Cutis

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Intravenous immunoglobulin (IVIg) has been advocated as therapy for several immune-mediated and autoimmune skin disorders, and side effects such as vasomotor symptoms, anaphylactic reactions, and renal failure have been well documented.1 Thrombotic complications, such as stroke and myocardial infarction, also have been documented in the neurologic and cardiologic literature but have received little notice from dermatologists.2,3 One recent report in the dermatologic literature described 2 cases of thrombotic events, including a 65-year-old woman with pemphigus vulgaris who developed an upper extremity deep venous thrombosis (DVT) after receiving IVIg.4 We now report a case of thrombosis in the setting of IVIg therapy, only the fourth such case, to our knowledge, in the dermatology literature. We also review some less commonly known clinical presentations of thrombotic events associated with this therapy. 

Case Report

We were treating a 43-year-old black man who had an 18-month history of oral pemphigus vulgaris. His disease, which had been limited to the oral mucosa, had been refractory to numerous therapies including prednisone alone or with mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, and oral cyclophosphamide. His trial of cyclosporine was complicated by the development of hypertension, which necessitated oral antihypertensive medication.

After much consideration and investigation into the literature supporting the use of IVIg in refractory pemphigus vulgaris,5,6 we decided to proceed with this therapy. In the first treatment session, the patient received IVIg 40 g daily for 5 consecutive days. He experienced mild chills but otherwise tolerated the therapy well. However, no clinical benefit was observed. After further evaluation of the literature on the benefit of repeated doses of IVIg, we elected to repeat the therapy, this time using a regimen advocated by Ahmed's group.7 In the second course, which was begun 3 months after the first course, the patient received IVIg 70 g daily for 3 consecutive days, for a total dose of 2 g/kg. A complete blood count and metabolic panel on the last day of the infusion were within reference range. The patient had no notable clinical benefit after the second course of IVIg therapy.

Sixteen days after his last IVIg treatment, the patient underwent elective surgery at a local hospital for an anal fissure. The patient noted that he was particularly lethargic for the 3 days of his hospital stay, but he resumed his normal active daily routine immediately after discharge. Twenty-six days after his last IVIg treatment and 10 days after his anal surgery, he noted significant swelling and pain in his left calf that progressed over the course of several days. Thirty days after his last therapy, he was admitted to the hospital for workup of his leg swelling. A Doppler study demonstrated thrombus in the superficial femoral vein, common femoral vein, and popliteal vein. A diagnosis of DVT was made, and the patient was discharged on a therapeutic regimen of warfarin.

Comment

To our knowledge, there are only 3 reports in the dermatologic literature regarding thrombotic complications in the setting of IVIg therapy. Katz et al4 described one patient with pemphigus vulgaris who developed an upper extremity DVT and a 67-year-old woman with dermatomyositis who had a thromboembolic stroke. Bystryn et al6 also described a patient with pemphigus vulgaris who developed a mild stroke that had been attributed to hypertension.

A review of the literature regarding thrombotic complications with IVIg also revealed several other clinical scenarios of which dermatologists should be made aware. Evangelou et al8 reported a case of transverse sinus thrombosis presenting as an acute, sudden, severe headache in a 54-year-old woman who had recently received IVIg replacement therapy. Of note, the woman was known to have thrombocytosis prior to the therapy.8 In addition, Klaesson et al9 reported fatal venoocclusive disease of the liver in 11% of patients who had bone marrow transplants and were treated with IVIg; none of the transplant patients who served as controls experienced fatal venoocclusive disease of the liver. The difference was statistically significant (P=.02).9 Finally, Steinberger and Coleman10 reported a case of Anton syndrome in a patient with Guillain-Barre syndrome who was treated with IVIg. Anton syndrome is a form of cortical blindness in which the patient denies the visual impairment and may even attempt to ambulate, bumping into surrounding objects. This syndrome arises from damage to the occipital lobes, and the authors speculated that it arose in the setting of hyperviscosity, a known consequence of treatment with IVIg.10

