Granuloma Annulare
Key Points
Granuloma annulare is a benign dermatological condition that occurs in healthy children
It occurs clinically as several different forms, including generalized, subcutaneous, and perforating variants
The etiology remains unknown, but inciting triggers include local trauma, insect bites, ultraviolet light exposure, viral infections, red tattoos, and tuberculin skin tests
GA is characterized by necrobiotic granulomas with blood vessel thickening suggesting an immunoglobulin-mediated vasculitis
Eyelid lesions usually present as a painless, flesh to yellow-tan-colored nodule commonly in the lateral aspect of the upper eyelid and the lateral canthal region but can show a more diffuse distribution of small multiple nodules
GA lesions are benign and often self-limited with approximately 50% of cases resolving spontaneously within 2 years
When symptoms are present or lesions are of cosmetic concern, lesions can be treated with local surgical excision, cryotherapy, laser ablation, intralesional corticosteroids, and psoralen plus ultraviolet A (PUVA) light therapy
The prognosis for GA is generally excellent
Granuloma annulare (GA) is a benign dermatological condition that occurs in healthy children.1 It was first described in 1895 by Fox,2 who referred to it as an inflammatory dermatosis. The term “granuloma annulare” was later introduced by Radcliffe Crocker in 1902.3 Mesara et al.4 studied deep periocular nodular lesions and in 1964 named them pseudorheumatoid nodules because they appeared pathologically identical to rheumatoid nodules. Similar lesions identified as pseudorheumatoid nodules were identified in the periorbital region of 21 patients by Rao et al. in 1975.5 Later, in 1994, Burnstine et al.6 referred to similar periocular lesions as GA, and since then, this has been the preferred terminology.7
GA is characterized by firm papules, plaques, or nodules that are usually organized in a ringlike fashion, with normal overlying skin.8 The distribution of GA lesions in children is located on the hands or arms in 60% of cases, on the feet and legs in 20%, on both upper and lower extremities in 7%, and on the trunk or head in 5% each.8 However, Coskey et al.9 reported a significantly higher incidence of facial GA occurring in adults.
The skin manifestations of GA are varied due to the many variants of this disease. The localized variant accounts for about 75% of GA cases. In this form, lesions are skin colored or erythematous and occur in annular groups of papules most commonly on the dorsal hands and feet. It is typically seen in patients younger than 30 years, with a female predilection in a ratio of 2:1.10
Generalized GA represents 8% to 10% of GA cases and is characterized by the simultaneous occurrence of multiple widespread annular plaques.11,12 It has been reported that this variant is more likely to occur in middle-aged or older individuals,13 but in a retrospective study involving 54 cases of generalized GA, this disease occurred predominantly in patients younger than 10 years or older than 40 years.14 Subcutaneous GA is more common in children and presents as firm subcutaneous nodules, more commonly on the lower legs.15 The perforating variant of GA differs from the other variants in that lesions show a central umbilication.
In addition to the classic variants, other rare subtypes of GA have been described. These include macular, patch, or pustular forms16,17; a palmar distribution18,19,20; and a form localized in photo-exposed skin.21,22,23 Rare subtypes have been based on their clinical appearance, anatomic location, and patient demographics. These include localized, generalized, perforating, and subcutaneous deep variants.8,24
Generalized GA is characterized by small, 1- to 2-mm diffuse papules on the trunk. Perforating GA most frequently presents as small papules on the hands or fingers, which may have central umbilication. Subcutaneous GA occurs almost exclusively in children and young adults presenting as an asymptomatic subcutaneous or deep dermal nodule. They are typically located in the pretibial skin, and less commonly on the hands, scalp, and eyelids.8,24 Most reported cases of periorbital and orbital GA are the subcutaneous variant.
