Granuloma annulare (GA) is a benign granulomatous dermatosis, classified into localized, generalized, subcutaneous, and perforating types, depending on clinical manifestations. It has been known that generalized granuloma annulare (GGA) occurs in about 8-15% of all types of GA, mostly in adults aged 50 years or over and children aged about 10 years1,2. It has been suggested that some GGAs are associated with diabetes, thyroid diseases, and infectious diseases, such as chronic hepatitis C and acquired immune deficiency syndrome. It has presented as a paraneoplastic syndrome accompanied by malignant tumor, and has been reported to occur after Bacillus Calmette-Guerin (BCG), hepatitis B, or diphtheria/tetanus vaccinations3-9. Herein, we report a rare case of GGA related to BCG vaccination in a 3-month-old female. Only one case has been reported in the Korean literature3 but none in the English literature.

A 3-month-old girl presented with a month history of generalized asymptomatic papules. She had received a BCG vaccination on the left upper arm 1 month prior. At that time, there was an inflammatory reaction at the BCG injection site, which spontaneously disappeared after several days. One month later, skin lesions developed on the left upper arm at the BCG injected site and disseminated all over the body. The personal and family histories were not remarkable. Dermatological examination revealed well-demarcated, slightly erythematous firm papules on the trunk and extremities (Fig. 1). A skin biopsy specimen, taken from a papule on the trunk, revealed mild parakeratosis, acanthosis, focal spongiosis, and pale eosinophilic granular areas of degenerated collagen bundles surrounded by dense infiltration of lymphohistiocytes and multinucleated giant cells in the dermis (Fig. 2). Although Alcian blue staining of the section was negative, elastic staining showed a decrease of elastic fibers in the dermis, especially at the area of degenerated collagen. AFB staining, PAS staining, and Tb-PCR showed all negative results. After the treatment with topical steroid (Desonide 0.05% lotion) for a month, the lesions were resolved, and no relapse has occurred for 6 months.

GGA is a rare variant of GA, which affects the trunk and extremities. It is characterized by a later age of onset, a wide distribution of lesions, a chronic course with only rare spontaneous resolution, and a poor response to therapy compared with the localized type2,10. Although the pathogenensis of GGA has not been fully elucidated, the presence of activated T-cells in GA suggests that cell-mediated immunity plays a role. Additionally, it has been reported that GA occurred in association with trauma, insect bite, sun exposure, virus infection, and BCG vaccination2-5.

Four cases of infantile GGA have been reported in Korea1,3,11. Of these, 1 case was related to BCG vaccination (Table 1)3. In our case, the patient's parents mentioned that erythema and edema with heating sensation were present in the vaccinated area after a month of BCG vaccination and that they spontaneously resolved without treatment. Therefore, it was diagnosed as BCGitis. The skin lesions started from the BCGitis area and disseminated to the whole body, suggesting that BCG vaccination was a precipitating factor of GGA in our case. BCG vaccine contains a live, attenuated strain of Mycobacterium bovis, which is used worldwide for the prevention of tuberculosis. It is known that BCG is relatively safe; however, it has been reported that it may cause cutaneous complications--specific reactions (lymphadenitis, scrofuloderma, lupus vulgaris, lichen nitidus, or tuberculid) and nonspecific reactions (urticaria, purpura, granuloma annulare, erythema nodosum, or erythema multiforme)3. In particular, GA as a complication of BCG vaccination was reported in 2 cases in the English literature and 1 case in the Korean literature 3-5. It suggested that GA might occur in relation to the physical trauma of vaccination or a cell-mediated delayed hypersensitivity reaction against a certain antigen of the vaccine.

It is necessary to distinguish GGA from interstitial granulomatous dermatitis, papular xanthoma, or other infectious diseases such as cutaneous tuberculosis that show granulomatous lesions on histology. Interstitial granulomatous dermatitis is characterized by symmetric distribution of asymptomatic erythematous plaques or papules on the trunk and extremities, and shows palisading granulomas surrounding degenerated collagen on histology. However, it is differentiated by the findings that the infiltrating cells usually are neutrophils and eosinophils, and that dense lymphohistiocytic infiltration over the reticular dermis is present. In case of papular xanthoma, the asymptomatic yellow papules are mostly distributed on the head, trunk and upper extremities, and interstitial granulomas and histiocytes are observed on histology, but mainly foam cells and Touton giant cells are observed. In addition, we performed AFB staining, PAS staining, and a Tb-PCR test to distinguish GGA from infectious diseases, and those results were all negative, thereby excluding infectious diseases.

It has been reported that GGA shows more resistance to therapy than the localized type. Various treatments, such as systemic/topical steroids, cyclosporine, PUVA (psoralen+ UVA therapy), retinoid, antimalarial agents, Dapsone, and so on have been tried; however, those were not apparently effective2,10. Though the prognosis of our case and previously reported cases in infants were relatively good, they regressed 1 to 3 months after administration of oral or topical steroids and GGA did not recur, presenting different clinical courses from GGA in adults.

Herein, we report an interesting case of GGA which occurred in a 3 month-old girl in association with BCG vaccination, and it was rapidly improved by only applying topical steroids for a month, a treatment course different from that provided to adults afflicted with the condition.