Serial measurements of serum viscosity in patients with amyotrophic lateral sclerosis and polyneuropathy associated with IgM paraproteinemia before and after treatment with IVIg demonstrated an increase in serum viscosity, with the majority of patients having values above the upper limit of the reference range.11 In addition to the hyperviscosity created by IVIg, other possible ways IVIg can predispose patients to thrombotic complications are through vasoactive effects and generation of platelet-activating factor.12 Specifically, IVIg has been shown to cause hypotension in a rat model, and in vitro incubation of human neutrophils with IVIg has elicited generation of platelet-activating factor.12

There are many known risk factors for thrombosis including immobility, obesity, surgery, trauma, pregnancy, oral contraceptive use, malignancy, and coagulation disorders. We believe our patient's DVT can be attributed at least in part to his IVIg therapy, though certainly his 3-day period of immobility after his anal fissure surgery, along with hypertension, could have been contributing factors. Other authors have noted that periods of immobility may have predisposed their patients to thrombosis after treatment with IVIg.13

Estimates regarding the absolute risk for thrombotic complications with IVIg therapy have ranged from 3% to 5%, although this has not been well-studied.11,14 At our institution, approximately 200 individuals received a total dose of 18,000 g of IVIg in 2003. Unfortunately, no mechanism is in place to record the frequency of complications. Certainly, more information is required to ascertain the overall frequency of clotting complications after IVIg.

Given the preponderance of evidence (including one controlled study) supporting a role for IVIg in causing thrombotic events, we believe physicians should consider traditional risk factors for thrombosis, particularly surgery and immobility, as possible contraindications to treatment with IVIg. There may be some benefit in performing a workup for more subtle predispositions for thrombosis such as factor V Leiden, protein C deficiency, or protein S deficiency. Additionally, if a patient has had a thrombotic complication while being treated with IVIg, caution should be exercised before reinstating therapy.

Emerson et al15 recently reported a case involving a 33-year-old woman who had DVT while being treated with IVIg for autoimmune thrombocytopenia and Coombs-positive hemolytic anemia. Five months after the DVT, IVIg therapy was reinstated, and the patient died from a pulmonary embolism. Further studies may be needed to determine if prophylactic anticoagulation with heparin or warfarin may be needed when IVIg is used in the setting of risk factors for thrombosis. 

Conclusion

We report the fourth case of thrombotic complications occurring with IVIg in the treatment of dermatologic diseases, and we maintain that caution should be exercised in employing this treatment modality in patients who have underlying risk factors for thrombotic events. In particular, caution should be used with immobile patients and with those who need to undergo surgery or other procedures that may render them susceptible to DVT. We reported this case to the US Food and Drug Administration Adverse Event Reporting System, and we encourage others to do the same if thrombotic complications with IVIg are encountered. 

Case Report

A healthy 12-year-old African American boy presented with a 3-month history of an asymptomatic, papular, perioral eruption. He had been previously treated by a primary care provider, who had prescribed a low-potency and then a medium-potency topical corticosteroid, without improvement. The patient's parents denied that he had used topical corticosteroids or other topical preparations prior to the eruption. He took no oral medications, and the findings of the review of systems were within reference range. Results of a physical examination revealed numerous, discrete and coalescing, firm, pink, hyperpigmented papules ranging from 2 to 4 mm in diameter, primarily located in the perioral area (Figure). A few papules were noted around the nose and eyes. Results of a shave biopsy of a perioral papule revealed dermal granulomatous inflammation. The infiltrate consisted of histiocytes and lymphocytes and also included several focal collections of neutrophils. There was overlying parakeratosis. Results of a periodic acid–Schiff, Gomori methenamine-silver, Brown-Brenn, and Fite-Farraco stains were negative for organisms.

