Case Letter

To the Editor:

A 26-year-old man was referred to our clinic for evaluation of a persistent red rash to rule out cutaneous lupus erythematosus (LE). The patient was diagnosed at 12 years of age with autosomal-recessive chronic granulomatous disease (CGD)(nitroblue tetrazolium test, 5.0; low normal, 20.6), type p47^phox mutation. At that time the patient had recurrent fevers, sinusitis, anemia, and noncaseating granulomatous liver lesions, but he lacked any cutaneous manifestations. The patient was then treated for approximately 2 years with interferon therapy but discontinued therapy given the absence of any signs or symptoms. He remained asymptomatic until approximately 16 years of age when he experienced the onset of an intermittently painful and pruritic rash on the face that slowly spread over the ensuing years to involve the trunk, arms, forearms, and hands. Although he reported that sunlight exacerbated the rash, the rash also persisted through the winter months when the majority of the sun-exposed areas of the trunk and arms were covered. He denied exposure to topical products and denied the use of any oral medications (prescription or over-the-counter).

Review of systems was negative for fever, fatigue, malaise, headaches, joint pain, arthritis, oral ulcers, dyspnea, or dysuria. Physical examination revealed a well-defined exanthem comprised of erythematous, mildly indurated papules coalescing into larger plaques with white scale that were exclusively limited to the photodistributed areas of the face (Figure 1), neck, arms, forearms, hands, chest, and back. Laboratory test results included the following: minimally elevated erythrocyte sedimentation rate of 31 mm/h (reference range, 0–15 mm/h) and rheumatoid factor of 45 IU/mL (reference range, <20 IU/mL; negative antinuclear antibody screen, Sjögren syndrome antigens A and B, double-stranded DNA, anti–extractable nuclear antigen antibody test, and anti-Jo-1 antibody; complete blood cell count revealed no abnormalities; basic metabolic panel, C3 and C4, CH50, glucose-6-phosphate dehydrogenase activity, total plasma porphyrins, and testing for hepatitis B and C virus and human immunodeficiency virus serologies were negative. Skin biopsy from a lesion on the lateral arm showed features consistent with interface dermatitis (Figure 2). Additional skin biopsies for direct immunofluorescence showed linear deposition of IgG at the dermoepidermal junction, both from involved and uninvolved neck skin (more focally from the involved site). Extensive photopatch testing did not show any clinically relevant positive reactions.

Figure 1. Erythematous patches and thin plaques in photodistributed areas on the face, with sparing of the nasolabial folds. Figure 2. A biopsy from the right lateral arm showed basal layer vacuolization; scattered individually necrotic keratinocytes (black arrows; H&E, original magnification ×400 [inset]); increased dermal mucin; and a mild superficial, predominantly perivascular, lymphocytic infiltrate with mild leukocytoclasis and focal extravasated erythrocytes (H&E, original magnification ×100).

Given the patient’s history of CGD and the extensive negative workup for rheumatologic, photoallergic, and phototoxic causes, the patient was diagnosed with a lupus-like rash of CGD. The rash failed to respond to rigorous sun avoidance and a 3-week on/1-week off regimen of high-potency class 1 topical steroids to the trunk, arms, forearms, and legs, and lower-potency class 4 topical steroid to the face, with disease flaring almost immediately on cessation of treatment during the rest weeks. Given the marked photodistribution resembling subacute cutaneous LE, oral hydroxychloroquine 200 mg (5.7 mg/kg) twice daily was initiated in addition to continued topical steroid therapy.

Four months after the addition of hydroxychloroquine, the patient showed considerable improvement of the rash. Seven months after initiation of hydroxychloroquine, the photodistributed rash was completely resolved and topical steroids were stopped. The rash remained in remission for an additional 24 months with hydroxychloroquine alone, at which time hydroxychloroquine was stopped; however, the rash flared 2 months later and hydroxychloroquine was restarted at 200 mg twice daily, resulting in clearance within 3 months. The patient was maintained on this dose of hydroxychloroquine.

During treatment, the patient had an episode of extensive furunculosis caused by Staphylococcus aureus that was successfully treated with a 14-day course of oral doxycycline 100 mg twice daily. He has since been maintained on prophylactic intranasal mupirocin ointment 2% for the first several days of each month and daily benzoyl peroxide wash 10% without further episodes. He also developed a single lesion of alopecia areata that was successfully treated with intralesional steroid injections.

Chronic granulomatous disease can either be X-linked or, less commonly, autosomal recessive, resulting from a defect in components of the nicotinamide adenine dinucleotide phosphate oxidase complex that is necessary to generate reactive oxygen intermediates for killing phagocytosed microbes. Cutaneous manifestations are relatively common in CGD (60%–70% of cases)¹ and include infectious lesions (eg, recurrent mucous membrane infections, impetigo, carbuncles, otitis externa, suppurative lymphadenopathy) as well as the less common chronic inflammatory conditions such as lupus-like eruption, aphthous stomatitis, Raynaud phenomenon, arcuate dermal erythema, and Jessner lymphocytic infiltrate.² The pathognomonic clinical feature of CGD is the presence of characteristic multinucleated giant cell granulomas distributed in multiple organ systems such as the gastrointestinal system, causing pyloric and/or small bowel obstruction, and the genitourinary system, causing ureter and/or bladder outlet obstruction.³

Importantly, CGD patients also demonstrate immune-related inflammatory disorders, most commonly inflammatory bowel disease, IgA nephropathy, sarcoidosis, and juvenile idiopathic arthritis.³ In addition, both CGD patients and female carriers of X-linked CGD have been reported to demonstrate lupus-like rashes that share overlapping clinical and histologic features with the rashes seen in true discoid LE and tumid LE patients without CGD.^4-6 This lupus-like rash is more commonly observed in adulthood and in carriers, possibly secondary to the high childhood mortality rate of CGD patients.^4,6

De Ravin et al³ proposed that autoimmune conditions arising in CGD patients who have met established criteria for a particular autoimmune disease should be treated for that condition rather than consider it as a part of the CGD spectrum. This theory has important therapeutic implications, including initiating paradoxical corticosteroid and/or steroid-sparing immunosuppressive agents in this otherwise immunocompromised patient population. They reported a 21-year-old man with cutaneous LE lesions and negative lupus serologies whose lesions were refractory to topical steroids but responded to systemic prednisone, requiring a low-dose alternate-day maintenance regimen.³ Beyond the development of a true autoimmune disease associated with CGD, systemic medications, specifically voriconazole, have been implicated as an alternative etiology for this rash in CGD.⁷ While important to consider, our patient’s rash presented in the absence of any systemic medications, supporting the former etiology over the latter.

Our case demonstrates the utility of hydroxychloroquine to treat the lupus-like rash of CGD. Similarly, the lupus-like symptoms of female carriers of X-linked CGD, predominantly with negative lupus serologies, also have been reported to respond to hydroxychloroquine and mepacrine.^4,5,8-10 Interestingly, the utility of monotherapy with hydroxychloroquine may extend beyond treating cutaneous lupus-like lesions, as this regimen also was reported to successfully treat gastric granulomatous involvement in a CGD patient.¹¹

Chronic granulomatous disease often is fatal in early childhood or adolescence due to sequelae from infections or chronic granulomatous infiltration of internal organs. Residual reactive oxygen intermediate production was shown to be a predictor of overall survival, and CGD patients with 1% of normal reactive oxygen intermediate production by neutrophils had a greater likelihood of survival.¹² In this regard, the otherwise good health of our patient at the time of presentation was consistent with his initial nitroblue tetrazolium test showing some residual oxidative activity, emphasizing the phenotypic variability of this rare genetic disorder and the importance of considering CGD in the diagnosis of seronegative cutaneous lupus-like reactions.

To the Editor:

A 26-year-old man was referred to our clinic for evaluation of a persistent red rash to rule out cutaneous lupus erythematosus (LE). The patient was diagnosed at 12 years of age with autosomal-recessive chronic granulomatous disease (CGD)(nitroblue tetrazolium test, 5.0; low normal, 20.6), type p47^phox mutation. At that time the patient had recurrent fevers, sinusitis, anemia, and noncaseating granulomatous liver lesions, but he lacked any cutaneous manifestations. The patient was then treated for approximately 2 years with interferon therapy but discontinued therapy given the absence of any signs or symptoms. He remained asymptomatic until approximately 16 years of age when he experienced the onset of an intermittently painful and pruritic rash on the face that slowly spread over the ensuing years to involve the trunk, arms, forearms, and hands. Although he reported that sunlight exacerbated the rash, the rash also persisted through the winter months when the majority of the sun-exposed areas of the trunk and arms were covered. He denied exposure to topical products and denied the use of any oral medications (prescription or over-the-counter).

Review of systems was negative for fever, fatigue, malaise, headaches, joint pain, arthritis, oral ulcers, dyspnea, or dysuria. Physical examination revealed a well-defined exanthem comprised of erythematous, mildly indurated papules coalescing into larger plaques with white scale that were exclusively limited to the photodistributed areas of the face (Figure 1), neck, arms, forearms, hands, chest, and back. Laboratory test results included the following: minimally elevated erythrocyte sedimentation rate of 31 mm/h (reference range, 0–15 mm/h) and rheumatoid factor of 45 IU/mL (reference range, <20 IU/mL; negative antinuclear antibody screen, Sjögren syndrome antigens A and B, double-stranded DNA, anti–extractable nuclear antigen antibody test, and anti-Jo-1 antibody; complete blood cell count revealed no abnormalities; basic metabolic panel, C3 and C4, CH50, glucose-6-phosphate dehydrogenase activity, total plasma porphyrins, and testing for hepatitis B and C virus and human immunodeficiency virus serologies were negative. Skin biopsy from a lesion on the lateral arm showed features consistent with interface dermatitis (Figure 2). Additional skin biopsies for direct immunofluorescence showed linear deposition of IgG at the dermoepidermal junction, both from involved and uninvolved neck skin (more focally from the involved site). Extensive photopatch testing did not show any clinically relevant positive reactions.

