Vincent Liu, MD

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Chlorotrichosis, or green hair discoloration, is a dermatologic condition secondary to copper deposition on the hair. It most often is seen among swimmers who have prolonged exposure to chlorinated pools. The classic patient has predisposing chemical, heat, or mechanical damage to the hair shaft and usually lighter-colored hair.^1-3 We present a case of chlorotrichosis in a young brunette patient who did not have predisposing factors except for chronic sun exposure.

A 13-year-old healthy adolescent girl with brown hair presented with persistent green hair for 2 years (Figure 1A). She had first noted hair discoloration after swimming in a neighbor’s chlorinated outdoor pool during summertime but experienced year-round persistence even without swimming. She denied any history of typical risk factors for hair damage, including exposure to hair dye or bleach, styling products, heat, or mechanical damage from excessive brushing. Her sister had blonde hair with a history of similar activities and exposures, and although she did style her hair with heat, she did not develop hair discoloration. The patient lived in a newer home, and prior tap water testing did not show elevated levels of copper. She admitted to strictly wearing her hair down at all times, including during strenuous activity and swimming. Excessive teasing at school prompted her mother to seek advice from hair salons. Bleaching test strips of hair reportedly caused paradoxical intensification of green, and the patient declined recommendations for red hair dye. The patient also tried Internet-based suggestions such as topically applying crushed aspirin, lemon juice, tea tree oil, and clarifying shampoos, which all failed to result in notable improvement.

Few individuals exposed to elevated levels of copper will develop chlorotrichosis, which emphasizes the critical role of predisposing hair damage in its pathogenesis. With violation of the hair cuticle, chlorine can crystallize and copper can adhere to the hair shaft.¹⁰ Bleaching and waving of the hair also appear to alter the composition of keratin by increasing the number of cysteic acid and similar anionic sulfonate groups, which can bind copper.⁸

Although not harmful, chlorotrichosis may be aesthetically undesirable and lead to considerable social ostracism. Without intrinsic hair defects or obvious differences in predisposing factors, the question was raised as to why our patient, as a brunette, experienced dramatic hair discoloration while her blonde sister was entirely unaffected. We postulated that our patient’s persistent green hair may have been due to her unique predisposition to extensive sun-induced and mechanical hair damage because of her unwavering tendency to wear her hair down at all times. A variety of treatments of variable reported efficacy have been proposed (Table); fortunately, if treatments fail, the discoloration resolves with hair growth.

To the Editor:

Chlorotrichosis, or green hair discoloration, is a dermatologic condition secondary to copper deposition on the hair. It most often is seen among swimmers who have prolonged exposure to chlorinated pools. The classic patient has predisposing chemical, heat, or mechanical damage to the hair shaft and usually lighter-colored hair.^1-3 We present a case of chlorotrichosis in a young brunette patient who did not have predisposing factors except for chronic sun exposure.

A 13-year-old healthy adolescent girl with brown hair presented with persistent green hair for 2 years (Figure 1A). She had first noted hair discoloration after swimming in a neighbor’s chlorinated outdoor pool during summertime but experienced year-round persistence even without swimming. She denied any history of typical risk factors for hair damage, including exposure to hair dye or bleach, styling products, heat, or mechanical damage from excessive brushing. Her sister had blonde hair with a history of similar activities and exposures, and although she did style her hair with heat, she did not develop hair discoloration. The patient lived in a newer home, and prior tap water testing did not show elevated levels of copper. She admitted to strictly wearing her hair down at all times, including during strenuous activity and swimming. Excessive teasing at school prompted her mother to seek advice from hair salons. Bleaching test strips of hair reportedly caused paradoxical intensification of green, and the patient declined recommendations for red hair dye. The patient also tried Internet-based suggestions such as topically applying crushed aspirin, lemon juice, tea tree oil, and clarifying shampoos, which all failed to result in notable improvement.