The patient was diagnosed with granulomatous periorificial dermatitis (GPD), and treatment with oral tetracycline 500 mg twice a day was initiated. Six days later, a tapering course of oral prednisone was added (consisting of 40 mg for 3 days, 30 mg for 3 days, 20 mg for 3 days, and 10 mg for 3 days) because of the severe extent of the eruption and the social distress it was causing the patient. Within 3 weeks, a dramatic decrease in the eruption was noted, with only a few small papules remaining. The patient was then switched from oral tetracycline to topical clindamycin twice a day for maintenance, but he did not return for follow-up. 

Comment

GPD is characterized by a monomorphic papular eruption occurring in the perinasal, perioral, and periocular areas. Gianotti et al1 first described the condition in 5 children, ranging in age from 2 to 7 years, who had asymptomatic, distinctive, flesh-colored, "micronodular," periorificial eruptions. In the literature, the condition has been variably called Gianotti-type perioral dermatitis, sarcoidlike granulomatous dermatitis, facial Afro-Caribbean childhood eruption, and childhood granulomatous perioral dermatitis. It has been proposed that GPD is a form of perioral dermatitis with granulomatous histologic features.^2,3 GPD typically affects prepubertal children, predominantly African Americans and others with dark skin. Several cases involving fair-skinned children have been reported.² Both genders are equally affected. Typical lesions have been described as flesh-colored, yellow-brown, or red papules or micronodules.^2,3 Slight scaling of lesions or surrounding erythema may occur.² Scarring is absent in most cases; however, pinpoint atrophy or scarring occasionally occurs.² In addition to the characteristic facial distribution, extrafacial and generalized lesions on the trunk, extremities, and labia majora have been described.² In all reported cases, the lesions, including extrafacial lesions, were histologically similar and self-limited and were not accompanied by associated systemic symptoms. The presence of extrafacial lesions did not affect the duration of disease or the response to treatment.

The etiology of GPD is unknown. It may represent an unusual inflammatory granulomatous response to allergens.³ The initial allergen may cause inflammation and a focal disruption of the follicular wall, inciting a granulomatous reaction.³ In 1978, Georgouras and Kocsard4 described a case of Gianotti-type perioral dermatitis as an unusual reaction to bubble gum. Other reports have implicated reactions to formaldehyde, cosmetic preparations, and antiseptic solutions.⁵ Topical corticosteroids may induce or exacerbate both perioral dermatitis and GPD.^3,6

Histologic findings consist of upper dermal and perifollicular granulomas admixed with lymphocytes. The inflammation surrounding a focally disrupted hair follicle may range from a primarily lymphocytic inflammation with focal granuloma formation to a denser dermal granulomatous infiltrate. The presence of lymphocytic inflammation can help distinguish GPD from the "naked" granulomas in cutaneous sarcoidosis that typically lack inflammatory cells. GPD also may show epidermal change with mild to moderate spongiosis.^3,7

The clinical differential diagnosis of granulomatous papules on the face of a child includes GPD, granulomatous rosacea, lupus miliaris disseminatus faciei, and cutaneous sarcoidosis. Other cutaneous diseases that may occur in a periorificial distribution include perioral dermatitis, telangiectatic fibromas, and trichoepitheliomas. Although similar in distribution to GPD, the primary lesions in these latter 3 conditions are not granulomatous and can often be distinguished clinically. Deep fungal infection, atypical mycobacterial infection, and leishmaniasis can be considered in the histologic differential diagnosis of granulomatous dermatitis, but these conditions usually present as nodules, plaques, or ulcers and not necessarily in a perioral distribution.

Granulomatous rosacea and GPD have a similar clinical and histopathologic presentation. Both conditions can present as red or yellow-brown, dome-shaped facial papules with histologic findings of a perifollicular lymphohistiocytic or granulomatous infiltrate. The major distinguishing features of granulomatous rosacea are erythema, telangiectasias, pustules, and edema.8 Granulomatous rosacea is not characterized by a concentration of lesions in the perioral area, and it is most common in 30- to 50-year-old women.⁹ Rosacea also involves the eyes in about 17% of patients seen by dermatologists.¹⁰ Ocular rosacea can manifest as blepharitis, conjunctival injection, and chalazion.