Figure 1. Erythematous patches and thin plaques in photodistributed areas on the face, with sparing of the nasolabial folds. Figure 2. A biopsy from the right lateral arm showed basal layer vacuolization; scattered individually necrotic keratinocytes (black arrows; H&E, original magnification ×400 [inset]); increased dermal mucin; and a mild superficial, predominantly perivascular, lymphocytic infiltrate with mild leukocytoclasis and focal extravasated erythrocytes (H&E, original magnification ×100).

Given the patient’s history of CGD and the extensive negative workup for rheumatologic, photoallergic, and phototoxic causes, the patient was diagnosed with a lupus-like rash of CGD. The rash failed to respond to rigorous sun avoidance and a 3-week on/1-week off regimen of high-potency class 1 topical steroids to the trunk, arms, forearms, and legs, and lower-potency class 4 topical steroid to the face, with disease flaring almost immediately on cessation of treatment during the rest weeks. Given the marked photodistribution resembling subacute cutaneous LE, oral hydroxychloroquine 200 mg (5.7 mg/kg) twice daily was initiated in addition to continued topical steroid therapy.

Four months after the addition of hydroxychloroquine, the patient showed considerable improvement of the rash. Seven months after initiation of hydroxychloroquine, the photodistributed rash was completely resolved and topical steroids were stopped. The rash remained in remission for an additional 24 months with hydroxychloroquine alone, at which time hydroxychloroquine was stopped; however, the rash flared 2 months later and hydroxychloroquine was restarted at 200 mg twice daily, resulting in clearance within 3 months. The patient was maintained on this dose of hydroxychloroquine.

During treatment, the patient had an episode of extensive furunculosis caused by Staphylococcus aureus that was successfully treated with a 14-day course of oral doxycycline 100 mg twice daily. He has since been maintained on prophylactic intranasal mupirocin ointment 2% for the first several days of each month and daily benzoyl peroxide wash 10% without further episodes. He also developed a single lesion of alopecia areata that was successfully treated with intralesional steroid injections.

Chronic granulomatous disease can either be X-linked or, less commonly, autosomal recessive, resulting from a defect in components of the nicotinamide adenine dinucleotide phosphate oxidase complex that is necessary to generate reactive oxygen intermediates for killing phagocytosed microbes. Cutaneous manifestations are relatively common in CGD (60%–70% of cases)¹ and include infectious lesions (eg, recurrent mucous membrane infections, impetigo, carbuncles, otitis externa, suppurative lymphadenopathy) as well as the less common chronic inflammatory conditions such as lupus-like eruption, aphthous stomatitis, Raynaud phenomenon, arcuate dermal erythema, and Jessner lymphocytic infiltrate.² The pathognomonic clinical feature of CGD is the presence of characteristic multinucleated giant cell granulomas distributed in multiple organ systems such as the gastrointestinal system, causing pyloric and/or small bowel obstruction, and the genitourinary system, causing ureter and/or bladder outlet obstruction.³

Importantly, CGD patients also demonstrate immune-related inflammatory disorders, most commonly inflammatory bowel disease, IgA nephropathy, sarcoidosis, and juvenile idiopathic arthritis.³ In addition, both CGD patients and female carriers of X-linked CGD have been reported to demonstrate lupus-like rashes that share overlapping clinical and histologic features with the rashes seen in true discoid LE and tumid LE patients without CGD.^4-6 This lupus-like rash is more commonly observed in adulthood and in carriers, possibly secondary to the high childhood mortality rate of CGD patients.^4,6

De Ravin et al³ proposed that autoimmune conditions arising in CGD patients who have met established criteria for a particular autoimmune disease should be treated for that condition rather than consider it as a part of the CGD spectrum. This theory has important therapeutic implications, including initiating paradoxical corticosteroid and/or steroid-sparing immunosuppressive agents in this otherwise immunocompromised patient population. They reported a 21-year-old man with cutaneous LE lesions and negative lupus serologies whose lesions were refractory to topical steroids but responded to systemic prednisone, requiring a low-dose alternate-day maintenance regimen.³ Beyond the development of a true autoimmune disease associated with CGD, systemic medications, specifically voriconazole, have been implicated as an alternative etiology for this rash in CGD.⁷ While important to consider, our patient’s rash presented in the absence of any systemic medications, supporting the former etiology over the latter.

Our case demonstrates the utility of hydroxychloroquine to treat the lupus-like rash of CGD. Similarly, the lupus-like symptoms of female carriers of X-linked CGD, predominantly with negative lupus serologies, also have been reported to respond to hydroxychloroquine and mepacrine.^4,5,8-10 Interestingly, the utility of monotherapy with hydroxychloroquine may extend beyond treating cutaneous lupus-like lesions, as this regimen also was reported to successfully treat gastric granulomatous involvement in a CGD patient.¹¹

Chronic granulomatous disease often is fatal in early childhood or adolescence due to sequelae from infections or chronic granulomatous infiltration of internal organs. Residual reactive oxygen intermediate production was shown to be a predictor of overall survival, and CGD patients with 1% of normal reactive oxygen intermediate production by neutrophils had a greater likelihood of survival.¹² In this regard, the otherwise good health of our patient at the time of presentation was consistent with his initial nitroblue tetrazolium test showing some residual oxidative activity, emphasizing the phenotypic variability of this rare genetic disorder and the importance of considering CGD in the diagnosis of seronegative cutaneous lupus-like reactions.

To the Editor:

A 26-year-old man was referred to our clinic for evaluation of a persistent red rash to rule out cutaneous lupus erythematosus (LE). The patient was diagnosed at 12 years of age with autosomal-recessive chronic granulomatous disease (CGD)(nitroblue tetrazolium test, 5.0; low normal, 20.6), type p47^phox mutation. At that time the patient had recurrent fevers, sinusitis, anemia, and noncaseating granulomatous liver lesions, but he lacked any cutaneous manifestations. The patient was then treated for approximately 2 years with interferon therapy but discontinued therapy given the absence of any signs or symptoms. He remained asymptomatic until approximately 16 years of age when he experienced the onset of an intermittently painful and pruritic rash on the face that slowly spread over the ensuing years to involve the trunk, arms, forearms, and hands. Although he reported that sunlight exacerbated the rash, the rash also persisted through the winter months when the majority of the sun-exposed areas of the trunk and arms were covered. He denied exposure to topical products and denied the use of any oral medications (prescription or over-the-counter).

Review of systems was negative for fever, fatigue, malaise, headaches, joint pain, arthritis, oral ulcers, dyspnea, or dysuria. Physical examination revealed a well-defined exanthem comprised of erythematous, mildly indurated papules coalescing into larger plaques with white scale that were exclusively limited to the photodistributed areas of the face (Figure 1), neck, arms, forearms, hands, chest, and back. Laboratory test results included the following: minimally elevated erythrocyte sedimentation rate of 31 mm/h (reference range, 0–15 mm/h) and rheumatoid factor of 45 IU/mL (reference range, <20 IU/mL; negative antinuclear antibody screen, Sjögren syndrome antigens A and B, double-stranded DNA, anti–extractable nuclear antigen antibody test, and anti-Jo-1 antibody; complete blood cell count revealed no abnormalities; basic metabolic panel, C3 and C4, CH50, glucose-6-phosphate dehydrogenase activity, total plasma porphyrins, and testing for hepatitis B and C virus and human immunodeficiency virus serologies were negative. Skin biopsy from a lesion on the lateral arm showed features consistent with interface dermatitis (Figure 2). Additional skin biopsies for direct immunofluorescence showed linear deposition of IgG at the dermoepidermal junction, both from involved and uninvolved neck skin (more focally from the involved site). Extensive photopatch testing did not show any clinically relevant positive reactions.

Figure 1. Erythematous patches and thin plaques in photodistributed areas on the face, with sparing of the nasolabial folds. Figure 2. A biopsy from the right lateral arm showed basal layer vacuolization; scattered individually necrotic keratinocytes (black arrows; H&E, original magnification ×400 [inset]); increased dermal mucin; and a mild superficial, predominantly perivascular, lymphocytic infiltrate with mild leukocytoclasis and focal extravasated erythrocytes (H&E, original magnification ×100).

Given the patient’s history of CGD and the extensive negative workup for rheumatologic, photoallergic, and phototoxic causes, the patient was diagnosed with a lupus-like rash of CGD. The rash failed to respond to rigorous sun avoidance and a 3-week on/1-week off regimen of high-potency class 1 topical steroids to the trunk, arms, forearms, and legs, and lower-potency class 4 topical steroid to the face, with disease flaring almost immediately on cessation of treatment during the rest weeks. Given the marked photodistribution resembling subacute cutaneous LE, oral hydroxychloroquine 200 mg (5.7 mg/kg) twice daily was initiated in addition to continued topical steroid therapy.

