Case Letter

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

 

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

 

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

 

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

 

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

To the Editor:

A 39-year-old man with a history of hypertension and vitiligo presented with a rapid-onset, generalized, pruritic rash covering the body of 4 weeks’ duration. He reported that the rash progressively worsened after developing mild sunburn. The patient stated that the rash was extremely pruritic with a burning sensation and was tender to touch. He was treated with betamethasone valerate cream 0.1% by an outside physician and an over-the-counter anti-itch lotion with no notable improvement. His only medication was telmisartan-hydrochlorothiazide (HCTZ) for hypertension. He denied any drug allergies.

Physical examination revealed multiple discrete and coalescent planar erythematous papules and plaques involving only the depigmented vitiliginous skin of the forehead, eyelids, and nape of the neck (Figure 1A), and confluent on the lateral aspect of the bilateral forearms (Figure 1B), dorsal aspect of the right hand, and bilateral dorsi of the feet. Wickham striae were noted on the lips (Figure 1C). A clinical diagnosis of lichen planus (LP) was made. The patient initially was prescribed halobetasol propionate ointment 0.05% twice daily. He reported notable relief of pruritus with reduction of overall symptoms and new lesion formation.

A 4-mm punch biopsy was performed on the left forearm. Histopathology revealed LP. Microscopic examination of the hematoxylin and eosin–stained specimen revealed a bandlike lymphohistiocytic infiltrate that extended across the papillary dermis, focally obscuring the dermoepidermal junction where there were vacuolar changes and colloid bodies. The epidermis showed sawtooth rete ridges, wedge-shaped foci of hypergranulosis, and compact hyperkeratosis (Figure 2).

 

On further questioning during follow-up, the patient revealed that his hypertensive medication was changed from HCTZ, which he had been taking for the last 8 years, to the combination antihypertensive medication telmisartan-HCTZ before the onset of the skin eruption. Due to the temporal relationship between the new medication and onset of the eruption, the clinical impression was highly suspicious for drug-induced eruptive LP with Köbner phenomenon caused by the recent sunburn. Systemic workup for underlying causes of LP was negative. Laboratory tests revealed normal complete blood cell counts. The hepatitis panel included hepatitis A antibodies; hepatitis B surface, e antigen, and core antibodies; hepatitis B surface antigen and e antibodies; hepatitis C antibodies; and antinuclear antibodies, which were all negative.

The patient continued to develop new pruritic papules clinically consistent with LP. He was instructed to return to his primary care physician to change the telmisartan-HCTZ to a different class of antihypertensive medication. His medication was changed to atenolol. The patient also was instructed to continue the halobetasol propionate ointment 0.05% twice daily to the affected areas.

The patient returned for a follow-up visit 1 month later and reported notable improvement in pruritus and near-complete resolution of the LP after discontinuation of telmisartan-HCTZ. He also noted some degree of perifollicular repigmentation of the vitiliginous skin that had been unresponsive to prior therapy (Figure 3).

Lichen planus is a pruritic and inflammatory papulosquamous skin condition that presents as scaly, flat-topped, violaceous, polygonal-shaped papules commonly involving the flexor surface of the arms and legs, oral mucosa, scalp, nails, and genitalia. Clinically, LP can present in various forms including actinic, annular, atrophic, erosive, follicular, hypertrophic, linear, pigmented, and vesicular/bullous types. Koebnerization is common, especially in the linear form of LP. There are no specific laboratory findings or serologic markers seen in LP.

The exact cause of LP remains unknown. Clinical observations and anecdotal evidence have directed the cell-mediated immune response to insulting agents such as medications or contact allergy to metals triggering an abnormal cellular immune response. Various viral agents have been reported including hepatitis C virus, human herpesvirus, herpes simplex virus, and varicella-zoster virus.^1-5 Other factors such as seasonal change and the environment may contribute to the development of LP and an increase in the incidence of LP eruption has been observed from January to July throughout the United States.⁶ Lichen planus also has been associated with other altered immune-related disease such as ulcerative colitis, alopecia areata, vitiligo, dermatomyositis, morphea, lichen sclerosis, and myasthenia gravis.⁷ Increased levels of emotional stress, particularly related to family members, often is related to the onset or aggravation of symptoms.^8,9

Many drug-related LP-like and lichenoid eruptions have been reported with antihypertensive drugs, antimalarial drugs, diuretics, antidepressants, nonsteroidal anti-inflammatory drugs, antimicrobial drugs, and metals. In particular, medications such as captopril, enalapril, labetalol, propranolol, chlorothiazide, HCTZ, methyldopa, chloroquine, hydroxychloroquine, quinacrine, gold salts, penicillamine, and quinidine commonly are reported to induce lichenoid drug eruption.¹⁰

Several inflammatory papulosquamous skin conditions should be considered in the differential diagnosis before confirming the diagnosis of LP. It is important to rule out lupus erythematosus, especially if the oral mucosa and scalp are involved. In addition, erosive paraneoplastic pemphigus involving primarily the oral mucosa can resemble oral LP. Nail diseases such as psoriasis, onychomycosis, and alopecia areata should be considered as the differential diagnosis of nail disease. Genital involvement also can be seen in psoriasis and lichen sclerosus.

 

Treatment of LP is mainly symptomatic because of the benign nature of the disease and the high spontaneous remission rate with varying amount of time. If drugs, dental/metal implants, or underlying viral infections are the identifiable triggering factors of LP, the offending agents should be discontinued or removed. Additionally, topical or systemic treatments can be given depending on the severity of the disease, focusing mainly on symptomatic relief as well as the balance of risks and benefits associated with treatment.

Treatment options include topical and intralesional corticosteroids. Systemic medications such as oral corticosteroids and/or acitretin commonly are used in acute, severe, and disseminated cases, though treatment duration varies depending on the clinical response. Other systemic agents used to treat LP include griseofulvin, metronidazole, sulfasalazine, cyclosporine, and mycophenolate mofetil.

Phototherapy is considered an alternative therapy, especially for recalcitrant LP. UVA1 and narrowband UVB (wavelength, 311 nm) have been reported to effectively treat long-standing and therapy-resistant LP.¹¹ In addition, a small study used the excimer laser (wavelength, 308 nm), which is well tolerated by patients, to treat focal recalcitrant oral lesions with excellent results.¹² Photochemotherapy has been used with notable improvement, but the potential of carcinogenicity, especially in patients with Fitzpatrick skin types I and II, has limited its use.¹³

Our patient developed an unusual extensive LP eruption involving only vitiliginous skin shortly after initiation of the combined antihypertensive medication telmisartan-HCTZ, an angiotensin receptor blocker with a thiazide diuretic. Telmisartan and other angiotensin receptor blockers have not been reported to trigger LP; HCTZ is listed as one of the common drugs causing photosensitivity and LP.^14,15 Although it is possible that our patient exhibited a delayed lichenoid drug eruption from the HCTZ, it is noteworthy that he did not experience a single episode of LP during his 8-year history of taking HCTZ. Instead, he developed the LP eruption shortly after the addition of telmisartan to his HCTZ antihypertensive regimen. The temporal relationship led us to direct the patient to the prescribing physician to discontinue telmisartan-HCTZ. After changing his antihypertensive medication to atenolol, the patient presented with improvement within the first month and near-complete resolution 2 months after the discontinuation of telmisartan-HCTZ.

Our patient’s LP lesions only manifested on the skin affected by vitiligo, sparing the normal-pigmented skin. Studies have demonstrated an increased ratio of CD8⁺ T cells to CD4⁺ T cells as well as increased intercellular adhesion molecule 1 at the dermal level.^10,16 Both vitiligo and LP share some common histopathologic features including highly populated CD8⁺ T cells and intercellular adhesion molecule 1. In our case, LP was triggered on the vitiliginous skin by telmisartan. Vitiligo in combination with trauma induced by sunburn may represent the trigger that altered the cellular immune response and created the telmisartan-induced LP. As a result, the LP eruption was confined to the vitiliginous skin lesions.

Perifollicular repigmentation was observed in our patient after the LP lesions resolved; the patient’s vitiligo was unresponsive to prior treatment. The inflammatory process occurring in LP may exert and interfere in the underlying autoimmune cytotoxic effect toward the melanocytes and the melanin synthesis. It may be of interest to find out if the inflammatory response of LP has a positive influence on the effect of melanogenesis pathways or on the underlying autoimmune-related inflammatory process in vitiligo. Further studies are needed to investigate the role of immunotherapy targeting specific inflammatory pathways and the impact on the repigmentation in vitiligo.

Acknowledgment—Special thanks to Paul Chu, MD (Port Chester, New York).

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

 

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

 

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

A 52-year-old woman with a history of arthralgia, rhinitis, sinusitis, and episodic epistaxis was admitted to the hospital with multiple nonhealing severe leg ulcerations. She noticed subcutaneous nodules on the legs 6 months prior to the development of ulcers. The lesions progressed from subcutaneous nodules to red-black skin discoloration, blister formation, and eventually ulceration. Over a period of months, the ulcers were treated with several courses of antibiotics and wound care including a single surgical debridement of one of the ulcers on the dorsum of the right foot. These interventions did not make a remarkable impact on ulcer healing.