Lupus miliaris disseminatus faciei is another chronic facial papular eruption with a high predilection for the eyelids. The lesions are usually red or yellow-brown dome-shaped papules. Histologic examination demonstrates well-formed granulomas with central caseation necrosis. Lesions resolve spontaneously in 12 to 24 months with scarring. To our knowledge, lupus miliaris disseminatus faciei has not been reported in children. It has been hypothesized that most patients with this eruption actually have a form of granulomatous rosacea.⁷

Sarcoidosis is a systemic granulomatous disease with cutaneous manifestations. Cutaneous involvement occurs in up to one third of patients and can present as macules, papules, nodules, plaques, subcutaneous nodules, infiltrative scars, and ichthyosis. Maculopapular lesions are the most common cutaneous manifestation of sarcoidosis and can occur anywhere on the skin.¹¹ Lupus pernio is a variant of sarcoidosis characterized by violaceous papules and plaques on the nasal alar rims, ears, and cheeks. This variant of sarcoidosis occurs most frequently in middle-aged women and is associated with chronic fibrotic respiratory tract involvement. Patients with cutaneous sarcoidosis may have systemic symptoms including weight loss, shortness of breath, cough, fatigue, and bone and joint pain.

Perioral dermatitis most commonly occurs in young women between 16 and 45 years of age. The characteristic eruption consists of pustular or papulovesicular lesions on an erythematous background.¹² The lesions are usually confined to the chin and nasolabial folds, with sparing around the vermilion border. GPD may be distinguished from perioral dermatitis by the presence of discrete yellow-brown papules rather than erythematous papules, the lack of pustules, and the presence of a perifollicular granulomatous infiltrate seen on examination of biopsy material.⁵

Treatment of GPD is based on anecdotal reports. Tetracycline has been recommended for GPD in children older than 8 years.^3,13 Recent studies have demonstrated that tetracyclines inhibit granuloma formation in vitro.¹⁴ Tetracyclines are also effective treatment for rosacea and perioral dermatitis because of their anti-inflammatory properties.¹⁵ According to anecdotal reports, topical tetracycline and topical clindamycin are sometimes effective therapy for perioral dermatitis and may be helpful in GPD when oral agents are undesirable. GPD also has responded to topical treatment with metronidazole gel in some reports.^3,16 Mild GPD may resolve spontaneously over several months without therapy. The use of oral steroids in this condition has not been reported, but in our patient, a tapering course of prednisone seemed justified because of the distressing nature of the eruption to the patient. Oral prednisone may produce anti-inflammatory effects more quickly than tetracycline, but it is not necessary in most patients.

GPD represents a benign cutaneous inflammatory process that resolves without serious sequelae. The granulomatous inflammation is most likely a nonspecific reaction to a variety of insults. Topical corticosteroids may initiate or exacerbate the granulomatous reaction and should be strictly avoided. Practitioners should recognize and distinguish this condition from other granulomatous eruptions so that patients are appropriately managed.

Case Report

A healthy 12-year-old African American boy presented with a 3-month history of an asymptomatic, papular, perioral eruption. He had been previously treated by a primary care provider, who had prescribed a low-potency and then a medium-potency topical corticosteroid, without improvement. The patient's parents denied that he had used topical corticosteroids or other topical preparations prior to the eruption. He took no oral medications, and the findings of the review of systems were within reference range. Results of a physical examination revealed numerous, discrete and coalescing, firm, pink, hyperpigmented papules ranging from 2 to 4 mm in diameter, primarily located in the perioral area (Figure). A few papules were noted around the nose and eyes. Results of a shave biopsy of a perioral papule revealed dermal granulomatous inflammation. The infiltrate consisted of histiocytes and lymphocytes and also included several focal collections of neutrophils. There was overlying parakeratosis. Results of a periodic acid–Schiff, Gomori methenamine-silver, Brown-Brenn, and Fite-Farraco stains were negative for organisms.