Four months after the addition of hydroxychloroquine, the patient showed considerable improvement of the rash. Seven months after initiation of hydroxychloroquine, the photodistributed rash was completely resolved and topical steroids were stopped. The rash remained in remission for an additional 24 months with hydroxychloroquine alone, at which time hydroxychloroquine was stopped; however, the rash flared 2 months later and hydroxychloroquine was restarted at 200 mg twice daily, resulting in clearance within 3 months. The patient was maintained on this dose of hydroxychloroquine.

During treatment, the patient had an episode of extensive furunculosis caused by Staphylococcus aureus that was successfully treated with a 14-day course of oral doxycycline 100 mg twice daily. He has since been maintained on prophylactic intranasal mupirocin ointment 2% for the first several days of each month and daily benzoyl peroxide wash 10% without further episodes. He also developed a single lesion of alopecia areata that was successfully treated with intralesional steroid injections.

Chronic granulomatous disease can either be X-linked or, less commonly, autosomal recessive, resulting from a defect in components of the nicotinamide adenine dinucleotide phosphate oxidase complex that is necessary to generate reactive oxygen intermediates for killing phagocytosed microbes. Cutaneous manifestations are relatively common in CGD (60%–70% of cases)¹ and include infectious lesions (eg, recurrent mucous membrane infections, impetigo, carbuncles, otitis externa, suppurative lymphadenopathy) as well as the less common chronic inflammatory conditions such as lupus-like eruption, aphthous stomatitis, Raynaud phenomenon, arcuate dermal erythema, and Jessner lymphocytic infiltrate.² The pathognomonic clinical feature of CGD is the presence of characteristic multinucleated giant cell granulomas distributed in multiple organ systems such as the gastrointestinal system, causing pyloric and/or small bowel obstruction, and the genitourinary system, causing ureter and/or bladder outlet obstruction.³

Importantly, CGD patients also demonstrate immune-related inflammatory disorders, most commonly inflammatory bowel disease, IgA nephropathy, sarcoidosis, and juvenile idiopathic arthritis.³ In addition, both CGD patients and female carriers of X-linked CGD have been reported to demonstrate lupus-like rashes that share overlapping clinical and histologic features with the rashes seen in true discoid LE and tumid LE patients without CGD.^4-6 This lupus-like rash is more commonly observed in adulthood and in carriers, possibly secondary to the high childhood mortality rate of CGD patients.^4,6

De Ravin et al³ proposed that autoimmune conditions arising in CGD patients who have met established criteria for a particular autoimmune disease should be treated for that condition rather than consider it as a part of the CGD spectrum. This theory has important therapeutic implications, including initiating paradoxical corticosteroid and/or steroid-sparing immunosuppressive agents in this otherwise immunocompromised patient population. They reported a 21-year-old man with cutaneous LE lesions and negative lupus serologies whose lesions were refractory to topical steroids but responded to systemic prednisone, requiring a low-dose alternate-day maintenance regimen.³ Beyond the development of a true autoimmune disease associated with CGD, systemic medications, specifically voriconazole, have been implicated as an alternative etiology for this rash in CGD.⁷ While important to consider, our patient’s rash presented in the absence of any systemic medications, supporting the former etiology over the latter.

Our case demonstrates the utility of hydroxychloroquine to treat the lupus-like rash of CGD. Similarly, the lupus-like symptoms of female carriers of X-linked CGD, predominantly with negative lupus serologies, also have been reported to respond to hydroxychloroquine and mepacrine.^4,5,8-10 Interestingly, the utility of monotherapy with hydroxychloroquine may extend beyond treating cutaneous lupus-like lesions, as this regimen also was reported to successfully treat gastric granulomatous involvement in a CGD patient.¹¹

Chronic granulomatous disease often is fatal in early childhood or adolescence due to sequelae from infections or chronic granulomatous infiltration of internal organs. Residual reactive oxygen intermediate production was shown to be a predictor of overall survival, and CGD patients with 1% of normal reactive oxygen intermediate production by neutrophils had a greater likelihood of survival.¹² In this regard, the otherwise good health of our patient at the time of presentation was consistent with his initial nitroblue tetrazolium test showing some residual oxidative activity, emphasizing the phenotypic variability of this rare genetic disorder and the importance of considering CGD in the diagnosis of seronegative cutaneous lupus-like reactions.

To the Editor:

Marjolin ulcers are malignancies arising in nonhealing cutaneous wounds. Although burn wounds are the most common type of cutaneous trauma associated with this entity, there are a multitude of possible lesions that may initiate this disease process including traumatic wounds, venous stasis ulcers, and vaccination sites.^1,2 The most common type of malignancy reported in a Marjolin ulcer is an aggressive squamous cell carcinoma (SCC).^1-3 Less commonly, basal cell carcinoma (BCC) also has been reported.^1,3,4 However, cases of BCCs developing in surgical scars are exceedingly rare. We describe a case of a morphoeic BCC in a long-standing surgical scar in a 50-year-old woman with Crohn disease.

A 50-year-old woman presented with an intermittent ulceration within a horizontal surgical scar on the right side of the upper abdomen of 2 years’ duration that had not healed over the course of the last 6 months. The scar was present from surgeries conducted while she was a teenager for complications associated with Crohn disease. She underwent her first abdominal surgery for a partial gastric resection at 16 years of age, followed by multiple laparotomies from a perforated bile duct that occurred during the first surgery. The original incision created for the partial gastric resection was used for all subsequent surgeries.

The patient’s medical history was notable for central nervous system vasculitis with vision loss, chronic pancreatitis, Crohn disease, arthritis, multiple superficial BCCs on the back that were successfully treated with imiquimod cream, a nodular BCC on the neck that was surgically removed, and facial actinic keratoses treated with liquid nitrogen. She had Fitzpatrick skin type I. She grew up in a residential area in Southern Ontario and did not have a history of heavy sun exposure. She did not receive notable radiation from treatment of Crohn disease, and she usually wore a 1-piece bathing suit when swimming outdoors. According to the patient, she had never been exposed to arsenic. The patient’s family history was negative for skin cancer and she was a nonsmoker. She was taking methotrexate, prednisone, folic acid, pentazocine, and vitamin B₁₂ injections at the time of presentation for the aforementioned conditions.

On physical examination a 1.5-cm honey-crusted ulcer with surrounding violaceous erythema in a long-standing surgical scar was observed (Figure 1). There was no palpable adenopathy in the inguinal or axillary regions. The suspected diagnosis prebiopsy was an SCC developing within the scar tissue. On histologic examination sections of small nests and strands of basal cell infiltrating thick collagen bundles were visualized. The appearance was consistent with a morphoeic BCC. The pathologist’s interpretation indicated that the lesion appeared to be a morphoeic BCC within the scar as opposed to a BCC that appeared morphoeic because of background scarring. Histologic images stained with hematoxylin and eosin showed small nests and strands of basal cells penetrating thick collagen bundles (Figure 2).

Figure 1. Complete visualization of the surgical scar with the associated ulcer in the epigastric region (A). Magnified view of a honey-crusted ulcer with surrounding violaceous erythema (B).

Figure 2. Histology showed small nests and strands of basal cells penetrating thick collagen bundles (A and B)(both H&E, original magnifications ×40 and ×100).

Marjolin ulcer was first described in 1828 by the French surgeon Jean-Nicolas Marjolin who published 4 cases of ulcers arising from scar tissue but did not appreciate their malignant capacity. However, the term Marjolin ulcer is now widely accepted as meaning any malignant tumor occurring within scar tissue or a chronic nonhealing wound.^1,2

The exact incidence of malignant transformation in cutaneous wounds remains unknown, but this phenomenon can occur in individuals of all races and across all age groups.^1,5-7 The most prevalent malignancy identified on biopsy is SCC, followed by BCC, melanoma, osteosarcoma, fibrosarcoma, and liposarcoma.^1,2,6,7 With this entity infrequently occurring in the clinical setting, it often is overlooked or misdiagnosed.² In addition, malignancies presenting as Marjolin ulcers have a greater tendency to metastasize and are reported to have a higher associated fatality rate.^2,8 Thus, early recognition is essential, as a delay in diagnosis can potentially allow the tumor to progress to a life-threatening stage. In our patient, malignancy was clinically suspected based on the presence of an ulcer that was not healing despite adequate wound care and the location in a scar that was present for more than 30 years. The surgical scar had been a place of repeated trauma given the number of surgical procedures and the perforated bile duct, which can increase the potential for malignant transformation. Furthermore, the patient also was on immunosuppressive therapy for an extended period of time, possibly contributing to the development of this cancerous lesion and prior cutaneous malignancies.

The pathogenesis of a Marjolin ulcer is unclear, though many hypotheses have been suggested.^1,2,6,9 Theories investigating decreased vascularity, lowered immune surveillance, decreased regenerative capacity, genetic mutations, and injury-related release of toxins have all been postulated as possible explanations for the increase in potential of malignant transformation.^1-3,6,9 However, despite the pathogenesis, the mainstay of treatment remains wide local excision with at least 2-cm margins.^1-3,10 Alternatively, Mohs micrographic surgery can be considered for Marjolin ulcers, but it is less frequently conducted in comparison to wide local excision. Radiation therapy often follows excision as adjuvant therapy, depending on the type of tumor.^2,10 Prophylactic lymph node dissection is not indicated in most cases, but regional node dissection is suggested when palpable lymphadenopathy is present.^1,2,10 Moreover, amputation is indicated with deep bone or joint involvement.^1-3,10 Recurrence rates are high, ranging from 20% to 50%, and metastases to the brain, liver, lungs, kidneys, and lymph nodes have been reported.^1,3 The prognosis of the cutaneous malignancy in this setting is not as favorable, and the 5-year survival rate is cited at approximately 60%.³ Overall prognosis depends on several factors including location, type of malignancy, immune status, progression of disease, and lymph node metastasis. Our patient’s presentation with a BCC instead of the more common SCC should carry a good overall prognosis, though she will need to be closely followed for recurrence after wide local excision.