On physical examination, the patient had scattered 4- to 5-mm palpable purpura on the knees, elbows, and feet bilaterally. She had multiple 1- to 8-cm indurated purple ulcerations with friable surfaces and raised irregular borders on the feet, toes, and lower legs bilaterally (Figure, A–C). One notably larger ulcer was found on the anterior aspect of the left thigh (Figure, A). Scattered 5- to 15-mm eschars were present on the legs bilaterally. She also had multiple large, firm, nonerythematous dermal plaques on the thighs bilaterally that measured several centimeters. There were no oral mucosal lesions and no ulcerations above the waist.

Magnetic resonance imaging of the foot showed some surrounding cellulitis but no osteomyelitis. Chest radiograph and computed tomography revealed bilateral apical nodules. Proteinase 3–antineutrophil cytoplasmic antibody (PR3-ANCA) testing was positive. Serum complement levels were normal. An antinuclear antibody test and rheumatoid factor were both negative. Skin biopsies were obtained from the thigh ulcer, foot ulcer, and purpuric lesions on the right knee. The results demonstrated leukocytoclastic vasculitis and neutrophilic small vessel vasculitis with necrotizing neutrophilic dermatitis and panniculitis. Granulomatosis with polyangiitis (GPA) was diagnosed based on these findings.

Initial inpatient treatment included intravenous methylprednisolone (100 mg every 8 hours for 3 doses), followed by oral prednisone 60 mg daily. Two weeks later the ulcers were reevaluated and only mild improvement had occurred with the steroids. Therefore, rituximab (RTX) was initiated at 375 mg/m² (700 mg) intravenously once weekly for 4 weeks. After 3 doses of RTX, the ulcerations were healing dramatically and the treatment was well tolerated. A rapid prednisone taper was started, and the patient received her fourth and final dose of RTX. Two months after the initial infusion, the thigh ulcer and most of the ulcerations on the feet and lower legs had almost completely resolved. Photographs were taken 5 months after initial RTX infusion (Figure, D–F). A chest radiograph 4 months after initial RTX infusion showed resolution of lung nodules. Two months after RTX induction therapy, azathioprine was added for maintenance but was stopped due to poor tolerance. Oral methotrexate 17.5 mg once weekly was added 5 months after RTX for maintenance and was well tolerated. At that time the prednisone dose was 10 mg daily and was successfully tapered to 5 mg by 9 months after RTX induction therapy.

Granulomatosis with polyangiitis (Wegener granulomatosis) is a granulomatous small- and medium-sized vessel vasculitis that traditionally affects the upper and lower respiratory tract and kidneys.¹ Skin lesions also are quite common and include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Patients with active GPA also tend to have ANCAs directed against proteinase 3 (PR3-ANCA). Although GPA was once considered a fatal disease, treatment with cyclophosphamide combined with corticosteroids has been shown to substantially improve outcomes.¹ Rituximab, a chimeric monoclonal anti-CD20 antibody, works by depleting B lymphocytes and has been used with success to treat diseases such as lymphoma and rheumatoid arthritis.^2,3 The US Food and Drug Administration approved RTX for GPA and microscopic polyangiitis in 2011, with a number of trials supporting its efficacy.⁴

The success of RTX in treating GPA has been documented in case reports as well as several trials with extended follow-up. A single-center observational study of 53 patients showed that RTX was safe and effective for induction and maintenance of remission in patients with refractory GPA. This study also uncovered the potential for predicting relapse based on following B cell and ANCA levels and preventing relapse by initializing further treatment.⁵ Other small studies and case reports have shown similar success using RTX for refractory GPA.^6-10 These studies included various combinations of concurrent therapies and various follow-up intervals. The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared RTX versus cyclophosphamide for ANCA-positive vasculitis.¹¹ This multicenter, randomized, double-blind study found that RTX was as efficacious as cyclophosphamide for induction of remission in severe GPA.The data also suggested that RTX may be superior for relapsing disease.¹¹ Another multicenter, open-label, randomized trial (RITUXVAS) compared RTX to cyclophosphamide in ANCA-associated renal vasculitis. This trial also found the 2 treatments to be similar in both efficacy in inducing remission and adverse events.¹²

 

Some conflicting reports have appeared on the effectiveness of using RTX for the granulomatous versus vasculitic manifestations of GPA. Aires et al¹³ showed failure of improvement in most patients with granulomatous manifestations of GPA in a study of 8 patients. A retrospective study including 59 patients who were treated with RTX also showed that complete remission was more common in patients with primarily vasculitic manifestations, not granulomatous manifestations.¹⁴ However, some case series that included patients with refractory ophthalmic GPA, a primarily granulomatous manifestation, have found success using RTX.^15,16 More studies are needed to determine if there truly is a difference and whether this difference has an effect on when to use RTX. The skin lesions our patient demonstrated were due to the vasculitic component of the disease, and consequently, the rapid and complete response we observed would be consistent with the premise that the therapy works best for vasculitis.

Most of the trials assessing the efficacy of RTX utilize a tool such as the Wegener granulomatosis-specific Birmingham Vasculitis Activity Score.¹⁷ This measure of treatment response does include a skin item, but it is part of the composite response score. Consequently, a specific statement regarding skin improvement cannot be made. Additionally, little is reported pertaining to the treatment of skin-related findings in GPA. One report did specifically address the treatment of dermatologic manifestations of GPA utilizing systemic tacrolimus with oral prednisone successfully in 1 patient with GPA and a history of recurrent lower extremity nodules and ulcers.¹⁸ The efficacy of RTX in limited GPA was good in a small study of 8 patients. However, the study had only 1 patient with purpura and 1 patient with a subcutaneous nodule.¹⁹ Several other case series and studies have included patients with various cutaneous findings associated with GPA.^5-7,9,11 However, they did not comment specifically on skin response to treatment, and the focus appeared to be on other organ system involvement. One case series did report improvement of lower extremity gangrene with RTX therapy for ANCA-associated vasculitis.⁸ Our report demonstrates a case of severe skin disease that responded well to RTX. It is common to have various skin findings in GPA, and our patient presented with notable skin disease. Although skin findings may not be the more life-threatening manifestations of the disease, they can be quite debilitating, as shown in our case report.

Our patient with notable leg ulcerations required hospitalization due to GPA and received RTX in addition to corticosteroids for treatment. We observed a rapid and dramatic improvement in the skin findings, which seemed to exceed expectations from steroids alone. The other manifestations of the disease including lung nodules also improved. Although cyclophosphamide and corticosteroids have been quite successful in induction of remission, cyclophosphamide is not without serious adverse effects. There also are some patients who have contraindications to cyclophosphamide or do not see successful results. In our brief review of the literature, RTX, a B cell–depleting antibody, has shown to have success in treating refractory and severe GPA. There is little reported specifically about treating the skin manifestations of GPA. A few studies and case reports mention skin findings but do not comment on the success of RTX in treating them. Although the severity of other organ involvement in GPA may take precedence, the skin findings can be quite debilitating, as in our patient. Patients with GPA and notable skin findings may benefit from RTX, and it would be beneficial to include these results in future studies using RTX to treat GPA.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

 

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

 

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:

RASopathies, a class of developmental disorders, are caused by mutations in genes that encode protein components of the RAS/mitogen-activated protein kinase (MAPK) pathway. Each syndrome exhibits its phenotypic features; however, because all of them cause dysregulation of the RAS/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes including cardiac defects, cutaneous abnormalities, characteristic facial features, neurocognitive impairment, and increased risk for developing some neoplastic disorders.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy and is a genetic sporadic disease characterized by multiple congenital anomalies associated with mental retardation. It has a complex dermatological phenotype with many cutaneous features that can be helpful to differentiate CFC syndrome from Noonan and Costello syndromes, which also are classified as RASopathies.

A 3-year-old girl presented with skin xerosis and follicular hyperkeratosis of the face, neck, trunk, and limbs (Figure 1). Facial follicular hyperkeratotic papules on an erythematous base were associated with alopecia of the eyebrows (ulerythema ophryogenes). Hair was sparse and curly (Figure 2A). Facial dysmorphic features included a prominent forehead with bitemporal constriction, bilateral ptosis, a broad nasal base, lip contour in a Cupid’s bow, low-set earlobes with creases (Figure 2B), and a short and webbed neck.

Congenital heart disease, hypothyroidism, bilateral hydronephrosis, delayed motor development, and seizures were noted for the first 2 years. Brain computed tomography detected a dilated ventricular system with hydrocephalus. There was no family history of consanguinity.

Pregnancy was complicated by polyhydramnios and preeclampsia. The neonate was delivered at full-term and was readmitted at 6 days of age due to respiratory failure secondary to congenital chylothorax. Cardiac malformation was diagnosed as the ostium secundum atrial septal defect and interventricular and atrioventricular septal defects. Up to this point she was being treated for Turner syndrome.