The patient was diagnosed with granulomatous periorificial dermatitis (GPD), and treatment with oral tetracycline 500 mg twice a day was initiated. Six days later, a tapering course of oral prednisone was added (consisting of 40 mg for 3 days, 30 mg for 3 days, 20 mg for 3 days, and 10 mg for 3 days) because of the severe extent of the eruption and the social distress it was causing the patient. Within 3 weeks, a dramatic decrease in the eruption was noted, with only a few small papules remaining. The patient was then switched from oral tetracycline to topical clindamycin twice a day for maintenance, but he did not return for follow-up. 

Comment

GPD is characterized by a monomorphic papular eruption occurring in the perinasal, perioral, and periocular areas. Gianotti et al1 first described the condition in 5 children, ranging in age from 2 to 7 years, who had asymptomatic, distinctive, flesh-colored, "micronodular," periorificial eruptions. In the literature, the condition has been variably called Gianotti-type perioral dermatitis, sarcoidlike granulomatous dermatitis, facial Afro-Caribbean childhood eruption, and childhood granulomatous perioral dermatitis. It has been proposed that GPD is a form of perioral dermatitis with granulomatous histologic features.^2,3 GPD typically affects prepubertal children, predominantly African Americans and others with dark skin. Several cases involving fair-skinned children have been reported.² Both genders are equally affected. Typical lesions have been described as flesh-colored, yellow-brown, or red papules or micronodules.^2,3 Slight scaling of lesions or surrounding erythema may occur.² Scarring is absent in most cases; however, pinpoint atrophy or scarring occasionally occurs.² In addition to the characteristic facial distribution, extrafacial and generalized lesions on the trunk, extremities, and labia majora have been described.² In all reported cases, the lesions, including extrafacial lesions, were histologically similar and self-limited and were not accompanied by associated systemic symptoms. The presence of extrafacial lesions did not affect the duration of disease or the response to treatment.

The etiology of GPD is unknown. It may represent an unusual inflammatory granulomatous response to allergens.³ The initial allergen may cause inflammation and a focal disruption of the follicular wall, inciting a granulomatous reaction.³ In 1978, Georgouras and Kocsard4 described a case of Gianotti-type perioral dermatitis as an unusual reaction to bubble gum. Other reports have implicated reactions to formaldehyde, cosmetic preparations, and antiseptic solutions.⁵ Topical corticosteroids may induce or exacerbate both perioral dermatitis and GPD.^3,6

Histologic findings consist of upper dermal and perifollicular granulomas admixed with lymphocytes. The inflammation surrounding a focally disrupted hair follicle may range from a primarily lymphocytic inflammation with focal granuloma formation to a denser dermal granulomatous infiltrate. The presence of lymphocytic inflammation can help distinguish GPD from the "naked" granulomas in cutaneous sarcoidosis that typically lack inflammatory cells. GPD also may show epidermal change with mild to moderate spongiosis.^3,7

The clinical differential diagnosis of granulomatous papules on the face of a child includes GPD, granulomatous rosacea, lupus miliaris disseminatus faciei, and cutaneous sarcoidosis. Other cutaneous diseases that may occur in a periorificial distribution include perioral dermatitis, telangiectatic fibromas, and trichoepitheliomas. Although similar in distribution to GPD, the primary lesions in these latter 3 conditions are not granulomatous and can often be distinguished clinically. Deep fungal infection, atypical mycobacterial infection, and leishmaniasis can be considered in the histologic differential diagnosis of granulomatous dermatitis, but these conditions usually present as nodules, plaques, or ulcers and not necessarily in a perioral distribution.