Few individuals exposed to elevated levels of copper will develop chlorotrichosis, which emphasizes the critical role of predisposing hair damage in its pathogenesis. With violation of the hair cuticle, chlorine can crystallize and copper can adhere to the hair shaft.¹⁰ Bleaching and waving of the hair also appear to alter the composition of keratin by increasing the number of cysteic acid and similar anionic sulfonate groups, which can bind copper.⁸

Although not harmful, chlorotrichosis may be aesthetically undesirable and lead to considerable social ostracism. Without intrinsic hair defects or obvious differences in predisposing factors, the question was raised as to why our patient, as a brunette, experienced dramatic hair discoloration while her blonde sister was entirely unaffected. We postulated that our patient’s persistent green hair may have been due to her unique predisposition to extensive sun-induced and mechanical hair damage because of her unwavering tendency to wear her hair down at all times. A variety of treatments of variable reported efficacy have been proposed (Table); fortunately, if treatments fail, the discoloration resolves with hair growth.

To the Editor:

Chlorotrichosis, or green hair discoloration, is a dermatologic condition secondary to copper deposition on the hair. It most often is seen among swimmers who have prolonged exposure to chlorinated pools. The classic patient has predisposing chemical, heat, or mechanical damage to the hair shaft and usually lighter-colored hair.^1-3 We present a case of chlorotrichosis in a young brunette patient who did not have predisposing factors except for chronic sun exposure.

A 13-year-old healthy adolescent girl with brown hair presented with persistent green hair for 2 years (Figure 1A). She had first noted hair discoloration after swimming in a neighbor’s chlorinated outdoor pool during summertime but experienced year-round persistence even without swimming. She denied any history of typical risk factors for hair damage, including exposure to hair dye or bleach, styling products, heat, or mechanical damage from excessive brushing. Her sister had blonde hair with a history of similar activities and exposures, and although she did style her hair with heat, she did not develop hair discoloration. The patient lived in a newer home, and prior tap water testing did not show elevated levels of copper. She admitted to strictly wearing her hair down at all times, including during strenuous activity and swimming. Excessive teasing at school prompted her mother to seek advice from hair salons. Bleaching test strips of hair reportedly caused paradoxical intensification of green, and the patient declined recommendations for red hair dye. The patient also tried Internet-based suggestions such as topically applying crushed aspirin, lemon juice, tea tree oil, and clarifying shampoos, which all failed to result in notable improvement.

Few individuals exposed to elevated levels of copper will develop chlorotrichosis, which emphasizes the critical role of predisposing hair damage in its pathogenesis. With violation of the hair cuticle, chlorine can crystallize and copper can adhere to the hair shaft.¹⁰ Bleaching and waving of the hair also appear to alter the composition of keratin by increasing the number of cysteic acid and similar anionic sulfonate groups, which can bind copper.⁸

Although not harmful, chlorotrichosis may be aesthetically undesirable and lead to considerable social ostracism. Without intrinsic hair defects or obvious differences in predisposing factors, the question was raised as to why our patient, as a brunette, experienced dramatic hair discoloration while her blonde sister was entirely unaffected. We postulated that our patient’s persistent green hair may have been due to her unique predisposition to extensive sun-induced and mechanical hair damage because of her unwavering tendency to wear her hair down at all times. A variety of treatments of variable reported efficacy have been proposed (Table); fortunately, if treatments fail, the discoloration resolves with hair growth.

The Diagnosis: Birt-Hogg-Dubé Syndrome 

Histopathologic examination revealed a collection of bland spindle cells with perifollicular fibrosis consistent with a fibrofolliculoma, confirming the diagnosis of Birt-Hogg-Dubé syndrome (Figure). Cosmetic treatment with ablative therapy was offered, but the patient declined.  

Birt-Hogg-Dubé syndrome is an autosomal-dominant genodermatosis caused by a loss-of-function mutation in the folliculin gene, FLCN, on chromosome arm 17p11.2.¹ Cutaneous findings include benign follicular hamartomas, such as fibrofolliculomas and trichodiscomas. Angiofibromas, perifollicular fibromas, oral papillomas, and acrochordons also can be present.¹ Cutaneous lesions usually appear on the head and neck in the third decade of life.  