 

The RASopathies are a class of human genetic syndromes that are caused by germ line mutations in genes that encode components of the RAS/MAPK pathway.¹ There are many syndromes classified as RASopathies (Table).^2,3

Cardiofaciocutaneous syndrome (Online Mendelian Inheritance in Man [OMIM] 115150) is a genetic disorder first described by Reynolds et al⁴ and is characterized by several cutaneous abnormalities, cardiac defects, dysmorphic craniofacial features, gastrointestinal dysmotility, and mental retardation. It occurs sporadically and is caused by functional activation of mutations in 4 different genes—BRAF, KRAS, MAP2K1, MAP2K2—of the RAS extracellular signal–regulated kinase molecular cascade that regulates cell differentiation, proliferation, and apoptosis.¹

As a RASopathy, CFC syndrome is a member of a family of syndromes with similar phenotypes, which includes mainly Noonan and Costello syndromes. Psychomotor retardation and physical anomalies, the common denominator of all syndromes, may be explained by the effects of the mutations during early development.^5,6

In CFC, relative macrocephaly, prominent forehead, bitemporal constriction, absence of eyebrows, palpebral ptosis, broad nasal root, bulbous nasal tip, and small chin commonly are found. The eyes are widely spaced and the palpebral fissures are downward slanting with epicanthic folds.^1,4,7

Follicular keratosis of the arms, legs, and face occurs in 80% of cases of CFC and ulerythema ophryogenes with sparse eyebrows in 90% of cases. Sparse, curly, and slow-growing hair is found in 93% of patients. Xerotic scaly skin, hyperkeratosis of the palms and soles, infantile hemangiomas, and multiple melanocytic nevi also may occur.⁸

Cardiac abnormalities are seen in 75.7% of patients.¹ Other features include mental retardation, delayed motor development, and structural abnormalities in the central nervous system, as well as seizures and electroencephalogram abnormalities. Unlike Noonan and Costello syndromes, it is unclear if patients with CFC syndrome are at an increased risk for cancer.¹

Noonan syndrome (OMIM #163950) is a disorder characterized by congenital heart defects, short stature, skeletal abnormalities, distinctive facial dysmorphic features, and variable cognitive deficits. Other associated features include cryptorchidism, lymphatic dysplasia, bleeding tendency, and occasional hematologic malignancies during childhood. This syndrome is related to mutations in the PTPN11, SOS1, SOS2, RAF1, BRAF, KRAS, NRAS, RIT1, and LZTR1 genes.^2,9-11 The typical ear shape and placement in Noonan syndrome is oval with an overfolded helix that is low set and posteriorly angulated, which is uncommon in CFC syndrome. Noonan syndrome is characterized by an inverted triangular face; hypertelorism; blue or blue-green iris color; webbed neck; limited skin involvement, mainly represented by multiple nevi; and a much milder developmental delay compared to CFC and Costello syndromes.^1,11

Costello syndrome (OMIM #218040) is a rare condition comprised of severe postnatal feeding difficulties, mental retardation, coarse facial features, cardiovascular abnormalities (eg, pulmonic stenosis, hypertrophic cardiomyopathy, atrial tachycardia), tumor predisposition, and skin and musculoskeletal abnormalities.¹² Costello syndrome is clinically diagnosed. This syndrome shows coarse facies with macrocephaly, downward-slanting palpebral fissures, epicanthal folds, bulbous nose with anteversed nostrils and low nasal bridge, full cheeks, large mouth, thick lips, large tongue, nasal papillomas, cutis laxa, low-set ears, short neck, diffuse skin hyperpigmentation, ulnar deviation of the hands, and nail dystrophy that are not observed in CFC. It is now accepted that the term Costello syndrome should be reserved for patients with HRAS mutation because of the specific risk profile of these patients.¹² Remarkably, patients with Costello syndrome are at increased tumor risk (eg, rhabdomyosarcoma, neuroblastoma, bladder carcinoma).^2,12

The diagnosis of CFC syndrome is purely clinical. There have been many attempts to delineate the syndrome, but none of the described traits are pathognomonic. In 2002, Kavamura et al⁷ created the CFC index, a useful diagnostic approach based on 82 clinical characteristics and their frequencies in the CFC population.

Skin abnormalities are helpful manifestations to differentiate CFC syndrome from Noonan and Costello syndromes. Patients with CFC syndrome present with follicular hyperkeratosis and absent eyebrows. Absent eyebrows, narrowed temples, and Cupid’s bow lip are hallmark features of CFC syndrome and are absent in Noonan and Costello syndromes. The presentation of palmoplantar hyperkeratosis also is a differentiating feature; in patients with Costello syndrome, it is found outside the pressure zones, whereas in those with CFC syndrome, it is present mainly in the pressure zones.¹ Dermatologists can assist geneticists in the differential diagnosis of these syndromes.

The treatment of disorders with follicular plugging and xerosis is challenging. Emollients with urea, glycolic acid, and lactic acid could improve the appearance of the skin. Treatment with mutated MEK gene inhibitors is under investigation to restore normal development of affected embryos with CFC.^2,13 This case and theoretical data show that skin manifestations can be helpful to differentiate CFC syndrome from other RASopathies such as Noonan and Costello syndromes.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.

To the Editor:
Down syndrome (DS) is associated with rare dermatological disorders, and the prevalence of some common dermatoses is greater in patients with DS. We report a case of milialike idiopathic calcinosis cutis (MICC) associated with syringomas in a patient with DS. We emphasize that MICC is one of the rare dermatoses associated with DS.

A 4-year-old girl with DS presented with a 4-mm, flesh-colored, regular-bordered, exophytic papular lesion on the left upper eyelid of 8 months' duration (Figure 1). It was clinically recognized as syringoma. On dermatologic examination of the patient, there also were 1- to 3-mm, round, whitish, painless, milialike papules on the dorsal surface of the hands and wrists (Figure 2). Some of these papules were surrounded by erythema. There was no sign of perforation. Her personal and family history were unremarkable.

Histopathologic examination of a biopsy from a  milialike lesion on the hand showed a hyperkeratotic epidermis. In the dermis there was a roundish calcific nodule surrounded by a fibrovascular rim. The patient's guardians refused a biopsy from the lesion on the eyelid.

Laboratory tests including serum vitamin D, thyroid and parathyroid hormone, calcium, phosphorus, and urinary calcium levels, as well as renal function tests, were within reference range. On the basis of these clinical and histopathological findings, the patient was diagnosed with MICC and palpebral syringoma.

Many dermatoses associated with DS have been reported including elastosis perforans serpiginosa, alopecia areata, and syringomas.^1-3 Sano et al4 first described MICC and syringomas in a patient with DS in 1978. Milialike idiopathic calcinosis cutis is characterized by asymptomatic, millimetric, firm, round, whitish papules that are sometimes surrounded by erythema. These papules may show perforation leading to transepidermal elimination of calcium, similar to the transdermal elimination of elastic fibrils in elastosis perforans serpiginosa. Although MICC usually is described in acral sites of children with DS, it also is reported in adults without DS and on other parts of the body.^5-7

The cause of MICC is unknown. One hypothesis of the development of MICC is an increase of the calcium content in the sweat leading to calcification of the acrosyringium.⁸ Milia are small keratin cysts that usually develop by occlusion of the hair follicle, sweat duct, or sebaceous duct. However, milia also can occur from occlusion of the eccrine ducts where syringomas originate.⁹ Therefore, syringomas can be seen in association with milia and calcium deposits.^5,9-11

We believe that MICC in DS may be more common than usually recognized, as the lesions often are asymptomatic. It is important to differentiate MICC from other dermatological diseases such as molluscum contagiosum, verruca plana, milia, and inclusion cysts. Histopathology and dermoscopy could aid in the accurate diagnosis of MICC.

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

To the Editor:

A 50-year-old man presented with a painful ulcer and a burning sensation on the tongue of 2 days’ duration (Figure, A). The ulcer had a yellowish white appearance with erythematous borders. The patient started taking tinidazole 500 mg twice daily 2 days prior, which was prescribed by his primary care physician for an episode of gastroenteritis. He was not taking any other medications and did not smoke or drink. Routine laboratory test results did not reveal any abnormalities. Based on the physical examination as well as the patient’s medical and medication history, a provisional diagnosis of fixed drug eruption (FDE) due to tinidazole was made. Tinidazole was immediately withdrawn and the patient was prescribed beclomethasone dipropionate ointment twice daily to relieve the burning sensation. A punch biopsy of the lesion was recommended; however, the patient opted to wait a week after discontinuing the drug. At follow-up 1 week later, complete healing of the ulcer was observed with no scarring and the burning sensation had resolved (Figure, B). After obtaining informed consent from the patient, an oral challenge test was conducted in the office with 50 mg of tinidazole. Four hours after taking the drug orally, the patient felt a burning sensation and a small ulcerative lesion was observed on the tongue at the same site the next day. The patient was informed of the fixed drug reaction to tinidazole, a drug belonging to the nitroimidazole group, and this information also was conveyed to the patient’s primary care physician.