This novel presentation of a morpheaform BCC in a surgical scar may serve as a reminder to consider this diagnosis and biopsy nonhealing ulcers within any type of chronic wound or scar.

To the Editor:

Marjolin ulcers are malignancies arising in nonhealing cutaneous wounds. Although burn wounds are the most common type of cutaneous trauma associated with this entity, there are a multitude of possible lesions that may initiate this disease process including traumatic wounds, venous stasis ulcers, and vaccination sites.^1,2 The most common type of malignancy reported in a Marjolin ulcer is an aggressive squamous cell carcinoma (SCC).^1-3 Less commonly, basal cell carcinoma (BCC) also has been reported.^1,3,4 However, cases of BCCs developing in surgical scars are exceedingly rare. We describe a case of a morphoeic BCC in a long-standing surgical scar in a 50-year-old woman with Crohn disease.

A 50-year-old woman presented with an intermittent ulceration within a horizontal surgical scar on the right side of the upper abdomen of 2 years’ duration that had not healed over the course of the last 6 months. The scar was present from surgeries conducted while she was a teenager for complications associated with Crohn disease. She underwent her first abdominal surgery for a partial gastric resection at 16 years of age, followed by multiple laparotomies from a perforated bile duct that occurred during the first surgery. The original incision created for the partial gastric resection was used for all subsequent surgeries.

The patient’s medical history was notable for central nervous system vasculitis with vision loss, chronic pancreatitis, Crohn disease, arthritis, multiple superficial BCCs on the back that were successfully treated with imiquimod cream, a nodular BCC on the neck that was surgically removed, and facial actinic keratoses treated with liquid nitrogen. She had Fitzpatrick skin type I. She grew up in a residential area in Southern Ontario and did not have a history of heavy sun exposure. She did not receive notable radiation from treatment of Crohn disease, and she usually wore a 1-piece bathing suit when swimming outdoors. According to the patient, she had never been exposed to arsenic. The patient’s family history was negative for skin cancer and she was a nonsmoker. She was taking methotrexate, prednisone, folic acid, pentazocine, and vitamin B₁₂ injections at the time of presentation for the aforementioned conditions.

On physical examination a 1.5-cm honey-crusted ulcer with surrounding violaceous erythema in a long-standing surgical scar was observed (Figure 1). There was no palpable adenopathy in the inguinal or axillary regions. The suspected diagnosis prebiopsy was an SCC developing within the scar tissue. On histologic examination sections of small nests and strands of basal cell infiltrating thick collagen bundles were visualized. The appearance was consistent with a morphoeic BCC. The pathologist’s interpretation indicated that the lesion appeared to be a morphoeic BCC within the scar as opposed to a BCC that appeared morphoeic because of background scarring. Histologic images stained with hematoxylin and eosin showed small nests and strands of basal cells penetrating thick collagen bundles (Figure 2).

Figure 1. Complete visualization of the surgical scar with the associated ulcer in the epigastric region (A). Magnified view of a honey-crusted ulcer with surrounding violaceous erythema (B).

Figure 2. Histology showed small nests and strands of basal cells penetrating thick collagen bundles (A and B)(both H&E, original magnifications ×40 and ×100).

Marjolin ulcer was first described in 1828 by the French surgeon Jean-Nicolas Marjolin who published 4 cases of ulcers arising from scar tissue but did not appreciate their malignant capacity. However, the term Marjolin ulcer is now widely accepted as meaning any malignant tumor occurring within scar tissue or a chronic nonhealing wound.^1,2

The exact incidence of malignant transformation in cutaneous wounds remains unknown, but this phenomenon can occur in individuals of all races and across all age groups.^1,5-7 The most prevalent malignancy identified on biopsy is SCC, followed by BCC, melanoma, osteosarcoma, fibrosarcoma, and liposarcoma.^1,2,6,7 With this entity infrequently occurring in the clinical setting, it often is overlooked or misdiagnosed.² In addition, malignancies presenting as Marjolin ulcers have a greater tendency to metastasize and are reported to have a higher associated fatality rate.^2,8 Thus, early recognition is essential, as a delay in diagnosis can potentially allow the tumor to progress to a life-threatening stage. In our patient, malignancy was clinically suspected based on the presence of an ulcer that was not healing despite adequate wound care and the location in a scar that was present for more than 30 years. The surgical scar had been a place of repeated trauma given the number of surgical procedures and the perforated bile duct, which can increase the potential for malignant transformation. Furthermore, the patient also was on immunosuppressive therapy for an extended period of time, possibly contributing to the development of this cancerous lesion and prior cutaneous malignancies.

The pathogenesis of a Marjolin ulcer is unclear, though many hypotheses have been suggested.^1,2,6,9 Theories investigating decreased vascularity, lowered immune surveillance, decreased regenerative capacity, genetic mutations, and injury-related release of toxins have all been postulated as possible explanations for the increase in potential of malignant transformation.^1-3,6,9 However, despite the pathogenesis, the mainstay of treatment remains wide local excision with at least 2-cm margins.^1-3,10 Alternatively, Mohs micrographic surgery can be considered for Marjolin ulcers, but it is less frequently conducted in comparison to wide local excision. Radiation therapy often follows excision as adjuvant therapy, depending on the type of tumor.^2,10 Prophylactic lymph node dissection is not indicated in most cases, but regional node dissection is suggested when palpable lymphadenopathy is present.^1,2,10 Moreover, amputation is indicated with deep bone or joint involvement.^1-3,10 Recurrence rates are high, ranging from 20% to 50%, and metastases to the brain, liver, lungs, kidneys, and lymph nodes have been reported.^1,3 The prognosis of the cutaneous malignancy in this setting is not as favorable, and the 5-year survival rate is cited at approximately 60%.³ Overall prognosis depends on several factors including location, type of malignancy, immune status, progression of disease, and lymph node metastasis. Our patient’s presentation with a BCC instead of the more common SCC should carry a good overall prognosis, though she will need to be closely followed for recurrence after wide local excision.

This novel presentation of a morpheaform BCC in a surgical scar may serve as a reminder to consider this diagnosis and biopsy nonhealing ulcers within any type of chronic wound or scar.

To the Editor:

Marjolin ulcers are malignancies arising in nonhealing cutaneous wounds. Although burn wounds are the most common type of cutaneous trauma associated with this entity, there are a multitude of possible lesions that may initiate this disease process including traumatic wounds, venous stasis ulcers, and vaccination sites.^1,2 The most common type of malignancy reported in a Marjolin ulcer is an aggressive squamous cell carcinoma (SCC).^1-3 Less commonly, basal cell carcinoma (BCC) also has been reported.^1,3,4 However, cases of BCCs developing in surgical scars are exceedingly rare. We describe a case of a morphoeic BCC in a long-standing surgical scar in a 50-year-old woman with Crohn disease.

A 50-year-old woman presented with an intermittent ulceration within a horizontal surgical scar on the right side of the upper abdomen of 2 years’ duration that had not healed over the course of the last 6 months. The scar was present from surgeries conducted while she was a teenager for complications associated with Crohn disease. She underwent her first abdominal surgery for a partial gastric resection at 16 years of age, followed by multiple laparotomies from a perforated bile duct that occurred during the first surgery. The original incision created for the partial gastric resection was used for all subsequent surgeries.

The patient’s medical history was notable for central nervous system vasculitis with vision loss, chronic pancreatitis, Crohn disease, arthritis, multiple superficial BCCs on the back that were successfully treated with imiquimod cream, a nodular BCC on the neck that was surgically removed, and facial actinic keratoses treated with liquid nitrogen. She had Fitzpatrick skin type I. She grew up in a residential area in Southern Ontario and did not have a history of heavy sun exposure. She did not receive notable radiation from treatment of Crohn disease, and she usually wore a 1-piece bathing suit when swimming outdoors. According to the patient, she had never been exposed to arsenic. The patient’s family history was negative for skin cancer and she was a nonsmoker. She was taking methotrexate, prednisone, folic acid, pentazocine, and vitamin B₁₂ injections at the time of presentation for the aforementioned conditions.

On physical examination a 1.5-cm honey-crusted ulcer with surrounding violaceous erythema in a long-standing surgical scar was observed (Figure 1). There was no palpable adenopathy in the inguinal or axillary regions. The suspected diagnosis prebiopsy was an SCC developing within the scar tissue. On histologic examination sections of small nests and strands of basal cell infiltrating thick collagen bundles were visualized. The appearance was consistent with a morphoeic BCC. The pathologist’s interpretation indicated that the lesion appeared to be a morphoeic BCC within the scar as opposed to a BCC that appeared morphoeic because of background scarring. Histologic images stained with hematoxylin and eosin showed small nests and strands of basal cells penetrating thick collagen bundles (Figure 2).

Figure 1. Complete visualization of the surgical scar with the associated ulcer in the epigastric region (A). Magnified view of a honey-crusted ulcer with surrounding violaceous erythema (B).

Figure 2. Histology showed small nests and strands of basal cells penetrating thick collagen bundles (A and B)(both H&E, original magnifications ×40 and ×100).

