Gianotti Crosti Syndrome

Sinonims: Benign Infantile Acropapulosis, Infantile Acropapulosis.

Gianotti-Crosti syndrome (GCS) is a relatively common dermatosis, seen worldwide, primarily affecting children between 2 and 6 years of age. The classic physical finding is an asymptomatic self-limited papulovesicular exanthem; on rare occasions there are associated systemic signs and symptoms. GCS is usually associated with viral infections or immunization, but the pathogenesis remains a mystery.

In 1970 the Australia antigen later found to be the hepatitis B surface antigen (HBsAg) was identified in the serum of affected children. From this point on, acrodermatitis papulosa eruptive infantilis was viewed or even defined as a hepatitis B virus (HBV)-associated dermatosis. Supporting the connection was the presence of hepatomegaly and an anicteric hepatitis in many patients.

Later was found that not all children with GCS have a HBV infection. Investigations revealed a number of other organisms capable of inducing the same or a very similar clinical picture. The other common trigger is Epstein-Barr virus (EBV).

EPIDEMIOLOGY

GCS has a worldwide distribution but is undoubtedly underdiagnosed, making it impossible to estimate the incidence. Almost all patients are between 3 months and 15 years of age, with a peak between 1 and 6 years of age.

According to Frieden and Penneys, more than 90% of patients are younger than 4 years. On the other hand, there are numerous case reports of GCS in adults, where exclusively women (average age 29.5, range 17-45 years) are affected, suggesting hormonal factors play a role.

Seasonal variations reflect the natural history of the triggering viral infection. A recent study showed an increased incidence of a personal or family history of atopy in children with GCS.

ORIGIN

The pathogenesis of GCS is much less clear than suggested a quarter-century ago when the connection with HBV was established.  Viral infections are still the key factor and many have postulated an infectious-allergic pathway.

The major HBV subtypes are adr, ayr, adw, and ayw; the last two are most common in Europe, but the ayw subtype from southern Europe is most often connected with GCS.

In contrast, in southeast Asia the responsible subtypes are usually adr and adw. Today, HBV seems to have taken a backseat to EBV in causing GCS, even in developing lands where HBV is very common.

The most likely explanation for the decline of HBV is the increasing use of anti-HBV immunizations around the world. Numerous studies confirm that EBV is now the most common cause of GCS.

EBV also has a worldwide distribution and can be transmitted by saliva (as reflected by the old name of kissing disease).

Most individuals have an EBV infection during childhood so that by young adult life, almost 100% have been affected.

After primary infection with EBV, the virus reproduces in the oropharyngeal epithelial cells and infects memory B cells, in which the virus persists lifelong in asymptomatic carriers.

In addition to HBV and EBV, many other viruses have been connected with GCS including hepatitis A virus; cytomegalovirus (CMV); human herpesvirus 6; coxsackievirus A16, B4, and B5; rotavirus; parvovirus B19; molluscum contagiosum, respiratory syncytial virus; mumps virus; and parainfluenza virus type 1 and 2.,  Apparently HIV can also be associated with acral papules. Bacteria also appear capable of triggering GCS, although it must be a rare event. Reported causative agents include Bartonella henselae, Mycoplasma pneumoniae, and b-hemolytic streptococci.

Borreliosis is perhaps another trigger as two children have been described in whom GCS occurred in association with fever, upper-airway infections, and serologic evidence of borrelial infection. The association between immunization and GCS has long been known. In 1960 Boyanov described a child who developed GCS after smallpox vaccination. Many other subsequent case reports have also documented this phenomenon days to weeks after vaccination. Despite the proven connection between HBV and GCS, immunization against HBV only rarely causes GCS.

PATHOGENESIS

The pathogenesis of GCS is still unclear, although a number of hypotheses have been proposed. Baldari et al consider a viral infection the most important factor and postulate that perhaps a second necessary event is some other form of immunostimulation or immunomodulation. They suggest that this could explain why children with an impaired immune system, such as those with atopic dermatitis, are more often affected. Colombo et al suggested that either circulating viruses or immune complexes are responsible for the skin findings, whereas Magyarlaki et al found increased numbers of activated CD4.

T cells in the dermal infiltrates and postulated a virus-induced delayed hypersensitivity reaction as a possible mechanism. Although many groups have tried using both electron microscopy and immunohistochemistry, neither viral particles nor viral antigens have been demonstrated in the skin lesions of GCS.

Thus, today it is accepted that the mechanism of lesion development does not involve a direct local interaction between viral antigens and immune-competent cells in the skin. Another contributing factor may be the already mentioned predisposition of patients with atopy to develop acral papules.

An unsolved mystery is why almost all patients are children and why the disease is so much milder in them than in adults. According to Mempel et al, the answer could be in the immature immune system of infants and the resulting differences in response to viral infections. In addition, EBV is common in children and rare as new infection in adults. As mentioned under ‘‘Epidemiology,’’ a personal or family history of atopic dermatitis appears to be more common in children with GCS than in the general population. Ricci et al suggest genetic factors or immunologic imbalance as possible explanations. Confusing the issue is the predilection of young patients with atopic dermatitis to develop other self-limited papular eruption, such as lichen striatus and frictional lichenoid dermatitis (sandbox dermatitis). Thus, GCS in patients who are atopic may reflect a special pattern of reaction to diverse stimuli.