Tinidazole is a synthetic antiprotozoal and antibacterial agent used primarily in infections such as amebiasis, giardiasis, and trichomoniasis.¹ Tinidazole may be a therapeutic alternative to metronidazole. Fixed drug eruption is a distinctive variant of drug eruption with characteristic recurrence at the same site of skin or mucous membranes. It is characterized by onset of round/oval, erythematous, well-defined macules on the skin and/or mucosa associated with itching and burning.¹ Fixed drug eruption generally is restricted to the mucous membrane and skin, with the lips, palms, soles, glans penis, and groin area being the most common sites. Intraoral involvement, excluding the lips, of FDE is rare. The tongue is a rare site of an FDE.² Fixed drug eruption on the tongue has been reported with clarithromycin.³ Dental clinicians have to be aware of the possibility of FDE due to commonly used drugs such tinidazole, which would help in prompt diagnosis of these lesions.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

A 32-year-old woman presented with a recurrent painful eruption on the scalp of 1 year's duration. The lesion occurred on the left temporal region 1 week prior to menstruation and spontaneously resolved following menses; it recurred every month for 1 year. She had no notable medical history. She had taken oral contraceptive pills for 4 years and stopped 2 years prior to the development of the lesions. Dermatologic examination revealed a purple-colored, violaceous, centrally elevated, painful plaque that measured 2 cm in diameter in the left temporal region of the scalp (Figure, A). Laboratory test results were within reference range. The lesion spontaneously resolved with mild residual erythema at a follow-up visit after menstruation (Figure, B).

Because the eruption occurred and relapsed with the patient's menstrual cycle, we suspected progesterone hypersensitivity. An intradermal skin test was performed on the forearm with 0.05 mL of medroxyprogesterone acetate, and saline was used as a negative control. An indurated erythematous nodule occurred on the progesterone-treated side within 6 hours. Based on these findings and the patient's history, she was diagnosed with autoimmune progesterone dermatitis (APD). We recommended her to use gonadotropin-releasing hormone agonists as treatment, but the patient refused. At 6-month follow-up she had recurrent lesions but did not report any concerns.

Autoimmune progesterone dermatitis is a rare condition that is characterized by cyclical skin eruptions, typically occurring in the luteal phase of the menstrual cycle with spontaneous resolution after menses.^1,2 It was first described by Geber3 in a patient with cyclical urticarial lesions. In 1964, Shelley et al⁴ characterized APD in a 27-year-old woman with a pruritic vesicular eruption with cyclical premenstrual exacerbations. Although it is believed there is no genetic predisposition to APD, a case series involving 3 sisters demonstrated that genetic susceptibility might play a role in the etiology.⁵ The etiology of APD is still unknown. It is thought to represent an autoimmune reaction to endogenous or exogenous progesterone.¹ Our patient also had used oral contraceptives for 4 years and this exogenous progesterone might have played a role in the sensitization of the patient and the development of this autoimmune reaction.

The clinical features of APD usually begin 3 to 10 days prior to menstruation and end 1 to 2 days after menses. Autoimmune progesterone dermatitis can present in a variety of forms including eczema, erythema multiforme, erythema annulare centrifugum, fixed drug eruption, stomatitis, folliculitis, urticaria, and angioedema.⁶ A case of APD presenting with petechiae and purpura has been reported.⁷ There are no specific histologic findings for APD.⁸ Demonstration of progesterone sensitivity with a progesterone challenge test is the mainstay of diagnosis. Immediate urticaria may occur in some patients, with others experiencing a delayed reaction peaking at 24 to 96 hours.⁹ The main criteria of APD include the following: recurrent cyclic lesions related to the menstrual cycle; positive intradermal progesterone skin test; and prevention of lesions by inhibiting ovulation.¹ Two of these criteria were positive in our patient, but we did not use any medications to prevent ovulation at the patient's request.

Current treatment modalities often attempt to inhibit the secretion of endogenous progesterone by suppressing ovulation. Oral contraceptives and conjugated estrogens have limited efficacy rates.⁸ Gonadotropin-releasing hormone agonists (ie, buserelin, triptorelin) have been used with success.^1,6 Tamoxifen and danazol are other treatment options. For cases refractory to medical treatments, bilateral oophorectomy can be considered a definitive treatment.⁶

Autoimmune progesterone dermatitis may present in many different clinical forms. It should be considered in the differential diagnosis in patients with recurrent skin lesions related to menstrual cycle both in women of childbearing age and in men taking synthetic progesterone.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

Acute generalized exanthematous pustulosis (AGEP) is an acute skin reaction that is characterized by generalized, nonfollicular, pinhead-sized, sterile pustules on an erythematous and edematous background. The eruption can be accompanied by fever and neutrophilic leukocytosis. Skin symptoms arise quickly (within a few hours), most commonly following drug administration. The medications most frequently responsible are beta-lactam antibiotics, macrolides, calcium channel blockers, and antimalarials. Pustules spontaneously resolve in 15 days and generalized desquamation occurs approximately 2 weeks later. The estimated incidence rate of AGEP is approximately 1 to 5 cases per million per year. Acute localized exanthematous pustulosis (ALEP) is a less common form of AGEP. We report a case of ALEP localized on the face that was caused by flurbiprofen, a propionic acid derivative from the family of nonsteroidal anti-inflammatory drugs (NSAIDs).

A 40-year-old woman was referred to the dermatology department due to the sudden onset of multiple pustules on the face. One week earlier she started oral flurbiprofen (8.75 mg daily) for a sore throat. After 3 days of therapy, multiple pruritic, erythematous and edematous lesions appeared abruptly on the face with associated multiple small nonfollicular pustules. At presentation the patient was febrile (temperature, 38.2°C) and presented with bilateral ocular edema and superficial small nonfollicular pustules on an erythematous background over the face, scalp, and oral mucosa (Figure 1). The rest of the body was not involved. The patient denied prior adverse reactions to other drugs. The white blood cell count was 15,000/μL (reference range, 4500–11,000/μL), with an increased neutrophil count (12,000/μL [reference range, 1800–7800/μL]). The erythrocyte sedimentation rate and C-reactive protein level was elevated (erythrocyte sedimentation rate, 53 mm/h [reference range, 0–20 mm/h]; C-reactive protein, 98 mg/dL [reference range, 0–5 mg/dL]). Bacterial and fungal cultures of skin lesions were negative. The results of a viral polymerase chain reaction analysis proved the absence of varicella-zoster virus or herpes simplex virus. Histopathology of a skin biopsy specimen showed subcorneal pustules composed of neutrophils and eosinophils, epidermal spongiosis, some necrotic keratinocytes, vacuolization of the basal layer, papillary edema, and a perivascular neutrophil and lymphocyte infiltrate (Figure 2). A leukocytoclastic infiltrate within and around the walls of blood vessels at the superficial level of the dermis and red cell extravasation in the epidermis was present. She discontinued use of flurbiprofen and was treated with a systemic corticosteroid (methylprednisolone 0.5 mg/kg daily). The pustules rapidly resolved within 7 days after discontinuation of flurbiprofen and were followed by transient scaling and discrete residual hyperpigmentation.

Acute localized exanthematous pustulosis is a less common form of a pustular drug eruption in which lesions are consistent with AGEP but typically are localized to the face, neck, or chest. The definition of ALEP was introduced by Prange et al¹ to describe a woman who was diagnosed with a localized pustular eruption on the face without a generalized distribution as in AGEP. In the past, this localized eruption was described under different names (eg, localized pustular eruption, localized toxin follicular pustuloderma, nongeneralized acute exanthematic pustulosis).^2-5 According to a PubMed search of articles indexed for MEDLINE using the terms localized pustulosis, localized pustular eruption, and localized pustuloderma, only 16 separate cases of ALEP have been documented since the report by Prange et al.¹ The medications most frequently responsible are antibiotics. Three cases developed following administration of amoxicillin^2,5,6; 2 cases of amoxicillin–clavulanic acid^7,8; 1 of penicillin¹; 1 of azithromycin⁹; 1 of levofloxacin¹⁰; and 1 of combination of cephalosporin, sulfamethoxazole-trimethoprim, and vancomycin.¹¹ Other nonantibiotic causative drugs include sulfamethoxazole-trimethoprim,¹² infliximab,¹³ sorafenib,¹⁴ docetaxel,¹⁵ finasteride,¹⁶ ibuprofen,¹⁷ and paracetamol.¹⁸ In reported cases, the lesions are consistent with the characteristics of AGEP both clinically and histopathologically but are localized typically to the face, neck, or chest. In the majority of patients with ALEP, the absence of fever has been observed, but it does not appear distinctive for diagnosis. Our patient represents another case of ALEP with flurbiprofen as the causative drug. The close relationship between the administration of the drug and the development of the pustules, the rapid acute resolution as soon as treatment was interrupted, and the histologic findings all supported the diagnosis of ALEP following administration of flurbiprofen. This NSAID—2-fluoro-α-methyl-(1,1'-biphenyl)-4-acetic acid—is a prostaglandin synthetase inhibitor with anti-inflammatory activity. It is a propionic acid derivative that is similar to ibuprofen, which was once involved in the occurrence of ALEP.¹⁷ In 2009, Rastogi et al¹⁷ reported a case of a 64-year-old woman with an acute outbreak of multiple pustular lesions and underlying erythema affecting the cheeks and chin without fever who had been taking ibuprofen for a toothache. The case is similar to ours and confirms that NSAIDs can induce ALEP. Compared with other NSAIDs, propionic acid derivatives are usually well tolerated and serious adverse reactions rarely have been documented.¹⁹

