in older children. Over days to weeks, the papules may acquire a smooth-topped, polished, or lichenoid appearance. Other findings upon physical examination include the following:

• Fever (27%)
• Lymphadenopathy (31%)
• Hepatosplenomegaly (4%)
• Pharyngeal erythema, oropharyngeal ulcers or vesicles, or tonsillar swelling in cases secondary to infections of the upper respiratory tract

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Complications

There are no expected complications of Gianotti-Crosti syndrome. Complications may arise from the inciting infection, if present.

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Approach Considerations

Diagnostic criteria for Gianotti-Crosti syndrome have been proposed.^{[5, 6]}  According to these criteria, all of the following positive clinical features must be present:

• Monomorphous, flat-topped, pink-brown papules or papulovesicles 1-10 mm in diameter
• At least three of the following four sites involved: cheeks, buttocks, extensor surfaces of forearms, extensor surfaces of legs
• Symmetric eruption
• Duration of at least 10 days

In addition, extensive truncal lesions and scaling are absent, alternative diagnoses based on clinical judgment have been excluded, and histopathologic findings are compatible, if skin biopsy is performed.

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Laboratory Studies

Laboratory studies are not generally indicated. Blood counts may reveal a lymphocytosis and a relative monocytosis or a lymphopenia secondary to an underlying viral infection, if present.

In cases associated with acute infection with the hepatitis B virus, EBV, or CMV, anicteric hepatitis is evident by elevations in the levels of hepatic transaminases and antiviral antibodies. A viral agent can be identified in approximately one third of cases. If a specific infectious etiology is suspected, testing can be directed at potential etiologies, as follows:

• EBV - Monospot, immunoglobulin M (IgM) and immunoglobulin G (IgG) titers, or serum polymerase chain reaction (PCR)
• CMV - IgM and IgG titers, serum CMV antigen levels, or serum PCR
• RSV, parainfluenza virus, other respiratory viral pathogens - Nasal washing for fluorescent antibody testing or PCR
• Enterovirus - Culture or PCR from serum
• Parvovirus B19 - IgM and IgG titers or serum PCR
• HHV-6 - Serum PCR
• Group A beta-hemolytic streptococci - Serum PCR or pharyngeal culture

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Histologic Findings

The histology of skin biopsy specimens is nonspecific. Mild epidermal acanthosis and spongiosis with focal parakeratosis can be seen. A lymphocytic exocytosis may also be seen. Edema of the papillary dermis and a superficial lymphohistiocytic infiltrate, sometimes with a perivascular localization or a lichenoid appearance, is common. Rarely, features of a lymphocytic vasculitis have been noted.

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Medical Care

Education and reassurance are usually sufficient for concerned parents. Some children may require general supportive and symptomatic care for the associated viral or streptococcal infection. Isolation is not necessary, and there are no activity restrictions.

Application of soothing, anti-itch topical preparations with menthol, colloidal oatmeal, or pramoxine in conjunction with oral antihistamines may be useful for relief of pruritus. Use of topical corticosteroids or calcineurin inhibitors may be considered but are of questionable efficacy. If an associated streptoccocal or other bacterial infection is identified, a course of an appropriate systemic antibiotic should be initiated.

One report describes rapid resolution of a case of Gianotti-Crosti syndrome occurring in a 6-year-old girl after administration of oral ribavirin.^[50]

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Consultations

As the diagnosis is clinical and as the condition is benign and self-limiting, consultation is generally not indicated. If there is concern for an issue related to a specific infectious etiology, such as acute hepatitis secondary to EBV or hepatitis virus infection, specialty consultation may be helpful.

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Long-Term Monitoring

A follow-up visit after 2 months for evaluation of persistent signs or symptoms is advisable. Children with atypical presentations should also be reevaluated after 2-4 weeks to evaluate progression and to confirm the diagnosis.

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Medication Summary

The goals of pharmacotherapy are to reduce associated symptoms, in particular pruritus. These agents do not appear to shorten the course of the disease or prevent complications.

For mild cases, no treatment is needed. For children who are symptomatic, topical corticosteroids or topical calcineurin inhibitor may be considered. Oral antihistamines may also help with pruritus, but the majority of cases occur in patients under 4 years age. Antihistamine use in this age group and cause paradoxical CNS agitation.

Systemic corticosteroids have reportedly been used for more severe cases.

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Diphenhydramine (Benadryl, Benylin, Diphen, AllerMax)

• Dosing, Interactions, etc.

Clinical Context:  Diphenhydramine is used for symptomatic relief of allergic symptoms caused by release of histamine. It competes with histamine for H1-receptor sites on effector cells.

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Hydroxyzine hydrochloride (Atarax, Vistaril)

• Dosing, Interactions, etc.

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

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Class Summary

These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

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