Granulomatous rosacea and GPD have a similar clinical and histopathologic presentation. Both conditions can present as red or yellow-brown, dome-shaped facial papules with histologic findings of a perifollicular lymphohistiocytic or granulomatous infiltrate. The major distinguishing features of granulomatous rosacea are erythema, telangiectasias, pustules, and edema.8 Granulomatous rosacea is not characterized by a concentration of lesions in the perioral area, and it is most common in 30- to 50-year-old women.⁹ Rosacea also involves the eyes in about 17% of patients seen by dermatologists.¹⁰ Ocular rosacea can manifest as blepharitis, conjunctival injection, and chalazion.

Lupus miliaris disseminatus faciei is another chronic facial papular eruption with a high predilection for the eyelids. The lesions are usually red or yellow-brown dome-shaped papules. Histologic examination demonstrates well-formed granulomas with central caseation necrosis. Lesions resolve spontaneously in 12 to 24 months with scarring. To our knowledge, lupus miliaris disseminatus faciei has not been reported in children. It has been hypothesized that most patients with this eruption actually have a form of granulomatous rosacea.⁷

Sarcoidosis is a systemic granulomatous disease with cutaneous manifestations. Cutaneous involvement occurs in up to one third of patients and can present as macules, papules, nodules, plaques, subcutaneous nodules, infiltrative scars, and ichthyosis. Maculopapular lesions are the most common cutaneous manifestation of sarcoidosis and can occur anywhere on the skin.¹¹ Lupus pernio is a variant of sarcoidosis characterized by violaceous papules and plaques on the nasal alar rims, ears, and cheeks. This variant of sarcoidosis occurs most frequently in middle-aged women and is associated with chronic fibrotic respiratory tract involvement. Patients with cutaneous sarcoidosis may have systemic symptoms including weight loss, shortness of breath, cough, fatigue, and bone and joint pain.

Perioral dermatitis most commonly occurs in young women between 16 and 45 years of age. The characteristic eruption consists of pustular or papulovesicular lesions on an erythematous background.¹² The lesions are usually confined to the chin and nasolabial folds, with sparing around the vermilion border. GPD may be distinguished from perioral dermatitis by the presence of discrete yellow-brown papules rather than erythematous papules, the lack of pustules, and the presence of a perifollicular granulomatous infiltrate seen on examination of biopsy material.⁵

Treatment of GPD is based on anecdotal reports. Tetracycline has been recommended for GPD in children older than 8 years.^3,13 Recent studies have demonstrated that tetracyclines inhibit granuloma formation in vitro.¹⁴ Tetracyclines are also effective treatment for rosacea and perioral dermatitis because of their anti-inflammatory properties.¹⁵ According to anecdotal reports, topical tetracycline and topical clindamycin are sometimes effective therapy for perioral dermatitis and may be helpful in GPD when oral agents are undesirable. GPD also has responded to topical treatment with metronidazole gel in some reports.^3,16 Mild GPD may resolve spontaneously over several months without therapy. The use of oral steroids in this condition has not been reported, but in our patient, a tapering course of prednisone seemed justified because of the distressing nature of the eruption to the patient. Oral prednisone may produce anti-inflammatory effects more quickly than tetracycline, but it is not necessary in most patients.

GPD represents a benign cutaneous inflammatory process that resolves without serious sequelae. The granulomatous inflammation is most likely a nonspecific reaction to a variety of insults. Topical corticosteroids may initiate or exacerbate the granulomatous reaction and should be strictly avoided. Practitioners should recognize and distinguish this condition from other granulomatous eruptions so that patients are appropriately managed.