Patients with Birt-Hogg-Dubé syndrome are at an increased risk for pneumothorax and renal cancer, specifically hybrid oncocytic-chromophobe renal cell carcinomas.² In a study of 89 patients with a FLCN mutation, 90% (80/89) of patients had cutaneous lesions, 84% (34/89) had pulmonary cysts, and 34% (30/89) had kidney tumors. Affected individuals were at a higher risk for pneumothorax and kidney tumors if there was a family history of these tumors.²  

Proposed diagnostic criteria include any 1 of the following: 2 or more skin lesions clinically consistent with fibrofolliculomas and 1 histologically confirmed fibrofolliculoma; multiple bilateral pulmonary cysts in the basilar lung with or without pneumothorax before 40 years of age; bilateral multifocal chromophobe renal carcinomas or hybrid oncocytic tumors; combination of cutaneous, pulmonary, or renal manifestation in the patient and family; or a FLCN mutation.³  

Current recommendations for the workup of a patient with Birt-Hogg-Dubé syndrome include referral to genetic counseling for the patient and family, a baseline computed tomography of the chest to evaluate for pulmonary cysts, and gadolinium-enhanced abdominal magnetic resonance imaging starting at 20 years of age and repeated every 3 to 4 years to screen for renal tumors.¹ Pulmonary function tests can be considered if the patient is symptomatic or has a high cyst burden. Patients should be advised against smoking and scuba diving. 

The differential diagnosis of multiple facial papules includes Cowden syndrome, tuberous sclerosis, Brooke-Spiegler syndrome, and Muir-Torre syndrome. Cowden syndrome is caused by a mutation in the protein tyrosine phosphatase gene, PTEN.⁴ The characteristic cutaneous findings on the face are trichilemmomas, which appear as flesh-colored papules that may have a verrucous surface.  

Tuberous sclerosis is caused by mutations in hamartin (TSC1) or tuberin (TSC2). Angiofibromas are most commonly found on the face and appear as flesh-colored to red-brown papules. Fibrous plaques, periungual fibromas, gingival fibromas, hypopigmented macules, and connective tissue nevi also are found in tuberous sclerosis.⁵  

Brooke-Spiegler syndrome is caused by a mutation in the CYLD lysine 63 deubiquitinase gene, CYLD. Trichoepitheliomas, cylindromas, and spiradenomas are caused by the CYLD mutation and appear on the head and neck. Trichoepitheliomas are flesh-colored to pink papules found on the face, often concentrated in the nasolabial folds.⁶ Cylindromas and spiradenomas are flesh-colored to pink papules or nodules most commonly found on the scalp.⁶  

Muir-Torre syndrome is caused by a mutation in DNA mismatch repair genes MSH2 and/or MLH1.⁷ Sebaceous neoplasms, including sebaceous adenomas, sebaceomas, and less frequently sebaceous carcinomas, are characteristic cutaneous findings and appear as pink to yellow papules commonly found on the head and neck.  

Careful history taking, physical examination, and histopathologic analysis are important in recognizing the features of Birt-Hogg-Dubé syndrome. Accurate and timely diagnosis is essential for the appropriate care of patients and their families, given the syndrome's systemic implications.  

The Diagnosis: Birt-Hogg-Dubé Syndrome 

Histopathologic examination revealed a collection of bland spindle cells with perifollicular fibrosis consistent with a fibrofolliculoma, confirming the diagnosis of Birt-Hogg-Dubé syndrome (Figure). Cosmetic treatment with ablative therapy was offered, but the patient declined.  