The physiopathologic mechanisms of ALEP are unknown but likely are similar to AGEP. The demonstration of drug-specific positive patch test responses and in vitro lymphocyte proliferative responses in patients with a history of AGEP strongly suggests that this adverse cutaneous reaction occurs via a drug-specific T cell–mediated process.²⁰

Further study is needed to understand the etiopathogenesis of the localized form of the disease and to facilitate a correct diagnosis of this rare disorder.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:

A 42-year-old woman who had a tattoo on the right wrist surgically removed 2 days prior developed severe erythema and swelling at the incision site (Figure 1). Exposure at the incision site was limited to bacitracin, poliglecaprone 25 suture, and plain cotton gauze. Patch testing of bacitracin was performed, which was ++ (moderately positive reaction) at the 96-hour reading, indicating that part of the reaction was due to the topical antibiotic. Testing of the suture was performed by tying the suture to the skin of the forearm and removing it at 48 hours. There was a ++ reaction to the suture prior to removal at 48 hours, which increased to +++ (severely positive reaction) after suture removal at 96 hours (Figure 2). Therefore, it appears that allergy to the suture also was partially responsible for the postsurgical reaction.

Poliglecaprone 25 suture is a monofilament synthetic absorbable material that is a copolymer of glycolide and ε-caprolactone. One case report of oral contact allergy to this suture material resulted in failure of an oral graft; however, no testing was performed to verify the contact allergy.¹ Caprolactam ([CH₂]₅C[O]NH) is a related chemical that can be synthesized by treating caprolactone ([CH₂]₅CO₂) with ammonia at elevated temperatures.² Contact allergy has been reported to polyamide 6 suture, which is obtained by polymerizing ε-caprolactam. This report stated that contact allergy to ε-caprolactam also has been reported occupationally during manufacture and from its use in fishing nets, socks, gloves, and stockings.³

The package insert for the poliglecaprone 25 suture states that the material is “nonantigenic, nonpyrogenic and elicits only a slight tissue reaction during absorption.”⁴ We present a case of contact allergy to poliglecaprone 25 suture that was confirmed by allergy testing.

To the Editor:
A 12-year-old girl presented with discomfort and walking limitation caused by cutaneous masses on the plantar aspects of the feet with associated bone abnormalities that had started as several flesh-colored papules on the plantar surface of both feet at the age of 1 year. Over time the lesions gradually enlarged and formed irregular masses, more prominently on the right foot. At the age of 6 years, surgical correction was performed due to increased walking impairment and a skin examination that suggested connective tissue nevus. The results were good. However, the local tissue overgrowth recurred after 1 year. Slowly growing lesions were found at the surgical site, which necessitated hospitalization. Her medical history was negative for other disease. There was no family history of similar skin conditions and her parents were nonconsanguineous.

Physical examination revealed malnutrition and poor development in height as well as difficulty walking. She also had moderate scoliosis with a curve to the left. Dermatological examination showed multiple reddish cerebriform hyperplasia in both plantar areas; the right side was more severely involved (Figure 1A). There was macrodactyly of 2 toes on the right foot (Figure 1B). All results of routine blood examinations were within reference range. There were no abnormalities noted in the abdominal ultrasound and cardiac examinations. Plain radiographs of the spine and feet demonstrated scoliosis and exostosis on the calcaneus and bottom of the scaphoid. Histopathologic examination of tissue from the plantar cerebriform hyperplasia revealed hyperkeratosis, slight acanthosis and papillomatosis in the epidermis, and dense collagen bands and sparse elastic fibers in the dermis (Figure 2).

Given the clinical and radiologic manifestation, the diagnosis of Proteus syndrome (PS) was established. After taking into account the severe discomfort and the success of the first surgery, we performed a resection and full-thickness skin graft surgery once again. The feet recovered without any discomfort in daily life. The appearance of the skin graft area was normal 1 year following surgery (Figure 3). She was treated with spinal plate fixation at another institution, progressed well for 2 years, and was subsequently lost to follow-up.

Proteus syndrome is a multisystem disorder with a difficult diagnosis due to the variability of its manifestations. The worldwide incidence of this rare disorder is less than 1 per 1 million individuals, and it is thought to be caused by a somatic genetic alteration.¹ Clinical characteristics include bone abnormalities, vascular malformations, dysregulation of fatty tissue, linear verrucous epidermal nevus, and cerebriform connective tissue nevus (CCTN). Although CCTN is not a common finding in patients with PS, it is considered a fairly specific sign with the greatest impact for the diagnosis of PS.²

The general feature of PS--asymmetric disproportionate overgrowth of tissues--appears at 6 to 18 months of age, which makes it challenging to diagnose disease earlier. The CCTN in our patient was present since 1 year of age.

 

To make a diagnosis of PS, one must have all the general criteria and various specific criteria. The revised diagnostic criteria for PS are given in the Table.³ According to the diagnostic criteria, our patient fulfilled the mandatory general criteria and had plantar CCTN, epidermal nevus, and dysregulated adipose tissue. The CCTN has notable diagnostic value in mildly affected patients, as it is absent in diseases included in the differential diagnosis such as neurofibromatosis, Klippel-Trenaunay-Weber syndrome, Maffucci syndrome, and Bannayan-Riley-Ruvalcaba syndrome. Hemihyperplasia-multiple lipomatosis syndrome and CLOVES (congenital, lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/spinal/skeletal anomalies) syndrome also can present on the plantar surfaces, and lesions may be overgrown at birth but are softer and compressible, have wrinkles instead of deep folds, and tend to grow with the child rather than disproportionately as in PS.⁴

The epidermal nevi and vascular malformations generally do not spread or increase in number. In contrast, CCTN in PS grows throughout childhood but tends to remain stable in adulthood.⁴ Postponing surgical treatment until skin lesions stabilize appears to be the best option. However, for practical purposes, surgical intervention may be required at an earlier phase to address the severe functional and cosmetic consequences. Some patients require multiple orthopedic procedures over the ensuing years or decades to control the hyperplasia.³ New CCTN that developed from the prior surgical incision, macrodactyly of the fourth and fifth right toes, and scoliosis appeared when the patient came to our clinic for retreatment 1 year after the initial presentation. The asymmetrical and disproportionate overgrowth of tissues had moderately accelerated in that period. Considering the increasingly impaired walking, we performed a second surgery. On follow-up visits, the patient expressed improvement in daily life.

Studies had been performed to clarify the genetic bases of PS, and the somatic activating mutation in AKT1 (AKT serine/threonine kinase 1) was reported to be the cause of the disease.^5,6 Germline PTEN (phosphatase and tensin homolog) mutations have been identified in some patients with overgrowth abnormalities of PS. However, given the misdiagnosis of PS with PTEN mutations and the notion that a gene alone cannot result in PS, the loss-of-function mutations of LEMD3 that have been reported in familial cutaneous collagenomas also may be related to the abnormal growth of connective and bone tissues that are typical of PS.^7,8 Lindhurst et al⁵ concluded that PS is caused by a somatic activating mutation in AKT1, which proved the hypothesis of somatic mosaicism and implicated activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. AKT1 is activated by loss-of-function mutations in PTEN, which explains why patients with these mutations (eg, those with the segmental overgrowth, lipomatosis, arteriovenous malformation, epidermal nevus, SOLAMEN [segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus] syndrome) and patients with activating mutations in AKT1 (eg, those with PS) have overlapping but distinct clinical manifestations. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals with clinical findings that are ambiguous or mild. Further studies are necessary to progress the understanding and management of PS, which will require cooperation of geneticists, surgeons, and other specialists.

To the Editor:
A 12-year-old girl presented with discomfort and walking limitation caused by cutaneous masses on the plantar aspects of the feet with associated bone abnormalities that had started as several flesh-colored papules on the plantar surface of both feet at the age of 1 year. Over time the lesions gradually enlarged and formed irregular masses, more prominently on the right foot. At the age of 6 years, surgical correction was performed due to increased walking impairment and a skin examination that suggested connective tissue nevus. The results were good. However, the local tissue overgrowth recurred after 1 year. Slowly growing lesions were found at the surgical site, which necessitated hospitalization. Her medical history was negative for other disease. There was no family history of similar skin conditions and her parents were nonconsanguineous.

Physical examination revealed malnutrition and poor development in height as well as difficulty walking. She also had moderate scoliosis with a curve to the left. Dermatological examination showed multiple reddish cerebriform hyperplasia in both plantar areas; the right side was more severely involved (Figure 1A). There was macrodactyly of 2 toes on the right foot (Figure 1B). All results of routine blood examinations were within reference range. There were no abnormalities noted in the abdominal ultrasound and cardiac examinations. Plain radiographs of the spine and feet demonstrated scoliosis and exostosis on the calcaneus and bottom of the scaphoid. Histopathologic examination of tissue from the plantar cerebriform hyperplasia revealed hyperkeratosis, slight acanthosis and papillomatosis in the epidermis, and dense collagen bands and sparse elastic fibers in the dermis (Figure 2).