Marjolin ulcer was first described in 1828 by the French surgeon Jean-Nicolas Marjolin who published 4 cases of ulcers arising from scar tissue but did not appreciate their malignant capacity. However, the term Marjolin ulcer is now widely accepted as meaning any malignant tumor occurring within scar tissue or a chronic nonhealing wound.^1,2

The exact incidence of malignant transformation in cutaneous wounds remains unknown, but this phenomenon can occur in individuals of all races and across all age groups.^1,5-7 The most prevalent malignancy identified on biopsy is SCC, followed by BCC, melanoma, osteosarcoma, fibrosarcoma, and liposarcoma.^1,2,6,7 With this entity infrequently occurring in the clinical setting, it often is overlooked or misdiagnosed.² In addition, malignancies presenting as Marjolin ulcers have a greater tendency to metastasize and are reported to have a higher associated fatality rate.^2,8 Thus, early recognition is essential, as a delay in diagnosis can potentially allow the tumor to progress to a life-threatening stage. In our patient, malignancy was clinically suspected based on the presence of an ulcer that was not healing despite adequate wound care and the location in a scar that was present for more than 30 years. The surgical scar had been a place of repeated trauma given the number of surgical procedures and the perforated bile duct, which can increase the potential for malignant transformation. Furthermore, the patient also was on immunosuppressive therapy for an extended period of time, possibly contributing to the development of this cancerous lesion and prior cutaneous malignancies.

The pathogenesis of a Marjolin ulcer is unclear, though many hypotheses have been suggested.^1,2,6,9 Theories investigating decreased vascularity, lowered immune surveillance, decreased regenerative capacity, genetic mutations, and injury-related release of toxins have all been postulated as possible explanations for the increase in potential of malignant transformation.^1-3,6,9 However, despite the pathogenesis, the mainstay of treatment remains wide local excision with at least 2-cm margins.^1-3,10 Alternatively, Mohs micrographic surgery can be considered for Marjolin ulcers, but it is less frequently conducted in comparison to wide local excision. Radiation therapy often follows excision as adjuvant therapy, depending on the type of tumor.^2,10 Prophylactic lymph node dissection is not indicated in most cases, but regional node dissection is suggested when palpable lymphadenopathy is present.^1,2,10 Moreover, amputation is indicated with deep bone or joint involvement.^1-3,10 Recurrence rates are high, ranging from 20% to 50%, and metastases to the brain, liver, lungs, kidneys, and lymph nodes have been reported.^1,3 The prognosis of the cutaneous malignancy in this setting is not as favorable, and the 5-year survival rate is cited at approximately 60%.³ Overall prognosis depends on several factors including location, type of malignancy, immune status, progression of disease, and lymph node metastasis. Our patient’s presentation with a BCC instead of the more common SCC should carry a good overall prognosis, though she will need to be closely followed for recurrence after wide local excision.

This novel presentation of a morpheaform BCC in a surgical scar may serve as a reminder to consider this diagnosis and biopsy nonhealing ulcers within any type of chronic wound or scar.

To the Editor:

Onychomycosis is a common nail disease that frequently is caused by dermatophytes and is diagnosed by direct microscopy. Conventional diagnostic methods are often time consuming and can produce false-positive or false-negative results. We report a case of onychomycosis diagnosed by confocal microscopy and confirmed with routine potassium hydroxide (KOH) examination and fungal culture. Confocal microscopy is a reliable, practical, and noninvasive technique in the diagnosis of onychomycosis.

A 46-year-old woman presented with yellow-brown discoloration and dystrophy of the toenails (Figure 1) that had become worse over a 5-year period. She was otherwise healthy and had no other dermatologic problems. Examination revealed yellow-brown discoloration, subungual hyperkeratosis, and onycholysis of the toenails. Clinically, a diagnosis of onychomycosis was made. Potassium hydroxide examination of a scraping from the subungual region showed fungal elements. Trichophyton rubrum on Sabouraud dextrose agar was determined.

Figure 1. Onycholysis and onychodystrophy affecting the toes. Figure 2. In vivo confocal image of hyphae (arrows).

We performed both in vivo and in vitro confocal laser scanning microscopic examination of the nail of the right great toe (Figure 2). For the diagnosis of onychomycosis in our case, we used a multilaser reflectance confocal microscope (RCM) with a wavelength of 786 nm. In vivo confocal microscopy of the nail revealed branching hyphae just below the surface of the nail plate. Hyphae were seen as refractile, bright, linear structures along the laminates of the nail.

Onychomycosis is a common condition affecting 5.5% of the population worldwide and representing 20% to 40% of all onychopathies and approximately 30% of cutaneous mycotic infections.^1,2 There are many methods available to confirm the clinical diagnosis of onychomycosis by detecting the causative organisms. Direct microscopic examination of the scraping with a KOH culture, histopathologic assessment with periodic acid–Schiff staining, immunofluorescence analysis with calcofluor white staining, enzyme analysis, and polymerase chain reaction can be used for diagnosis of fungal infections. The most frequently used diagnostic method for onychomycosis is KOH examination of the scraping; however, fungal culture and histopathologic examination also can be used in cases having diagnostic difficulties.^1,3,4 There are many studies comparing the efficacies of these methods in the literature.^5-9

The causative fungal agent should be determined with at least 1 laboratory method due to the high cost, long duration, and serious potential adverse effects of systemic antifungal treatment. Direct microscopic examination with KOH in the diagnosis of onychomycosis is simple, fast, and inexpensive. However, inadequate material, using crystallized KOH for hydrolysis, insufficient or too much hydrolysis of scrapings, inappropriate staining, and not scanning all areas in the microscopy produce false-negative results. Similarly, secondary contamination of hair, cotton, yarn, or air bubbles mimicking fungal structures can cause false-positive results.^9,10

Fungal culture is another diagnostic method that is accepted as the gold standard for diagnosis of onychomycosis.⁹ However, fungal cultures were positive in only 43% to 50% of all cases of onychomycosis that were diagnosed with other methods,^11,12 which may be due to the loss of viability and ability of the fungi to grow in culture media during the transport. A major advantage of fungal culture is that the fungal agent can be classified as dermatophyte, nondermatophyte, mold, or yeast. However, culture does determine if the growing fungi is contamination or the real pathogen. Moreover, it is necessary to wait 3 to 4 weeks for culture results. For nondermatophyte fungi this time may be much longer.¹²

In vivo RCM is a noninvasive imaging method that allows optical en face sectioning of the living tissue with high resolution. Currently, RCM has a wide range of applications, such as the evaluation of both benign and malignant skin lesions in clinical dermatology.¹³

In vivo RCM was used first by Hongcharu et al.¹⁴ The diagnoses of onychomycosis and fungal hyphae were shown both in vivo and in vitro.¹⁴ The sensitivity and specificity of confocal examination in the diagnosis of onychomycosis is not known yet. Large clinical trials are needed to assess the sensitivity and specificity of this method in diagnosing fungal infections.

Onychomycosis is a contagious infectious disease characterized by hyphae proliferation in the nail plate. Definitive diagnosis is necessary before treatment because onychomycosis can be mistaken for many infectious or noninfectious skin diseases with nail involvement. Conventional methods are time consuming, laborious, and less reliable. Instead of high-cost procedures, in vivo confocal microscopic examination can be a rapid and reliable diagnostic method for onychomycosis in the near future.

To the Editor:

Onychomycosis is a common nail disease that frequently is caused by dermatophytes and is diagnosed by direct microscopy. Conventional diagnostic methods are often time consuming and can produce false-positive or false-negative results. We report a case of onychomycosis diagnosed by confocal microscopy and confirmed with routine potassium hydroxide (KOH) examination and fungal culture. Confocal microscopy is a reliable, practical, and noninvasive technique in the diagnosis of onychomycosis.

A 46-year-old woman presented with yellow-brown discoloration and dystrophy of the toenails (Figure 1) that had become worse over a 5-year period. She was otherwise healthy and had no other dermatologic problems. Examination revealed yellow-brown discoloration, subungual hyperkeratosis, and onycholysis of the toenails. Clinically, a diagnosis of onychomycosis was made. Potassium hydroxide examination of a scraping from the subungual region showed fungal elements. Trichophyton rubrum on Sabouraud dextrose agar was determined.

Figure 1. Onycholysis and onychodystrophy affecting the toes. Figure 2. In vivo confocal image of hyphae (arrows).

We performed both in vivo and in vitro confocal laser scanning microscopic examination of the nail of the right great toe (Figure 2). For the diagnosis of onychomycosis in our case, we used a multilaser reflectance confocal microscope (RCM) with a wavelength of 786 nm. In vivo confocal microscopy of the nail revealed branching hyphae just below the surface of the nail plate. Hyphae were seen as refractile, bright, linear structures along the laminates of the nail.