Birt-Hogg-Dubé syndrome is an autosomal-dominant genodermatosis caused by a loss-of-function mutation in the folliculin gene, FLCN, on chromosome arm 17p11.2.¹ Cutaneous findings include benign follicular hamartomas, such as fibrofolliculomas and trichodiscomas. Angiofibromas, perifollicular fibromas, oral papillomas, and acrochordons also can be present.¹ Cutaneous lesions usually appear on the head and neck in the third decade of life.  

Patients with Birt-Hogg-Dubé syndrome are at an increased risk for pneumothorax and renal cancer, specifically hybrid oncocytic-chromophobe renal cell carcinomas.² In a study of 89 patients with a FLCN mutation, 90% (80/89) of patients had cutaneous lesions, 84% (34/89) had pulmonary cysts, and 34% (30/89) had kidney tumors. Affected individuals were at a higher risk for pneumothorax and kidney tumors if there was a family history of these tumors.²  

Proposed diagnostic criteria include any 1 of the following: 2 or more skin lesions clinically consistent with fibrofolliculomas and 1 histologically confirmed fibrofolliculoma; multiple bilateral pulmonary cysts in the basilar lung with or without pneumothorax before 40 years of age; bilateral multifocal chromophobe renal carcinomas or hybrid oncocytic tumors; combination of cutaneous, pulmonary, or renal manifestation in the patient and family; or a FLCN mutation.³  

Current recommendations for the workup of a patient with Birt-Hogg-Dubé syndrome include referral to genetic counseling for the patient and family, a baseline computed tomography of the chest to evaluate for pulmonary cysts, and gadolinium-enhanced abdominal magnetic resonance imaging starting at 20 years of age and repeated every 3 to 4 years to screen for renal tumors.¹ Pulmonary function tests can be considered if the patient is symptomatic or has a high cyst burden. Patients should be advised against smoking and scuba diving. 

The differential diagnosis of multiple facial papules includes Cowden syndrome, tuberous sclerosis, Brooke-Spiegler syndrome, and Muir-Torre syndrome. Cowden syndrome is caused by a mutation in the protein tyrosine phosphatase gene, PTEN.⁴ The characteristic cutaneous findings on the face are trichilemmomas, which appear as flesh-colored papules that may have a verrucous surface.  

Tuberous sclerosis is caused by mutations in hamartin (TSC1) or tuberin (TSC2). Angiofibromas are most commonly found on the face and appear as flesh-colored to red-brown papules. Fibrous plaques, periungual fibromas, gingival fibromas, hypopigmented macules, and connective tissue nevi also are found in tuberous sclerosis.⁵  

Brooke-Spiegler syndrome is caused by a mutation in the CYLD lysine 63 deubiquitinase gene, CYLD. Trichoepitheliomas, cylindromas, and spiradenomas are caused by the CYLD mutation and appear on the head and neck. Trichoepitheliomas are flesh-colored to pink papules found on the face, often concentrated in the nasolabial folds.⁶ Cylindromas and spiradenomas are flesh-colored to pink papules or nodules most commonly found on the scalp.⁶  

Muir-Torre syndrome is caused by a mutation in DNA mismatch repair genes MSH2 and/or MLH1.⁷ Sebaceous neoplasms, including sebaceous adenomas, sebaceomas, and less frequently sebaceous carcinomas, are characteristic cutaneous findings and appear as pink to yellow papules commonly found on the head and neck.  

Careful history taking, physical examination, and histopathologic analysis are important in recognizing the features of Birt-Hogg-Dubé syndrome. Accurate and timely diagnosis is essential for the appropriate care of patients and their families, given the syndrome's systemic implications.  

The Diagnosis: Birt-Hogg-Dubé Syndrome 

Histopathologic examination revealed a collection of bland spindle cells with perifollicular fibrosis consistent with a fibrofolliculoma, confirming the diagnosis of Birt-Hogg-Dubé syndrome (Figure). Cosmetic treatment with ablative therapy was offered, but the patient declined.  