Case Report

A healthy 12-year-old African American boy presented with a 3-month history of an asymptomatic, papular, perioral eruption. He had been previously treated by a primary care provider, who had prescribed a low-potency and then a medium-potency topical corticosteroid, without improvement. The patient's parents denied that he had used topical corticosteroids or other topical preparations prior to the eruption. He took no oral medications, and the findings of the review of systems were within reference range. Results of a physical examination revealed numerous, discrete and coalescing, firm, pink, hyperpigmented papules ranging from 2 to 4 mm in diameter, primarily located in the perioral area (Figure). A few papules were noted around the nose and eyes. Results of a shave biopsy of a perioral papule revealed dermal granulomatous inflammation. The infiltrate consisted of histiocytes and lymphocytes and also included several focal collections of neutrophils. There was overlying parakeratosis. Results of a periodic acid–Schiff, Gomori methenamine-silver, Brown-Brenn, and Fite-Farraco stains were negative for organisms.

The patient was diagnosed with granulomatous periorificial dermatitis (GPD), and treatment with oral tetracycline 500 mg twice a day was initiated. Six days later, a tapering course of oral prednisone was added (consisting of 40 mg for 3 days, 30 mg for 3 days, 20 mg for 3 days, and 10 mg for 3 days) because of the severe extent of the eruption and the social distress it was causing the patient. Within 3 weeks, a dramatic decrease in the eruption was noted, with only a few small papules remaining. The patient was then switched from oral tetracycline to topical clindamycin twice a day for maintenance, but he did not return for follow-up. 

Comment

GPD is characterized by a monomorphic papular eruption occurring in the perinasal, perioral, and periocular areas. Gianotti et al1 first described the condition in 5 children, ranging in age from 2 to 7 years, who had asymptomatic, distinctive, flesh-colored, "micronodular," periorificial eruptions. In the literature, the condition has been variably called Gianotti-type perioral dermatitis, sarcoidlike granulomatous dermatitis, facial Afro-Caribbean childhood eruption, and childhood granulomatous perioral dermatitis. It has been proposed that GPD is a form of perioral dermatitis with granulomatous histologic features.^2,3 GPD typically affects prepubertal children, predominantly African Americans and others with dark skin. Several cases involving fair-skinned children have been reported.² Both genders are equally affected. Typical lesions have been described as flesh-colored, yellow-brown, or red papules or micronodules.^2,3 Slight scaling of lesions or surrounding erythema may occur.² Scarring is absent in most cases; however, pinpoint atrophy or scarring occasionally occurs.² In addition to the characteristic facial distribution, extrafacial and generalized lesions on the trunk, extremities, and labia majora have been described.² In all reported cases, the lesions, including extrafacial lesions, were histologically similar and self-limited and were not accompanied by associated systemic symptoms. The presence of extrafacial lesions did not affect the duration of disease or the response to treatment.

The etiology of GPD is unknown. It may represent an unusual inflammatory granulomatous response to allergens.³ The initial allergen may cause inflammation and a focal disruption of the follicular wall, inciting a granulomatous reaction.³ In 1978, Georgouras and Kocsard4 described a case of Gianotti-type perioral dermatitis as an unusual reaction to bubble gum. Other reports have implicated reactions to formaldehyde, cosmetic preparations, and antiseptic solutions.⁵ Topical corticosteroids may induce or exacerbate both perioral dermatitis and GPD.^3,6

Histologic findings consist of upper dermal and perifollicular granulomas admixed with lymphocytes. The inflammation surrounding a focally disrupted hair follicle may range from a primarily lymphocytic inflammation with focal granuloma formation to a denser dermal granulomatous infiltrate. The presence of lymphocytic inflammation can help distinguish GPD from the "naked" granulomas in cutaneous sarcoidosis that typically lack inflammatory cells. GPD also may show epidermal change with mild to moderate spongiosis.^3,7

The clinical differential diagnosis of granulomatous papules on the face of a child includes GPD, granulomatous rosacea, lupus miliaris disseminatus faciei, and cutaneous sarcoidosis. Other cutaneous diseases that may occur in a periorificial distribution include perioral dermatitis, telangiectatic fibromas, and trichoepitheliomas. Although similar in distribution to GPD, the primary lesions in these latter 3 conditions are not granulomatous and can often be distinguished clinically. Deep fungal infection, atypical mycobacterial infection, and leishmaniasis can be considered in the histologic differential diagnosis of granulomatous dermatitis, but these conditions usually present as nodules, plaques, or ulcers and not necessarily in a perioral distribution.