Given the clinical and radiologic manifestation, the diagnosis of Proteus syndrome (PS) was established. After taking into account the severe discomfort and the success of the first surgery, we performed a resection and full-thickness skin graft surgery once again. The feet recovered without any discomfort in daily life. The appearance of the skin graft area was normal 1 year following surgery (Figure 3). She was treated with spinal plate fixation at another institution, progressed well for 2 years, and was subsequently lost to follow-up.

Proteus syndrome is a multisystem disorder with a difficult diagnosis due to the variability of its manifestations. The worldwide incidence of this rare disorder is less than 1 per 1 million individuals, and it is thought to be caused by a somatic genetic alteration.¹ Clinical characteristics include bone abnormalities, vascular malformations, dysregulation of fatty tissue, linear verrucous epidermal nevus, and cerebriform connective tissue nevus (CCTN). Although CCTN is not a common finding in patients with PS, it is considered a fairly specific sign with the greatest impact for the diagnosis of PS.²

The general feature of PS--asymmetric disproportionate overgrowth of tissues--appears at 6 to 18 months of age, which makes it challenging to diagnose disease earlier. The CCTN in our patient was present since 1 year of age.

 

To make a diagnosis of PS, one must have all the general criteria and various specific criteria. The revised diagnostic criteria for PS are given in the Table.³ According to the diagnostic criteria, our patient fulfilled the mandatory general criteria and had plantar CCTN, epidermal nevus, and dysregulated adipose tissue. The CCTN has notable diagnostic value in mildly affected patients, as it is absent in diseases included in the differential diagnosis such as neurofibromatosis, Klippel-Trenaunay-Weber syndrome, Maffucci syndrome, and Bannayan-Riley-Ruvalcaba syndrome. Hemihyperplasia-multiple lipomatosis syndrome and CLOVES (congenital, lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/spinal/skeletal anomalies) syndrome also can present on the plantar surfaces, and lesions may be overgrown at birth but are softer and compressible, have wrinkles instead of deep folds, and tend to grow with the child rather than disproportionately as in PS.⁴

The epidermal nevi and vascular malformations generally do not spread or increase in number. In contrast, CCTN in PS grows throughout childhood but tends to remain stable in adulthood.⁴ Postponing surgical treatment until skin lesions stabilize appears to be the best option. However, for practical purposes, surgical intervention may be required at an earlier phase to address the severe functional and cosmetic consequences. Some patients require multiple orthopedic procedures over the ensuing years or decades to control the hyperplasia.³ New CCTN that developed from the prior surgical incision, macrodactyly of the fourth and fifth right toes, and scoliosis appeared when the patient came to our clinic for retreatment 1 year after the initial presentation. The asymmetrical and disproportionate overgrowth of tissues had moderately accelerated in that period. Considering the increasingly impaired walking, we performed a second surgery. On follow-up visits, the patient expressed improvement in daily life.

Studies had been performed to clarify the genetic bases of PS, and the somatic activating mutation in AKT1 (AKT serine/threonine kinase 1) was reported to be the cause of the disease.^5,6 Germline PTEN (phosphatase and tensin homolog) mutations have been identified in some patients with overgrowth abnormalities of PS. However, given the misdiagnosis of PS with PTEN mutations and the notion that a gene alone cannot result in PS, the loss-of-function mutations of LEMD3 that have been reported in familial cutaneous collagenomas also may be related to the abnormal growth of connective and bone tissues that are typical of PS.^7,8 Lindhurst et al⁵ concluded that PS is caused by a somatic activating mutation in AKT1, which proved the hypothesis of somatic mosaicism and implicated activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. AKT1 is activated by loss-of-function mutations in PTEN, which explains why patients with these mutations (eg, those with the segmental overgrowth, lipomatosis, arteriovenous malformation, epidermal nevus, SOLAMEN [segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus] syndrome) and patients with activating mutations in AKT1 (eg, those with PS) have overlapping but distinct clinical manifestations. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals with clinical findings that are ambiguous or mild. Further studies are necessary to progress the understanding and management of PS, which will require cooperation of geneticists, surgeons, and other specialists.

To the Editor:
A 12-year-old girl presented with discomfort and walking limitation caused by cutaneous masses on the plantar aspects of the feet with associated bone abnormalities that had started as several flesh-colored papules on the plantar surface of both feet at the age of 1 year. Over time the lesions gradually enlarged and formed irregular masses, more prominently on the right foot. At the age of 6 years, surgical correction was performed due to increased walking impairment and a skin examination that suggested connective tissue nevus. The results were good. However, the local tissue overgrowth recurred after 1 year. Slowly growing lesions were found at the surgical site, which necessitated hospitalization. Her medical history was negative for other disease. There was no family history of similar skin conditions and her parents were nonconsanguineous.

Physical examination revealed malnutrition and poor development in height as well as difficulty walking. She also had moderate scoliosis with a curve to the left. Dermatological examination showed multiple reddish cerebriform hyperplasia in both plantar areas; the right side was more severely involved (Figure 1A). There was macrodactyly of 2 toes on the right foot (Figure 1B). All results of routine blood examinations were within reference range. There were no abnormalities noted in the abdominal ultrasound and cardiac examinations. Plain radiographs of the spine and feet demonstrated scoliosis and exostosis on the calcaneus and bottom of the scaphoid. Histopathologic examination of tissue from the plantar cerebriform hyperplasia revealed hyperkeratosis, slight acanthosis and papillomatosis in the epidermis, and dense collagen bands and sparse elastic fibers in the dermis (Figure 2).

Given the clinical and radiologic manifestation, the diagnosis of Proteus syndrome (PS) was established. After taking into account the severe discomfort and the success of the first surgery, we performed a resection and full-thickness skin graft surgery once again. The feet recovered without any discomfort in daily life. The appearance of the skin graft area was normal 1 year following surgery (Figure 3). She was treated with spinal plate fixation at another institution, progressed well for 2 years, and was subsequently lost to follow-up.

Proteus syndrome is a multisystem disorder with a difficult diagnosis due to the variability of its manifestations. The worldwide incidence of this rare disorder is less than 1 per 1 million individuals, and it is thought to be caused by a somatic genetic alteration.¹ Clinical characteristics include bone abnormalities, vascular malformations, dysregulation of fatty tissue, linear verrucous epidermal nevus, and cerebriform connective tissue nevus (CCTN). Although CCTN is not a common finding in patients with PS, it is considered a fairly specific sign with the greatest impact for the diagnosis of PS.²

The general feature of PS--asymmetric disproportionate overgrowth of tissues--appears at 6 to 18 months of age, which makes it challenging to diagnose disease earlier. The CCTN in our patient was present since 1 year of age.

 

To make a diagnosis of PS, one must have all the general criteria and various specific criteria. The revised diagnostic criteria for PS are given in the Table.³ According to the diagnostic criteria, our patient fulfilled the mandatory general criteria and had plantar CCTN, epidermal nevus, and dysregulated adipose tissue. The CCTN has notable diagnostic value in mildly affected patients, as it is absent in diseases included in the differential diagnosis such as neurofibromatosis, Klippel-Trenaunay-Weber syndrome, Maffucci syndrome, and Bannayan-Riley-Ruvalcaba syndrome. Hemihyperplasia-multiple lipomatosis syndrome and CLOVES (congenital, lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/spinal/skeletal anomalies) syndrome also can present on the plantar surfaces, and lesions may be overgrown at birth but are softer and compressible, have wrinkles instead of deep folds, and tend to grow with the child rather than disproportionately as in PS.⁴

The epidermal nevi and vascular malformations generally do not spread or increase in number. In contrast, CCTN in PS grows throughout childhood but tends to remain stable in adulthood.⁴ Postponing surgical treatment until skin lesions stabilize appears to be the best option. However, for practical purposes, surgical intervention may be required at an earlier phase to address the severe functional and cosmetic consequences. Some patients require multiple orthopedic procedures over the ensuing years or decades to control the hyperplasia.³ New CCTN that developed from the prior surgical incision, macrodactyly of the fourth and fifth right toes, and scoliosis appeared when the patient came to our clinic for retreatment 1 year after the initial presentation. The asymmetrical and disproportionate overgrowth of tissues had moderately accelerated in that period. Considering the increasingly impaired walking, we performed a second surgery. On follow-up visits, the patient expressed improvement in daily life.