Onychomycosis is a common condition affecting 5.5% of the population worldwide and representing 20% to 40% of all onychopathies and approximately 30% of cutaneous mycotic infections.^1,2 There are many methods available to confirm the clinical diagnosis of onychomycosis by detecting the causative organisms. Direct microscopic examination of the scraping with a KOH culture, histopathologic assessment with periodic acid–Schiff staining, immunofluorescence analysis with calcofluor white staining, enzyme analysis, and polymerase chain reaction can be used for diagnosis of fungal infections. The most frequently used diagnostic method for onychomycosis is KOH examination of the scraping; however, fungal culture and histopathologic examination also can be used in cases having diagnostic difficulties.^1,3,4 There are many studies comparing the efficacies of these methods in the literature.^5-9

The causative fungal agent should be determined with at least 1 laboratory method due to the high cost, long duration, and serious potential adverse effects of systemic antifungal treatment. Direct microscopic examination with KOH in the diagnosis of onychomycosis is simple, fast, and inexpensive. However, inadequate material, using crystallized KOH for hydrolysis, insufficient or too much hydrolysis of scrapings, inappropriate staining, and not scanning all areas in the microscopy produce false-negative results. Similarly, secondary contamination of hair, cotton, yarn, or air bubbles mimicking fungal structures can cause false-positive results.^9,10

Fungal culture is another diagnostic method that is accepted as the gold standard for diagnosis of onychomycosis.⁹ However, fungal cultures were positive in only 43% to 50% of all cases of onychomycosis that were diagnosed with other methods,^11,12 which may be due to the loss of viability and ability of the fungi to grow in culture media during the transport. A major advantage of fungal culture is that the fungal agent can be classified as dermatophyte, nondermatophyte, mold, or yeast. However, culture does determine if the growing fungi is contamination or the real pathogen. Moreover, it is necessary to wait 3 to 4 weeks for culture results. For nondermatophyte fungi this time may be much longer.¹²

In vivo RCM is a noninvasive imaging method that allows optical en face sectioning of the living tissue with high resolution. Currently, RCM has a wide range of applications, such as the evaluation of both benign and malignant skin lesions in clinical dermatology.¹³

In vivo RCM was used first by Hongcharu et al.¹⁴ The diagnoses of onychomycosis and fungal hyphae were shown both in vivo and in vitro.¹⁴ The sensitivity and specificity of confocal examination in the diagnosis of onychomycosis is not known yet. Large clinical trials are needed to assess the sensitivity and specificity of this method in diagnosing fungal infections.

Onychomycosis is a contagious infectious disease characterized by hyphae proliferation in the nail plate. Definitive diagnosis is necessary before treatment because onychomycosis can be mistaken for many infectious or noninfectious skin diseases with nail involvement. Conventional methods are time consuming, laborious, and less reliable. Instead of high-cost procedures, in vivo confocal microscopic examination can be a rapid and reliable diagnostic method for onychomycosis in the near future.

To the Editor:

Onychomycosis is a common nail disease that frequently is caused by dermatophytes and is diagnosed by direct microscopy. Conventional diagnostic methods are often time consuming and can produce false-positive or false-negative results. We report a case of onychomycosis diagnosed by confocal microscopy and confirmed with routine potassium hydroxide (KOH) examination and fungal culture. Confocal microscopy is a reliable, practical, and noninvasive technique in the diagnosis of onychomycosis.

A 46-year-old woman presented with yellow-brown discoloration and dystrophy of the toenails (Figure 1) that had become worse over a 5-year period. She was otherwise healthy and had no other dermatologic problems. Examination revealed yellow-brown discoloration, subungual hyperkeratosis, and onycholysis of the toenails. Clinically, a diagnosis of onychomycosis was made. Potassium hydroxide examination of a scraping from the subungual region showed fungal elements. Trichophyton rubrum on Sabouraud dextrose agar was determined.

Figure 1. Onycholysis and onychodystrophy affecting the toes. Figure 2. In vivo confocal image of hyphae (arrows).

We performed both in vivo and in vitro confocal laser scanning microscopic examination of the nail of the right great toe (Figure 2). For the diagnosis of onychomycosis in our case, we used a multilaser reflectance confocal microscope (RCM) with a wavelength of 786 nm. In vivo confocal microscopy of the nail revealed branching hyphae just below the surface of the nail plate. Hyphae were seen as refractile, bright, linear structures along the laminates of the nail.

Onychomycosis is a common condition affecting 5.5% of the population worldwide and representing 20% to 40% of all onychopathies and approximately 30% of cutaneous mycotic infections.^1,2 There are many methods available to confirm the clinical diagnosis of onychomycosis by detecting the causative organisms. Direct microscopic examination of the scraping with a KOH culture, histopathologic assessment with periodic acid–Schiff staining, immunofluorescence analysis with calcofluor white staining, enzyme analysis, and polymerase chain reaction can be used for diagnosis of fungal infections. The most frequently used diagnostic method for onychomycosis is KOH examination of the scraping; however, fungal culture and histopathologic examination also can be used in cases having diagnostic difficulties.^1,3,4 There are many studies comparing the efficacies of these methods in the literature.^5-9

The causative fungal agent should be determined with at least 1 laboratory method due to the high cost, long duration, and serious potential adverse effects of systemic antifungal treatment. Direct microscopic examination with KOH in the diagnosis of onychomycosis is simple, fast, and inexpensive. However, inadequate material, using crystallized KOH for hydrolysis, insufficient or too much hydrolysis of scrapings, inappropriate staining, and not scanning all areas in the microscopy produce false-negative results. Similarly, secondary contamination of hair, cotton, yarn, or air bubbles mimicking fungal structures can cause false-positive results.^9,10

Fungal culture is another diagnostic method that is accepted as the gold standard for diagnosis of onychomycosis.⁹ However, fungal cultures were positive in only 43% to 50% of all cases of onychomycosis that were diagnosed with other methods,^11,12 which may be due to the loss of viability and ability of the fungi to grow in culture media during the transport. A major advantage of fungal culture is that the fungal agent can be classified as dermatophyte, nondermatophyte, mold, or yeast. However, culture does determine if the growing fungi is contamination or the real pathogen. Moreover, it is necessary to wait 3 to 4 weeks for culture results. For nondermatophyte fungi this time may be much longer.¹²

In vivo RCM is a noninvasive imaging method that allows optical en face sectioning of the living tissue with high resolution. Currently, RCM has a wide range of applications, such as the evaluation of both benign and malignant skin lesions in clinical dermatology.¹³

In vivo RCM was used first by Hongcharu et al.¹⁴ The diagnoses of onychomycosis and fungal hyphae were shown both in vivo and in vitro.¹⁴ The sensitivity and specificity of confocal examination in the diagnosis of onychomycosis is not known yet. Large clinical trials are needed to assess the sensitivity and specificity of this method in diagnosing fungal infections.

Onychomycosis is a contagious infectious disease characterized by hyphae proliferation in the nail plate. Definitive diagnosis is necessary before treatment because onychomycosis can be mistaken for many infectious or noninfectious skin diseases with nail involvement. Conventional methods are time consuming, laborious, and less reliable. Instead of high-cost procedures, in vivo confocal microscopic examination can be a rapid and reliable diagnostic method for onychomycosis in the near future.

To the Editor:

A 38-year-old microbiologist presented to a primary care physician with fevers, night sweats, myalgia, and headaches of 2 weeks’ duration. She was treated for a presumed viral illness with antipyretics and fluids. The patient subsequently developed a persistent nonproductive cough and chest pain as well as painful nodules of the lower legs and a vesicular rash over the trunk and arms. The patient worked closely with Yersinia pestis and Francisella tularensis and because of the occupational exposure had a thorough evaluation. An increased bacterial agglutinin titer for F tularensis from 1:40 to 1:1280 was noted during repeat testing over a 1-week period and a polymerase chain reaction test of sputum was positive for F tularensis. Chest radiography revealed right lower lobe pneumonia and adenopathy. The patient was admitted to the hospital for pneumonic tularemia and was treated with streptomycin with rapid improvement; however, after development of tinnitus and vertigo she was switched to ciprofloxacin.

Figure 1. Scattered erythematous vesicular papules and plaques on the upper back. Figure 2. Several plaques on the mid back reveal a rim of vesicles.

Dermatology was consulted to evaluate the patient’s nonpruritic vesicular rash that had been present for 6 days. Examination revealed multiple erythematous papules and plaques with vesicles rimming the periphery or studded throughout the lesions (Figures 1 and 2). Tender ecchymotic subcutaneous nodules of the lower extremities consistent with erythema nodosum also were present. Punch biopsies taken from vesicular papules of the back showed superficial perivascular inflammation and vesiculation within the epidermis (Figure 3). Polymerase chain reaction analysis revealed F tularensis. The patient was discharged with continued improvement after completion of the 1-month antibiotic regimen.

Vesicular papules and plaques are uncommon cutaneous manifestations of tularemia with few reports since the first documented cases of vesicular tularemia.^1,2 A summary of 654 cases of tularemia in 1928 revealed 1 case with a vesicular rash.³ A retrospective review of 234 cases in Sweden in 2007 noted a vesicular rash in 7 patients (3.0%),⁴ and 2 subsequent cases of vesicular skin lesions in children with culture-positive tularemia initially were misdiagnosed as herpes simplex virus or varicella-zoster virus.⁵

Fewer than 200 cases of tularemia are reported to the Centers for Disease Control and Prevention annually, yet outbreaks do occur.⁵ Tularemia is primarily contracted through contact with infected animals (eg, rabbits) or vector insects (eg, deer flies, Dermacentor ticks). However, the disease remains a concern as a potential bioweapon via inhalation of aerosolized particles. A victim of bioterrorism may present in a manner similar to our patient. Although the threat of bioterrorism and incidence of tularemia in the United States is low, vesicular papules may be a presentation of tularemia and should be considered in the evaluation of a vesicular rash.

Figure 3. Lymphocytic perivascular inflammation with intraepidermal vesiculation (A and B)(both H&E, original magnifications ×10 and ×40).