Etiology and Pathogenesis
The etiology of GA remains unknown. Several inciting triggers have been recognized, which include local trauma, insect bites, ultraviolet light exposure, viral infections, red tattoos, and tuberculin skin tests.7,8,25,26 GA has also been seen at sites of healing herpes zoster and verruca vulgaris lesions, suggesting a possible viral etiology.6 GA developing at sites of direct local trauma possibly results from primary degeneration of the connective tissue at the site of injury that can stimulate a granulomatous inflammation, a lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue with increased deposition of mucin.27
GA is characterized by necrobiotic granulomas and biopsy specimens frequently show blood vessel thickening, suggesting
that occlusion or other events involving blood vessels may partially be responsible for the necrobiosis. In 1977, Dahl et al.28 studied GA specimens by conventional light and immunofluorescence microscopy. In 30% of blood vessels in involved skin, they identified IgM, and in 50%, they found complement C3. IgM, C3, or fibrinogen was also observed at the dermal-epidermal junction of 8 out of 20 GA patients, and necrobiotic areas contained fibrinogen. The authors suggested that an immunoglobulin-mediated vasculitis may be involved in the pathogenesis of GA. In an earlier study by Umbert and Winkelmann in 1976,29 deposition of fibrin and circulating macrophage migration inhibition factors were found in the granulomas and necrobiotic lesions of 11 GA patients, suggesting an etiology of delayed hypersensitivity with involvement of the clotting factors. Thornsberry et al. and Mempel et al.30,31 studied GA biopsies and reported increased production of interleukin-2, suggesting a T helper 1 cell-mediated process. Elastic fiber degeneration was demonstrated by electron microscopy by Hanna et al.,32 suggesting that the elastic tissue may be a target tissue in GA.
that occlusion or other events involving blood vessels may partially be responsible for the necrobiosis. In 1977, Dahl et al.28 studied GA specimens by conventional light and immunofluorescence microscopy. In 30% of blood vessels in involved skin, they identified IgM, and in 50%, they found complement C3. IgM, C3, or fibrinogen was also observed at the dermal-epidermal junction of 8 out of 20 GA patients, and necrobiotic areas contained fibrinogen. The authors suggested that an immunoglobulin-mediated vasculitis may be involved in the pathogenesis of GA. In an earlier study by Umbert and Winkelmann in 1976,29 deposition of fibrin and circulating macrophage migration inhibition factors were found in the granulomas and necrobiotic lesions of 11 GA patients, suggesting an etiology of delayed hypersensitivity with involvement of the clotting factors. Thornsberry et al. and Mempel et al.30,31 studied GA biopsies and reported increased production of interleukin-2, suggesting a T helper 1 cell-mediated process. Elastic fiber degeneration was demonstrated by electron microscopy by Hanna et al.,32 suggesting that the elastic tissue may be a target tissue in GA.
The role of ultraviolet light in the pathogenesis of GA is unclear, but generalized GA in sun-exposed areas has been described in several cases.33,34,35
 FIGURE 65.1 Granuloma annulare (GA) involving the eyelids. A, Nodular subcutaneous lesion in the lateral upper eyelid. B, GA nodule in the upper medial canthus. C and D, Small nodules of GA in the upper and lower eyelids. Arrows indicated the subcutaneous lesions. |
Clinical Characteristics
Lesions of GA most often involve the dorsal surfaces of the hands or feet, arms, legs, and trunk, and less frequently the scalp, face, and eyelids. They often present as a localized, erythematous, skin-colored, or violaceous cutaneous annular plaque, nodule, or papule with an elevated border.48
Fewer than 30 cases have been described involving the eyelids and periorbital region.1,6,7,8,25,48,49,50,51,52,53,54,55,56,57,58,59,60,61 The typical presentation is as a painless, flesh to yellow-tan-colored nodule present for 3 months to 4 years. Eyelid lesions most commonly involve the lateral aspect of the upper eyelid and the lateral canthal region but can show a more diffuse distribution of small multiple nodules (Figure 65.1). Females predominate in a ratio of 3:1, and in 40% of reported cases, the patients are of African heritage. The age range is from 2 to 69 years, with a mean age at presentation of 21 years. However, two-thirds
of cases are younger than 18 years, and the median age is 11 years old. Lesions typically present as small 1 to 5 mm diameter nodules, but in rare cases can be up to 1.5 cm. In 40% of reported cases, lesions can be multiple on the same eyelid, and in 35%, they can be bilateral.
of cases are younger than 18 years, and the median age is 11 years old. Lesions typically present as small 1 to 5 mm diameter nodules, but in rare cases can be up to 1.5 cm. In 40% of reported cases, lesions can be multiple on the same eyelid, and in 35%, they can be bilateral.
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