Studies had been performed to clarify the genetic bases of PS, and the somatic activating mutation in AKT1 (AKT serine/threonine kinase 1) was reported to be the cause of the disease.^5,6 Germline PTEN (phosphatase and tensin homolog) mutations have been identified in some patients with overgrowth abnormalities of PS. However, given the misdiagnosis of PS with PTEN mutations and the notion that a gene alone cannot result in PS, the loss-of-function mutations of LEMD3 that have been reported in familial cutaneous collagenomas also may be related to the abnormal growth of connective and bone tissues that are typical of PS.^7,8 Lindhurst et al⁵ concluded that PS is caused by a somatic activating mutation in AKT1, which proved the hypothesis of somatic mosaicism and implicated activation of the PI3K-AKT pathway in the characteristic clinical findings of overgrowth and tumor susceptibility in this disorder. AKT1 is activated by loss-of-function mutations in PTEN, which explains why patients with these mutations (eg, those with the segmental overgrowth, lipomatosis, arteriovenous malformation, epidermal nevus, SOLAMEN [segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus] syndrome) and patients with activating mutations in AKT1 (eg, those with PS) have overlapping but distinct clinical manifestations. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals with clinical findings that are ambiguous or mild. Further studies are necessary to progress the understanding and management of PS, which will require cooperation of geneticists, surgeons, and other specialists.

To the Editor:

A 34-year-old man presented with fever, easy bruising, and pancytopenia with increased peripheral blasts of 77%. Bone marrow biopsy showed hypercellular marrow with 80% to 90% involvement by acute promyelocytic leukemia (APL) with complex cytogenetics: 47,XY,t(4;17;18)(p16;q21,q25;q21.1),+8, ins(15;17)(q22;q21q25). He underwent induction chemotherapy with all-trans retinoic acid (ATRA) and idarubicin, which was complicated by differentiation syndrome that presented with fever and fluid retention. Discontinuation of ATRA and initiation of dexamethasone led to resolution of the symptoms. Complete hematologic and molecular remission was achieved after the induction chemotherapy.

Following a risk-adapted treatment protocol for consolidation therapy,¹ he underwent an uneventful first cycle of consolidation therapy. On day 15 of the second cycle of consolidation therapy with ATRA and mitoxantrone he was hospitalized with a fever (temperature, 38°C) in a setting of neutropenia (absolute neutrophil count [ANC], 0/µL [reference range, 1500–7200/µL]). He was empirically treated with ceftazidime and vancomycin and maintained on prophylactic acyclovir and fluconazole. Routine workup was negative for infection. He became afebrile within 24 hours. With negative infectious workup, vancomycin was discontinued on day 17. On day 33 he again developed a fever (temperature, 38.8°C) when the ANC started to recover (570/µL). A new skin rash was noted at this time. Physical examination revealed generalized, nonpruritic, tender, pink papules and plaques with dusky centers and central pustules on the trunk as well as the upper and lower extremities. The palms and soles were spared. The rash was somewhat reminiscent of Sweet syndrome (SS). No vesicles, bullae, or erosions were seen (Figure 1). Repeat blood and urine cultures and chest radiograph were unremarkable. Ceftazidime was discontinued due to concern of drug-associated rash. Within the next 48 hours, the patient developed rigors and a worsening rash that led to reinitiation of broad-spectrum antibiotic coverage with meropenem and vancomycin. Computed tomography of the chest, abdomen, and pelvis did not show any evidence of infection or other abnormalities. Skin biopsy showed an acute folliculitis and multiple foci of mixed granulomatous inflammation consisting of histiocytes, lymphocytes, and neutrophils with focal necrosis present in the dermis, dermis-subcutis junction, and subcutis (Figure 2). Diagnostic features of vasculitis were not seen. Viral cytopathic features were not identified. Tissue culture and special stains including Gram, acid-fast bacteria, and Grocott methenamine silver stains were negative for infectious organisms in the biopsy. Both direct fluorescent antibody study and cell cultures for varicella-zoster virus, cytomegalovirus, and herpes simplex virus also were negative.

 

In the absence of microorganisms on skin biopsy and low clinical suspicion of infection, vancomycin and meropenem were discontinued on day 35 and empiric treatment with oral prednisone 40 mg daily was initiated on day 38, which resulted in a rapid improvement of the patient’s rash within 24 hours with complete resolution after a 7-day course of prednisone. Notably, the patient manifested concomitant recovery of the ANC. The patient completed his last cycle of consolidation therapy with ATRA and idarubicin without further complications and remains in molecular remission.

Neutrophilic dermatoses (NDs) are a group of disorders characterized by neutrophilic cutaneous infiltration without evidence of infection. These entities include SS, pyoderma gangrenosum, subcorneal pustular dermatosis, erythema elevatum diutinum, and neutrophilic eccrine hidradenitis.² Neutrophilic dermatoses commonly present with acute onset of skin lesions and fever. Underlying systemic disease such as malignancy, inflammatory disease, autoimmune disease, pregnancy, and medications are known to be associated with ND. Although the rash clinically was reminiscent of SS, the histopathologic features were inconsistent with SS. Sweet syndrome typically presents with extensive monotonous neutrophilic infiltrates in the dermis. In this case, the neutrophilic infiltrates were localized and associated with the hair follicle, in the dermis and subcutis, and were accompanied by a granulomatous inflammation. Neutrophilic eccrine hidradenitis clinically is similar to SS and the distinction usually is made on the basis of histopathologic examination. Lack of the neutrophilic infiltrates within the eccrine secretary coils in our case did not support the diagnosis of neutrophilic eccrine hidradenitis.

Although the histopathologic features of the presented case were inconsistent with a particular subtype of ND, the clinical presentation and response to corticosteroids suggested that this unusual mixed inflammatory skin reaction might share a similar pathophysiologic mechanism.

A review of 20 patients with sterile neutrophilic folliculitis demonstrated an association with systemic diseases including cutaneous T-cell lymphoma, monoclonal gammopathy, Crohn disease, and autoimmune disorders.³ In acute myeloid leukemia, sterile neutrophilic folliculitis may be part of the initial presentation and responds to induction chemotherapy.⁴ An extensive search of PubMed articles indexed for MEDLINE using the search terms folliculitis, APL, and neutrophilic dermatoses did not reveal any prior reports of isolated neutrophilic folliculitis or mixed granulomatous reaction in patients with APL in molecular remission.

Although rare, cases of ATRA-induced SS have been reported. Some authors believe that SS in APL may represent a partial form of differentiation syndrome.⁵ Those cases usually occur during first induction. However, a recurrent episode of differentiation syndrome cannot be excluded in this patient.

A cutaneous reaction to chemotherapy with mitoxantrone as a cause also should be considered, given that the rash occurred only during the second cycle of consolidation therapy when mitoxantrone was used. However, this rash is rare in patients receiving mitoxantrone. The late onset of the rash from the time of last mitoxantrone administration argues against this diagnosis.

In summary, we describe an unusual presentation of a sterile mixed inflammatory skin reaction that occurred in a setting of neutrophil recovery following a second cycle of induction chemotherapy with ATRA and mitoxantrone for APL.

To the Editor:

A 34-year-old man presented with fever, easy bruising, and pancytopenia with increased peripheral blasts of 77%. Bone marrow biopsy showed hypercellular marrow with 80% to 90% involvement by acute promyelocytic leukemia (APL) with complex cytogenetics: 47,XY,t(4;17;18)(p16;q21,q25;q21.1),+8, ins(15;17)(q22;q21q25). He underwent induction chemotherapy with all-trans retinoic acid (ATRA) and idarubicin, which was complicated by differentiation syndrome that presented with fever and fluid retention. Discontinuation of ATRA and initiation of dexamethasone led to resolution of the symptoms. Complete hematologic and molecular remission was achieved after the induction chemotherapy.

Following a risk-adapted treatment protocol for consolidation therapy,¹ he underwent an uneventful first cycle of consolidation therapy. On day 15 of the second cycle of consolidation therapy with ATRA and mitoxantrone he was hospitalized with a fever (temperature, 38°C) in a setting of neutropenia (absolute neutrophil count [ANC], 0/µL [reference range, 1500–7200/µL]). He was empirically treated with ceftazidime and vancomycin and maintained on prophylactic acyclovir and fluconazole. Routine workup was negative for infection. He became afebrile within 24 hours. With negative infectious workup, vancomycin was discontinued on day 17. On day 33 he again developed a fever (temperature, 38.8°C) when the ANC started to recover (570/µL). A new skin rash was noted at this time. Physical examination revealed generalized, nonpruritic, tender, pink papules and plaques with dusky centers and central pustules on the trunk as well as the upper and lower extremities. The palms and soles were spared. The rash was somewhat reminiscent of Sweet syndrome (SS). No vesicles, bullae, or erosions were seen (Figure 1). Repeat blood and urine cultures and chest radiograph were unremarkable. Ceftazidime was discontinued due to concern of drug-associated rash. Within the next 48 hours, the patient developed rigors and a worsening rash that led to reinitiation of broad-spectrum antibiotic coverage with meropenem and vancomycin. Computed tomography of the chest, abdomen, and pelvis did not show any evidence of infection or other abnormalities. Skin biopsy showed an acute folliculitis and multiple foci of mixed granulomatous inflammation consisting of histiocytes, lymphocytes, and neutrophils with focal necrosis present in the dermis, dermis-subcutis junction, and subcutis (Figure 2). Diagnostic features of vasculitis were not seen. Viral cytopathic features were not identified. Tissue culture and special stains including Gram, acid-fast bacteria, and Grocott methenamine silver stains were negative for infectious organisms in the biopsy. Both direct fluorescent antibody study and cell cultures for varicella-zoster virus, cytomegalovirus, and herpes simplex virus also were negative.