To the Editor:

A 38-year-old microbiologist presented to a primary care physician with fevers, night sweats, myalgia, and headaches of 2 weeks’ duration. She was treated for a presumed viral illness with antipyretics and fluids. The patient subsequently developed a persistent nonproductive cough and chest pain as well as painful nodules of the lower legs and a vesicular rash over the trunk and arms. The patient worked closely with Yersinia pestis and Francisella tularensis and because of the occupational exposure had a thorough evaluation. An increased bacterial agglutinin titer for F tularensis from 1:40 to 1:1280 was noted during repeat testing over a 1-week period and a polymerase chain reaction test of sputum was positive for F tularensis. Chest radiography revealed right lower lobe pneumonia and adenopathy. The patient was admitted to the hospital for pneumonic tularemia and was treated with streptomycin with rapid improvement; however, after development of tinnitus and vertigo she was switched to ciprofloxacin.

Figure 1. Scattered erythematous vesicular papules and plaques on the upper back. Figure 2. Several plaques on the mid back reveal a rim of vesicles.

Dermatology was consulted to evaluate the patient’s nonpruritic vesicular rash that had been present for 6 days. Examination revealed multiple erythematous papules and plaques with vesicles rimming the periphery or studded throughout the lesions (Figures 1 and 2). Tender ecchymotic subcutaneous nodules of the lower extremities consistent with erythema nodosum also were present. Punch biopsies taken from vesicular papules of the back showed superficial perivascular inflammation and vesiculation within the epidermis (Figure 3). Polymerase chain reaction analysis revealed F tularensis. The patient was discharged with continued improvement after completion of the 1-month antibiotic regimen.

Vesicular papules and plaques are uncommon cutaneous manifestations of tularemia with few reports since the first documented cases of vesicular tularemia.^1,2 A summary of 654 cases of tularemia in 1928 revealed 1 case with a vesicular rash.³ A retrospective review of 234 cases in Sweden in 2007 noted a vesicular rash in 7 patients (3.0%),⁴ and 2 subsequent cases of vesicular skin lesions in children with culture-positive tularemia initially were misdiagnosed as herpes simplex virus or varicella-zoster virus.⁵

Fewer than 200 cases of tularemia are reported to the Centers for Disease Control and Prevention annually, yet outbreaks do occur.⁵ Tularemia is primarily contracted through contact with infected animals (eg, rabbits) or vector insects (eg, deer flies, Dermacentor ticks). However, the disease remains a concern as a potential bioweapon via inhalation of aerosolized particles. A victim of bioterrorism may present in a manner similar to our patient. Although the threat of bioterrorism and incidence of tularemia in the United States is low, vesicular papules may be a presentation of tularemia and should be considered in the evaluation of a vesicular rash.

Figure 3. Lymphocytic perivascular inflammation with intraepidermal vesiculation (A and B)(both H&E, original magnifications ×10 and ×40).

To the Editor:

A 38-year-old microbiologist presented to a primary care physician with fevers, night sweats, myalgia, and headaches of 2 weeks’ duration. She was treated for a presumed viral illness with antipyretics and fluids. The patient subsequently developed a persistent nonproductive cough and chest pain as well as painful nodules of the lower legs and a vesicular rash over the trunk and arms. The patient worked closely with Yersinia pestis and Francisella tularensis and because of the occupational exposure had a thorough evaluation. An increased bacterial agglutinin titer for F tularensis from 1:40 to 1:1280 was noted during repeat testing over a 1-week period and a polymerase chain reaction test of sputum was positive for F tularensis. Chest radiography revealed right lower lobe pneumonia and adenopathy. The patient was admitted to the hospital for pneumonic tularemia and was treated with streptomycin with rapid improvement; however, after development of tinnitus and vertigo she was switched to ciprofloxacin.

Figure 1. Scattered erythematous vesicular papules and plaques on the upper back. Figure 2. Several plaques on the mid back reveal a rim of vesicles.

Dermatology was consulted to evaluate the patient’s nonpruritic vesicular rash that had been present for 6 days. Examination revealed multiple erythematous papules and plaques with vesicles rimming the periphery or studded throughout the lesions (Figures 1 and 2). Tender ecchymotic subcutaneous nodules of the lower extremities consistent with erythema nodosum also were present. Punch biopsies taken from vesicular papules of the back showed superficial perivascular inflammation and vesiculation within the epidermis (Figure 3). Polymerase chain reaction analysis revealed F tularensis. The patient was discharged with continued improvement after completion of the 1-month antibiotic regimen.

Vesicular papules and plaques are uncommon cutaneous manifestations of tularemia with few reports since the first documented cases of vesicular tularemia.^1,2 A summary of 654 cases of tularemia in 1928 revealed 1 case with a vesicular rash.³ A retrospective review of 234 cases in Sweden in 2007 noted a vesicular rash in 7 patients (3.0%),⁴ and 2 subsequent cases of vesicular skin lesions in children with culture-positive tularemia initially were misdiagnosed as herpes simplex virus or varicella-zoster virus.⁵

Fewer than 200 cases of tularemia are reported to the Centers for Disease Control and Prevention annually, yet outbreaks do occur.⁵ Tularemia is primarily contracted through contact with infected animals (eg, rabbits) or vector insects (eg, deer flies, Dermacentor ticks). However, the disease remains a concern as a potential bioweapon via inhalation of aerosolized particles. A victim of bioterrorism may present in a manner similar to our patient. Although the threat of bioterrorism and incidence of tularemia in the United States is low, vesicular papules may be a presentation of tularemia and should be considered in the evaluation of a vesicular rash.

Figure 3. Lymphocytic perivascular inflammation with intraepidermal vesiculation (A and B)(both H&E, original magnifications ×10 and ×40).

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

To the Editor:

A 61-year-old man with a medical history of type 2 diabetes mellitus presented to us with a 2.5×3.0-cm erythematous, ulcerated, and exophytic tumor on the right dorsal forearm that had rapidly developed over 2 weeks. A tangential biopsy was performed followed by treatment with electrodesiccation and curettage (ED&C). Histology revealed a squamous cell carcinoma (SCC), keratoacanthoma (KA) type. Over the next 11 days the lesion rapidly recurred and the patient returned with his own daily photodocumentation of the KA’s progression (Figure). The lesion was re-excised with 5-mm margins; histology again revealed SCC, KA type, with deep margin involvement. Chest radiograph revealed findings suspicious for metastatic lesions in the right lung. He was referred to oncology for metastatic workup; positron emission tomography was negative and ultimately the lung lesion was found to be benign. The patient underwent adjuvant radia-tion to the KA resection bed and lymph nodes with minimal side effects. The patient has remained cancer free to date.

Keratoacanthomas are rapidly growing, typically painless, cutaneous neoplasms that often develop on sun-exposed areas. They can occur spontaneously or following trauma and have the propensity to regress with time.^1-3 They are described as progressing through 3 clinical stages: rapid proliferation, mature/stable, and involution. However, KAs can be aggressive, becoming locally destructive; therefore, KAs are typically treated to avoid further morbidity. Keratoacanthomas may be considered a subtype of SCC, as some have the potential to become locally destructive and metastasize.^3-5 There are reports of spontaneous resolution of KAs over weeks to months, though surgical excision is the gold standard of treatment.^3,5

Reactive KA is a subtype that is thought to develop at the site of prior trauma, representing a sort of Köbner phenomenon.^3,4 We demonstrated a case of a recurrent KA in the setting of recent ED&C. Several reports describe KAs developing after dermatologic surgery, including Mohs micrographic surgery, laser resurfacing, radiation therapy, and after skin grafting.^3,4,6 Trauma-induced epidermal injury and dermal inflammation may play a role in postoperative KA formation or recurrence.⁶

Keratoacanthoma recurrence has been reported in 3% to 8% of cases within a few weeks after treatment, as seen in our current patient.^3,5 In our case, the patient photodocumented the regrowth of his lesion (Figure). Treatment of reactive KAs may be therapeutically challenging, as they can form or worsen with repeated surgeries and may require several treatment modalities to eradicate them.⁴ Treatment options include observation, ED&C, excision, Mohs micrographic surgery, radiation, cryosurgery, laser, isotretinoin, acitretin, imiquimod, 5-fluorouracil, methotrexate, interferon alfa-2b, or bleomycin, to name a few.^3,4,7

Keratoacanthoma recurrence at day 1 (A), day 3 (B), day 5 (C),day 6 (D), day 7 (E), and day 9 (F) following electrodesiccation and curettage.

Combination therapy should be considered in the presence of recurrent and/or aggressive KAs, such as in our case. Our patient has remained disease free after a combination of surgical excision with radiation therapy.

To the Editor:

A 17-year-old adolescent girl presented to our clinic for evaluation of diffuse acanthosis nigricans (AN) that had been present since 7 years of age. The patient had a history of hypothyroidism, insulin resistance, ovarian cysts, and developmental delay. On examination, she presented with thick and verrucous plaques of AN involving the neck, abdomen, trunk, arms, and legs (Figure). The intertriginous areas were affected the most. The examination also was notable for dysmorphic facies and an endomorphic body habitus. Both parents denied similar health problems in their family and were normal in appearance. Although the patient was receiving metformin treatment for insulin resistance, she had not undergone any prior workup to identify a unifying syndromic cause for her physical and biochemical findings. A review of the literature showed a 1993 case report of a 5-year-old boy with mental retardation, body overgrowth, remarkable facies, and AN, which was termed Morfan syndrome.¹ Because of the similarity in features, we believe that our patient’s presentation fits this syndrome. This report represents the second documented case of Morfan syndrome according to a PubMed search of articles indexed for MEDLINE using the search term Morfan. Additional searches using the terms acanthosis nigricans and syndrome also failed to identify any reports describing patients with a similar constellation of findings.