CLINICAL FEATURES

The disease usually starts abruptly with cutaneous lesions. Sometimes there may be a prodrome with pharyngitis, upper-airway infection, or diarrhea. The cutaneous signs and symptoms seem to depend more on the individual characteristics of the patient than on the causative virus.

The classic finding is multiple, monomorphous pink to red-brown papules or papulovesicles, which may be slightly pruritic and can become confluent . The individual lesions are 1 to 5 mm in diameter and rarely exceed 10 mm, often flat-topped, and occasionally with hemorrhage or, less often, scale. The papules are symmetrically distributed on the cheeks, extensor aspects of the extremities, and buttocks. They last for many weeks. The trunk, knees and elbows, along with palms and soles are usually spared, but can occasionally show a few lesions, so that their involvement does not exclude the diagnosis of GCS. Sometimes just a few papules are present or other areas are involved, making the diagnosis most difficult.

During the early phase of the disease, Koebner’s phenomenon may be seen. Mucosal surfaces are not affected.

Systemic findings may include malaise, low-grade fever, or diarrhea. In 25% to 35% of patients, lymphadenopathy can be found, usually favoring the cervical, axillary, or inguinal regions.

LABORATORY

The peripheral blood may show modest lymphocytosis or lymphopenia. Occasionally the number of monocytes is increased, probably in patients with EBV. If the liver enzymes are elevated, the usual  cause is EBV or CMV. Today hepatitis is only rarely associated with CGS, even in developing lands. If hepatitis is suggested, then anti-hepatitis A virus-IgM and -IgG, HBsAg, and anti-HCV-IgG should be sought. Liver biopsy is not indicated but, not surprisingly, shows acute hepatitis with periportal lymphocytic infiltrates and hepatocellular degeneration.

HISTOLOGY

The histologic picture of GCS may be dramatic but is not diagnostic. Both vesicular and nonvesicular patterns can be seen. The vesicular variant shows striking epidermal changes with mild acanthosis accompanied by diffuse spongiosis and vesicles. The dominant cells in the vesicles are Langerhans cells. Occasionally exocytosis of lymphocytes can be marked, mimicking Pautrier’s microabscesses of mycosis fungoides.

The papillary dermis features an intense lymphocytic perivascular infiltrate consisting of T cells and dendritic cells, as is seen in many inflammatory dermatoses.

Most of the lymphocytes are CD4 and CD8 T cells; cytotoxic T cells seem to be a special feature of EBVinduced GCS. In the nonvesicular form, the epidermis may have modest acanthosis and focal parakeratosis and spongiosis.

The dermis features a patchy perivascular superficial or superficial and deep infiltrate composed mainly of lymphocytes with some histiocytes. On rare occasions, GCS may feature a lichenoid dermatitis or even a lymphocytic vasculitis with hemorrhage.

Other reports have emphasized focal lichenoid infiltrates associated with vacuolar degeneration.

Differential Diagnosis

THERAPY

Because CGS is both self-limited and associated with few symptoms, in most cases no treatment is required. The lesions blanch and resolve more rapidly with midpotency topical corticosteroids applied once daily for 7 to 14 days but this effect has never been established in a controlled setting. Although worsening of findings with topical corticosteroids has been described, it must be very rare and does not pose a contraindication. Systemic corticosteroid pulse therapy has been recommended for severe cases. If the lesions are pruritic, oral antihistamines or topical antipruritics (polidocanol) may be useful.

COURSE AND PROGNOSIS

The course is benign but often long, at least in the eyes of the patient or parents. The lesions heal without scarring over 10 to 60 days; both extremely rapid (5 days) and very long (12 months) courses have been described.

Rarely postinflammatory hypopigmentation or hyperpigmentation may evolve. Recurrences are possible but rare.

The lymphadenopathy may persist for several months. Similarly, hepatosplenomegaly takes longer to resolve than the cutaneous lesions. The rare cases associated with HBV experience an unproblematic resolution of the acute hepatitis but most have long-term hepatitis B surface antigenemia and can infect others. Chronic hepatitis or a fatal course are both extremely uncommon.

CONCLUSION

GCS is a common well-established clinical entity. Since its first description 50 years ago, the role of viruses and, to a lesser extent, bacteria as triggering agents has been well established. There has been a striking shift from HBV to EBV as the most common cause. How the infectious agents cause the classic cutaneous pattern remains a mystery. Other puzzles are why only a small number of individuals infected with EBV develop GCS and why their clinical features vary so greatly. The diagnosis of GCS is usually straightforward.

One should then be alert to the rare possibility of systemic signs and symptoms. If there is hepatosplenomegaly or malaise, viral hepatitis should be excluded, especially in countries where immunization programs are not standard. The most likely marker is the HBsAg, which also confirms the potential infectivity of the patient. Other viruses such as EBV and CMV may also cause hepatitis.

Therapy is rarely needed. Most important is to reassure the parents who are understandably worried by the dramatic skin changes with its persistent nature that GCS is a benign, harmless disease in morethan 99% of cases.

MEDIA

REFERENCES

O. Brandt, D. Abeck, R. Gianotti and W. Burgdorf, Gianotti-Crosti syndrome. J Am Acad Dermatol 54  (2006), pp. 136–145.

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