Birt-Hogg-Dubé syndrome is an autosomal-dominant genodermatosis caused by a loss-of-function mutation in the folliculin gene, FLCN, on chromosome arm 17p11.2.¹ Cutaneous findings include benign follicular hamartomas, such as fibrofolliculomas and trichodiscomas. Angiofibromas, perifollicular fibromas, oral papillomas, and acrochordons also can be present.¹ Cutaneous lesions usually appear on the head and neck in the third decade of life.  

Patients with Birt-Hogg-Dubé syndrome are at an increased risk for pneumothorax and renal cancer, specifically hybrid oncocytic-chromophobe renal cell carcinomas.² In a study of 89 patients with a FLCN mutation, 90% (80/89) of patients had cutaneous lesions, 84% (34/89) had pulmonary cysts, and 34% (30/89) had kidney tumors. Affected individuals were at a higher risk for pneumothorax and kidney tumors if there was a family history of these tumors.²  

Proposed diagnostic criteria include any 1 of the following: 2 or more skin lesions clinically consistent with fibrofolliculomas and 1 histologically confirmed fibrofolliculoma; multiple bilateral pulmonary cysts in the basilar lung with or without pneumothorax before 40 years of age; bilateral multifocal chromophobe renal carcinomas or hybrid oncocytic tumors; combination of cutaneous, pulmonary, or renal manifestation in the patient and family; or a FLCN mutation.³  

Current recommendations for the workup of a patient with Birt-Hogg-Dubé syndrome include referral to genetic counseling for the patient and family, a baseline computed tomography of the chest to evaluate for pulmonary cysts, and gadolinium-enhanced abdominal magnetic resonance imaging starting at 20 years of age and repeated every 3 to 4 years to screen for renal tumors.¹ Pulmonary function tests can be considered if the patient is symptomatic or has a high cyst burden. Patients should be advised against smoking and scuba diving. 

The differential diagnosis of multiple facial papules includes Cowden syndrome, tuberous sclerosis, Brooke-Spiegler syndrome, and Muir-Torre syndrome. Cowden syndrome is caused by a mutation in the protein tyrosine phosphatase gene, PTEN.⁴ The characteristic cutaneous findings on the face are trichilemmomas, which appear as flesh-colored papules that may have a verrucous surface.  

Tuberous sclerosis is caused by mutations in hamartin (TSC1) or tuberin (TSC2). Angiofibromas are most commonly found on the face and appear as flesh-colored to red-brown papules. Fibrous plaques, periungual fibromas, gingival fibromas, hypopigmented macules, and connective tissue nevi also are found in tuberous sclerosis.⁵  

Brooke-Spiegler syndrome is caused by a mutation in the CYLD lysine 63 deubiquitinase gene, CYLD. Trichoepitheliomas, cylindromas, and spiradenomas are caused by the CYLD mutation and appear on the head and neck. Trichoepitheliomas are flesh-colored to pink papules found on the face, often concentrated in the nasolabial folds.⁶ Cylindromas and spiradenomas are flesh-colored to pink papules or nodules most commonly found on the scalp.⁶  

Muir-Torre syndrome is caused by a mutation in DNA mismatch repair genes MSH2 and/or MLH1.⁷ Sebaceous neoplasms, including sebaceous adenomas, sebaceomas, and less frequently sebaceous carcinomas, are characteristic cutaneous findings and appear as pink to yellow papules commonly found on the head and neck.  

Careful history taking, physical examination, and histopathologic analysis are important in recognizing the features of Birt-Hogg-Dubé syndrome. Accurate and timely diagnosis is essential for the appropriate care of patients and their families, given the syndrome's systemic implications.  