 

In the absence of microorganisms on skin biopsy and low clinical suspicion of infection, vancomycin and meropenem were discontinued on day 35 and empiric treatment with oral prednisone 40 mg daily was initiated on day 38, which resulted in a rapid improvement of the patient’s rash within 24 hours with complete resolution after a 7-day course of prednisone. Notably, the patient manifested concomitant recovery of the ANC. The patient completed his last cycle of consolidation therapy with ATRA and idarubicin without further complications and remains in molecular remission.

Neutrophilic dermatoses (NDs) are a group of disorders characterized by neutrophilic cutaneous infiltration without evidence of infection. These entities include SS, pyoderma gangrenosum, subcorneal pustular dermatosis, erythema elevatum diutinum, and neutrophilic eccrine hidradenitis.² Neutrophilic dermatoses commonly present with acute onset of skin lesions and fever. Underlying systemic disease such as malignancy, inflammatory disease, autoimmune disease, pregnancy, and medications are known to be associated with ND. Although the rash clinically was reminiscent of SS, the histopathologic features were inconsistent with SS. Sweet syndrome typically presents with extensive monotonous neutrophilic infiltrates in the dermis. In this case, the neutrophilic infiltrates were localized and associated with the hair follicle, in the dermis and subcutis, and were accompanied by a granulomatous inflammation. Neutrophilic eccrine hidradenitis clinically is similar to SS and the distinction usually is made on the basis of histopathologic examination. Lack of the neutrophilic infiltrates within the eccrine secretary coils in our case did not support the diagnosis of neutrophilic eccrine hidradenitis.

Although the histopathologic features of the presented case were inconsistent with a particular subtype of ND, the clinical presentation and response to corticosteroids suggested that this unusual mixed inflammatory skin reaction might share a similar pathophysiologic mechanism.

A review of 20 patients with sterile neutrophilic folliculitis demonstrated an association with systemic diseases including cutaneous T-cell lymphoma, monoclonal gammopathy, Crohn disease, and autoimmune disorders.³ In acute myeloid leukemia, sterile neutrophilic folliculitis may be part of the initial presentation and responds to induction chemotherapy.⁴ An extensive search of PubMed articles indexed for MEDLINE using the search terms folliculitis, APL, and neutrophilic dermatoses did not reveal any prior reports of isolated neutrophilic folliculitis or mixed granulomatous reaction in patients with APL in molecular remission.

Although rare, cases of ATRA-induced SS have been reported. Some authors believe that SS in APL may represent a partial form of differentiation syndrome.⁵ Those cases usually occur during first induction. However, a recurrent episode of differentiation syndrome cannot be excluded in this patient.

A cutaneous reaction to chemotherapy with mitoxantrone as a cause also should be considered, given that the rash occurred only during the second cycle of consolidation therapy when mitoxantrone was used. However, this rash is rare in patients receiving mitoxantrone. The late onset of the rash from the time of last mitoxantrone administration argues against this diagnosis.

In summary, we describe an unusual presentation of a sterile mixed inflammatory skin reaction that occurred in a setting of neutrophil recovery following a second cycle of induction chemotherapy with ATRA and mitoxantrone for APL.

To the Editor:

A 34-year-old man presented with fever, easy bruising, and pancytopenia with increased peripheral blasts of 77%. Bone marrow biopsy showed hypercellular marrow with 80% to 90% involvement by acute promyelocytic leukemia (APL) with complex cytogenetics: 47,XY,t(4;17;18)(p16;q21,q25;q21.1),+8, ins(15;17)(q22;q21q25). He underwent induction chemotherapy with all-trans retinoic acid (ATRA) and idarubicin, which was complicated by differentiation syndrome that presented with fever and fluid retention. Discontinuation of ATRA and initiation of dexamethasone led to resolution of the symptoms. Complete hematologic and molecular remission was achieved after the induction chemotherapy.

Following a risk-adapted treatment protocol for consolidation therapy,¹ he underwent an uneventful first cycle of consolidation therapy. On day 15 of the second cycle of consolidation therapy with ATRA and mitoxantrone he was hospitalized with a fever (temperature, 38°C) in a setting of neutropenia (absolute neutrophil count [ANC], 0/µL [reference range, 1500–7200/µL]). He was empirically treated with ceftazidime and vancomycin and maintained on prophylactic acyclovir and fluconazole. Routine workup was negative for infection. He became afebrile within 24 hours. With negative infectious workup, vancomycin was discontinued on day 17. On day 33 he again developed a fever (temperature, 38.8°C) when the ANC started to recover (570/µL). A new skin rash was noted at this time. Physical examination revealed generalized, nonpruritic, tender, pink papules and plaques with dusky centers and central pustules on the trunk as well as the upper and lower extremities. The palms and soles were spared. The rash was somewhat reminiscent of Sweet syndrome (SS). No vesicles, bullae, or erosions were seen (Figure 1). Repeat blood and urine cultures and chest radiograph were unremarkable. Ceftazidime was discontinued due to concern of drug-associated rash. Within the next 48 hours, the patient developed rigors and a worsening rash that led to reinitiation of broad-spectrum antibiotic coverage with meropenem and vancomycin. Computed tomography of the chest, abdomen, and pelvis did not show any evidence of infection or other abnormalities. Skin biopsy showed an acute folliculitis and multiple foci of mixed granulomatous inflammation consisting of histiocytes, lymphocytes, and neutrophils with focal necrosis present in the dermis, dermis-subcutis junction, and subcutis (Figure 2). Diagnostic features of vasculitis were not seen. Viral cytopathic features were not identified. Tissue culture and special stains including Gram, acid-fast bacteria, and Grocott methenamine silver stains were negative for infectious organisms in the biopsy. Both direct fluorescent antibody study and cell cultures for varicella-zoster virus, cytomegalovirus, and herpes simplex virus also were negative.

 

In the absence of microorganisms on skin biopsy and low clinical suspicion of infection, vancomycin and meropenem were discontinued on day 35 and empiric treatment with oral prednisone 40 mg daily was initiated on day 38, which resulted in a rapid improvement of the patient’s rash within 24 hours with complete resolution after a 7-day course of prednisone. Notably, the patient manifested concomitant recovery of the ANC. The patient completed his last cycle of consolidation therapy with ATRA and idarubicin without further complications and remains in molecular remission.

Neutrophilic dermatoses (NDs) are a group of disorders characterized by neutrophilic cutaneous infiltration without evidence of infection. These entities include SS, pyoderma gangrenosum, subcorneal pustular dermatosis, erythema elevatum diutinum, and neutrophilic eccrine hidradenitis.² Neutrophilic dermatoses commonly present with acute onset of skin lesions and fever. Underlying systemic disease such as malignancy, inflammatory disease, autoimmune disease, pregnancy, and medications are known to be associated with ND. Although the rash clinically was reminiscent of SS, the histopathologic features were inconsistent with SS. Sweet syndrome typically presents with extensive monotonous neutrophilic infiltrates in the dermis. In this case, the neutrophilic infiltrates were localized and associated with the hair follicle, in the dermis and subcutis, and were accompanied by a granulomatous inflammation. Neutrophilic eccrine hidradenitis clinically is similar to SS and the distinction usually is made on the basis of histopathologic examination. Lack of the neutrophilic infiltrates within the eccrine secretary coils in our case did not support the diagnosis of neutrophilic eccrine hidradenitis.

Although the histopathologic features of the presented case were inconsistent with a particular subtype of ND, the clinical presentation and response to corticosteroids suggested that this unusual mixed inflammatory skin reaction might share a similar pathophysiologic mechanism.

A review of 20 patients with sterile neutrophilic folliculitis demonstrated an association with systemic diseases including cutaneous T-cell lymphoma, monoclonal gammopathy, Crohn disease, and autoimmune disorders.³ In acute myeloid leukemia, sterile neutrophilic folliculitis may be part of the initial presentation and responds to induction chemotherapy.⁴ An extensive search of PubMed articles indexed for MEDLINE using the search terms folliculitis, APL, and neutrophilic dermatoses did not reveal any prior reports of isolated neutrophilic folliculitis or mixed granulomatous reaction in patients with APL in molecular remission.

Although rare, cases of ATRA-induced SS have been reported. Some authors believe that SS in APL may represent a partial form of differentiation syndrome.⁵ Those cases usually occur during first induction. However, a recurrent episode of differentiation syndrome cannot be excluded in this patient.

A cutaneous reaction to chemotherapy with mitoxantrone as a cause also should be considered, given that the rash occurred only during the second cycle of consolidation therapy when mitoxantrone was used. However, this rash is rare in patients receiving mitoxantrone. The late onset of the rash from the time of last mitoxantrone administration argues against this diagnosis.

In summary, we describe an unusual presentation of a sterile mixed inflammatory skin reaction that occurred in a setting of neutrophil recovery following a second cycle of induction chemotherapy with ATRA and mitoxantrone for APL.