Granulomatous rosacea and GPD have a similar clinical and histopathologic presentation. Both conditions can present as red or yellow-brown, dome-shaped facial papules with histologic findings of a perifollicular lymphohistiocytic or granulomatous infiltrate. The major distinguishing features of granulomatous rosacea are erythema, telangiectasias, pustules, and edema.8 Granulomatous rosacea is not characterized by a concentration of lesions in the perioral area, and it is most common in 30- to 50-year-old women.⁹ Rosacea also involves the eyes in about 17% of patients seen by dermatologists.¹⁰ Ocular rosacea can manifest as blepharitis, conjunctival injection, and chalazion.

Lupus miliaris disseminatus faciei is another chronic facial papular eruption with a high predilection for the eyelids. The lesions are usually red or yellow-brown dome-shaped papules. Histologic examination demonstrates well-formed granulomas with central caseation necrosis. Lesions resolve spontaneously in 12 to 24 months with scarring. To our knowledge, lupus miliaris disseminatus faciei has not been reported in children. It has been hypothesized that most patients with this eruption actually have a form of granulomatous rosacea.⁷

Sarcoidosis is a systemic granulomatous disease with cutaneous manifestations. Cutaneous involvement occurs in up to one third of patients and can present as macules, papules, nodules, plaques, subcutaneous nodules, infiltrative scars, and ichthyosis. Maculopapular lesions are the most common cutaneous manifestation of sarcoidosis and can occur anywhere on the skin.¹¹ Lupus pernio is a variant of sarcoidosis characterized by violaceous papules and plaques on the nasal alar rims, ears, and cheeks. This variant of sarcoidosis occurs most frequently in middle-aged women and is associated with chronic fibrotic respiratory tract involvement. Patients with cutaneous sarcoidosis may have systemic symptoms including weight loss, shortness of breath, cough, fatigue, and bone and joint pain.

Perioral dermatitis most commonly occurs in young women between 16 and 45 years of age. The characteristic eruption consists of pustular or papulovesicular lesions on an erythematous background.¹² The lesions are usually confined to the chin and nasolabial folds, with sparing around the vermilion border. GPD may be distinguished from perioral dermatitis by the presence of discrete yellow-brown papules rather than erythematous papules, the lack of pustules, and the presence of a perifollicular granulomatous infiltrate seen on examination of biopsy material.⁵

Treatment of GPD is based on anecdotal reports. Tetracycline has been recommended for GPD in children older than 8 years.^3,13 Recent studies have demonstrated that tetracyclines inhibit granuloma formation in vitro.¹⁴ Tetracyclines are also effective treatment for rosacea and perioral dermatitis because of their anti-inflammatory properties.¹⁵ According to anecdotal reports, topical tetracycline and topical clindamycin are sometimes effective therapy for perioral dermatitis and may be helpful in GPD when oral agents are undesirable. GPD also has responded to topical treatment with metronidazole gel in some reports.^3,16 Mild GPD may resolve spontaneously over several months without therapy. The use of oral steroids in this condition has not been reported, but in our patient, a tapering course of prednisone seemed justified because of the distressing nature of the eruption to the patient. Oral prednisone may produce anti-inflammatory effects more quickly than tetracycline, but it is not necessary in most patients.

GPD represents a benign cutaneous inflammatory process that resolves without serious sequelae. The granulomatous inflammation is most likely a nonspecific reaction to a variety of insults. Topical corticosteroids may initiate or exacerbate the granulomatous reaction and should be strictly avoided. Practitioners should recognize and distinguish this condition from other granulomatous eruptions so that patients are appropriately managed.