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Folliculotropic Mycosis Fungoides

Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that occurs mostly in adults with a male predilection. The disease clinically favors the head and neck. Patients commonly present with pruritic papules that often are grouped, alopecia, and frequent secondary bacterial infections. Less commonly patients present with acneiform lesions and mucinorrhea. Patients often experience more pruritus in FMF than in classic MF, which can provide a good means of assessing disease activity. Disease-specific 5-year survival is approximately 70% to 80%, which is worse than classic plaque-stage MF and similar to tumor-stage MF.¹

Treatment of FMF differs from classic MF in that the lesions are less responsive to skin-targeted therapies due to the perifollicular nature of dermal infiltrates. Superficial skin lesions can be treated with psoralen plus UVA (PUVA) therapy. Other options include PUVA in combination with interferon alfa or retinoids and local radiotherapy for solitary thick tumors; however, in patients who have more infiltrative skin lesions or had PUVA therapy that failed, total skin electron beam therapy may be required.²

On histologic examination, there typically is perivascular and periadnexal localization of dermal infiltrates with varied involvement of the follicular epithelium and damage to hair follicles by atypical small, medium, and large hyperchromatic lymphocytes with cerebriform nuclei. Mucinous degeneration of the follicular epithelium can be seen, as highlighted on Alcian blue staining, and a mixed infiltrate of eosinophils and plasma cells often is present (quiz image and Figure 1). Frequent sparing of the epidermis is noteworthy.^2-4 In most cases, the neoplastic T lymphocytes are characterized by a CD3⁺CD4⁺CD8^-immunophenotype as is seen in classic MF. Sometimes an admixture of CD30⁺ blast cells is seen.¹

Histologic differential considerations for FMF include eosinophilic pustular folliculitis (EPF), primary follicular mucinosis, lupus erythematosus, and pityrosporum folliculitis.

Eosinophilic pustular folliculitis has several clinical subtypes, such as classic Ofuji disease and immunosuppression-associated EPF secondary to human immunodeficiency virus. Histologically, EPF is characterized by spongiosis of the hair follicle epithelium with exocytosis of a mixed infiltrate of lymphocytes and eosinophils extending from the sebaceous gland and its duct to the infundibulum with formation of hallmark eosinophilic pustules (Figure 2). Infiltration of neutrophils in inflamed lesions generally is seen. Eosinophilic pustular folliculitis is an important differential for FMF, as follicular mucinosis has been observed in lesions of EPF.⁵ Both EPF and FMF can exhibit eosinophils and lymphocytes in the upper dermis, spongiosis of the hair follicle epithelium, and mucinous degeneration of follicles,⁶ though lymphocytic atypia and relatively fewer eosinophils are suggestive of the latter.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Primary follicular mucinosis (PFM) tends to occur as a solitary lesion in younger female patients in contrast to the multiple lesions that typically appear in older male patients with FMF. Histologically, PFM usually manifests as large, cystic, mucin-filled spaces and polyclonal perivascular and periadnexal lymphocytic infiltrate without notable cellular atypia or epidermotropism (Figure 3). Because follicular mucinosis is a common feature of FMF, its distinction from PFM can be challenging and often is aided by the absence of cellular atypia and relatively mild lymphocytic infiltrate in the latter.⁷

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Cutaneous lupus erythematosus with its characteristic folliculocentric lymphocytic infiltration and associated dermal mucin also qualifies as a potential differential possibility for FMF; however, the perivascular and periadnexal pattern of lymphocytic infiltration as well as the localization of mucin to the reticular dermal interstitium^8,9 are key histopathologic distinctions (Figure 4). Furthermore, although the histologic presentation of lupus erythematosus can be variable, it also classically shows interface dermatitis, basement membrane thickening, and follicular plugging.

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).

Pityrosporum folliculitis is the most common cause of fungal folliculitis and is caused by the Malassezia species. On histology, there typically is an unremarkable epithelium with plugged follicles and suppurative folliculitis. Serial sections of the biopsy specimen often are required to identify dilated, follicle-containing, budding yeast cells (Figure 5). Organisms are located predominantly within the infundibulum and orifice of follicular lumen, are positive for periodic acid-Schiff, and are diastase resistant.¹⁰

Photograph courtesy of Brian Swick, MD (Iowa City, Iowa).