Thick and verrucous brown plaques involving the neck and upper arms (A) as well as the trunk (B).

First described by Santi Unna and Monatsh Pollitzer in 1890, AN is a common dermatosis that is characterized by thick, hyperpigmented, and verrucous plaques.^2,3 Although most common in symmetric distribution on flexural and intertriginous areas, AN also may involve mucosal surfaces.⁴ Acanthosis nigricans is associated with multiple etiologic factors, including direct autosomal transmission, genetic abnormalities, medications, malignancy, and endocrine imbalance.² However, the diffuse generalized form of AN is almost always found in the context of malignancy or genetic syndromes.⁵ Historically, most attention on AN has focused on its eruptive form (so-called malignant AN), which is usually associated with internal malignancy but also may result from benign pituitary adenomas.⁶ Although the precise mechanism for paraneoplastic AN is still a matter of debate, it is likely the result of overactive growth factors, such as transforming growth factor α, epidermal growth factor, and α melanocyte-stimulating hormone.⁷ Generalized AN also has been associated with genetic abnormalities. Multiple genetic mutations have been associated with AN, including the genes coding for the insulin receptor, fibroblast growth receptors 2 and 3, lamin A/C, and seipin.^8-12 Acanthosis nigricans has been described as a feature in other genetic syndromes but may represent an incidental finding.⁴ In 1976, Kahn et al¹³ linked AN with insulin resistance, which subsequently shifted the focus on AN’s link with obesity and as a precursor of type 2 diabetes mellitus.^6,14 In these cases, it is hypothesized that excess insulin activates the insulinlike growth factor 1 receptor to stimulate keratinocyte and dermal fibroblast proliferation. It is likely that hyperinsulinemia also induces cellular proliferation indirectly through other pathways.^15,16 Compared with paraneoplastic and syndromic causes, AN secondary to hyperinsulinemia and obesity does not tend to be generalized but instead is proportionate to the degree of metabolic derangement.¹⁷

Because our patient’s AN presentation was diffuse, long-standing, and occurred in the context of morphologic abnormalities, it was consistent with a syndrome. Based on the constellation of findings, we believe our patient fit the rare markers indicating Morfan syndrome. Because of its extreme rarity, there is no specific diagnostic algorithm for Morfan syndrome. As additional cases are reported, we hope that further biochemical, physical, and genetic studies may be pursued to better identify the syndrome and elucidate its pathogenesis.

To the Editor:

A 17-year-old adolescent girl presented to our clinic for evaluation of diffuse acanthosis nigricans (AN) that had been present since 7 years of age. The patient had a history of hypothyroidism, insulin resistance, ovarian cysts, and developmental delay. On examination, she presented with thick and verrucous plaques of AN involving the neck, abdomen, trunk, arms, and legs (Figure). The intertriginous areas were affected the most. The examination also was notable for dysmorphic facies and an endomorphic body habitus. Both parents denied similar health problems in their family and were normal in appearance. Although the patient was receiving metformin treatment for insulin resistance, she had not undergone any prior workup to identify a unifying syndromic cause for her physical and biochemical findings. A review of the literature showed a 1993 case report of a 5-year-old boy with mental retardation, body overgrowth, remarkable facies, and AN, which was termed Morfan syndrome.¹ Because of the similarity in features, we believe that our patient’s presentation fits this syndrome. This report represents the second documented case of Morfan syndrome according to a PubMed search of articles indexed for MEDLINE using the search term Morfan. Additional searches using the terms acanthosis nigricans and syndrome also failed to identify any reports describing patients with a similar constellation of findings.

Thick and verrucous brown plaques involving the neck and upper arms (A) as well as the trunk (B).

First described by Santi Unna and Monatsh Pollitzer in 1890, AN is a common dermatosis that is characterized by thick, hyperpigmented, and verrucous plaques.^2,3 Although most common in symmetric distribution on flexural and intertriginous areas, AN also may involve mucosal surfaces.⁴ Acanthosis nigricans is associated with multiple etiologic factors, including direct autosomal transmission, genetic abnormalities, medications, malignancy, and endocrine imbalance.² However, the diffuse generalized form of AN is almost always found in the context of malignancy or genetic syndromes.⁵ Historically, most attention on AN has focused on its eruptive form (so-called malignant AN), which is usually associated with internal malignancy but also may result from benign pituitary adenomas.⁶ Although the precise mechanism for paraneoplastic AN is still a matter of debate, it is likely the result of overactive growth factors, such as transforming growth factor α, epidermal growth factor, and α melanocyte-stimulating hormone.⁷ Generalized AN also has been associated with genetic abnormalities. Multiple genetic mutations have been associated with AN, including the genes coding for the insulin receptor, fibroblast growth receptors 2 and 3, lamin A/C, and seipin.^8-12 Acanthosis nigricans has been described as a feature in other genetic syndromes but may represent an incidental finding.⁴ In 1976, Kahn et al¹³ linked AN with insulin resistance, which subsequently shifted the focus on AN’s link with obesity and as a precursor of type 2 diabetes mellitus.^6,14 In these cases, it is hypothesized that excess insulin activates the insulinlike growth factor 1 receptor to stimulate keratinocyte and dermal fibroblast proliferation. It is likely that hyperinsulinemia also induces cellular proliferation indirectly through other pathways.^15,16 Compared with paraneoplastic and syndromic causes, AN secondary to hyperinsulinemia and obesity does not tend to be generalized but instead is proportionate to the degree of metabolic derangement.¹⁷

Because our patient’s AN presentation was diffuse, long-standing, and occurred in the context of morphologic abnormalities, it was consistent with a syndrome. Based on the constellation of findings, we believe our patient fit the rare markers indicating Morfan syndrome. Because of its extreme rarity, there is no specific diagnostic algorithm for Morfan syndrome. As additional cases are reported, we hope that further biochemical, physical, and genetic studies may be pursued to better identify the syndrome and elucidate its pathogenesis.

To the Editor:

A 17-year-old adolescent girl presented to our clinic for evaluation of diffuse acanthosis nigricans (AN) that had been present since 7 years of age. The patient had a history of hypothyroidism, insulin resistance, ovarian cysts, and developmental delay. On examination, she presented with thick and verrucous plaques of AN involving the neck, abdomen, trunk, arms, and legs (Figure). The intertriginous areas were affected the most. The examination also was notable for dysmorphic facies and an endomorphic body habitus. Both parents denied similar health problems in their family and were normal in appearance. Although the patient was receiving metformin treatment for insulin resistance, she had not undergone any prior workup to identify a unifying syndromic cause for her physical and biochemical findings. A review of the literature showed a 1993 case report of a 5-year-old boy with mental retardation, body overgrowth, remarkable facies, and AN, which was termed Morfan syndrome.¹ Because of the similarity in features, we believe that our patient’s presentation fits this syndrome. This report represents the second documented case of Morfan syndrome according to a PubMed search of articles indexed for MEDLINE using the search term Morfan. Additional searches using the terms acanthosis nigricans and syndrome also failed to identify any reports describing patients with a similar constellation of findings.

Thick and verrucous brown plaques involving the neck and upper arms (A) as well as the trunk (B).

First described by Santi Unna and Monatsh Pollitzer in 1890, AN is a common dermatosis that is characterized by thick, hyperpigmented, and verrucous plaques.^2,3 Although most common in symmetric distribution on flexural and intertriginous areas, AN also may involve mucosal surfaces.⁴ Acanthosis nigricans is associated with multiple etiologic factors, including direct autosomal transmission, genetic abnormalities, medications, malignancy, and endocrine imbalance.² However, the diffuse generalized form of AN is almost always found in the context of malignancy or genetic syndromes.⁵ Historically, most attention on AN has focused on its eruptive form (so-called malignant AN), which is usually associated with internal malignancy but also may result from benign pituitary adenomas.⁶ Although the precise mechanism for paraneoplastic AN is still a matter of debate, it is likely the result of overactive growth factors, such as transforming growth factor α, epidermal growth factor, and α melanocyte-stimulating hormone.⁷ Generalized AN also has been associated with genetic abnormalities. Multiple genetic mutations have been associated with AN, including the genes coding for the insulin receptor, fibroblast growth receptors 2 and 3, lamin A/C, and seipin.^8-12 Acanthosis nigricans has been described as a feature in other genetic syndromes but may represent an incidental finding.⁴ In 1976, Kahn et al¹³ linked AN with insulin resistance, which subsequently shifted the focus on AN’s link with obesity and as a precursor of type 2 diabetes mellitus.^6,14 In these cases, it is hypothesized that excess insulin activates the insulinlike growth factor 1 receptor to stimulate keratinocyte and dermal fibroblast proliferation. It is likely that hyperinsulinemia also induces cellular proliferation indirectly through other pathways.^15,16 Compared with paraneoplastic and syndromic causes, AN secondary to hyperinsulinemia and obesity does not tend to be generalized but instead is proportionate to the degree of metabolic derangement.¹⁷

Because our patient’s AN presentation was diffuse, long-standing, and occurred in the context of morphologic abnormalities, it was consistent with a syndrome. Based on the constellation of findings, we believe our patient fit the rare markers indicating Morfan syndrome. Because of its extreme rarity, there is no specific diagnostic algorithm for Morfan syndrome. As additional cases are reported, we hope that further biochemical, physical, and genetic studies may be pursued to better identify the syndrome and elucidate its pathogenesis.