Photo Challenge

The Diagnosis: Kaposi Sarcoma 

On initial presentation, the differential diagnosis included secondary syphilis, Kaposi sarcoma (KS), lichen planus pigmentosus, sarcoidosis, and psoriasis. A laboratory workup was ordered, which included complete blood cell count, comprehensive metabolic panel, antinuclear antibodies, anti-Ro/Sjögren syndrome antigen A and anti-La/Sjögren syndrome antigen B autoantibodies, angiotensin-converting enzyme, rapid plasma reagin, and human immunodeficiency virus (HIV) antibodies. A 4-mm punch biopsy of the rash also was performed from the right upper back. Histology revealed a vascular proliferation that was diffusely positive for human herpesvirus 8 (HHV-8)(Figure 1). The patient was informed of the diagnosis, at which time he revealed he had a history of homosexual relationships, with his last sexual contact being more than 1 year prior to presentation. The laboratory workup confirmed a diagnosis of HIV, and the remainder of the tests were unremarkable. 

He was referred to our university's HIV clinic where he was started on highly active antiretroviral therapy (HAART). His facial swelling worsened, leading to hospital admission. Computed tomography (CT) of the chest, abdomen, and pelvis showed diffuse lymphadenopathy and lung nodules concerning for visceral involvement of KS. Hematology and oncology was consulted for further evaluation, and he was treated with 6 cycles of doxorubicin 20 mg/m², which led to resolution of the lung nodules on CT and improvement of the rash burden. He was then started on alitretinoin gel 0.1% twice daily, which led to continued slow improvement (Figure 2). 

Kaposi sarcoma is a vascular neoplasm that occurs from infection with HHV-8. It typically presents as painless, reddish to violaceous macules or patches involving the skin and mucosa that often progress to plaques or nodules with possible visceral involvement. Kaposi sarcoma is classified into 4 subtypes based on epidemiology and clinical presentation: classic, endemic, iatrogenic, and AIDS associated.^1,2  

Classic KS primarily affects elderly males of Mediterranean or Eastern European descent, with a mean age of 64.¹ years and a male to female ratio of 3 to 1. It has an indolent course and a strong predilection for the skin of the lower extremities. The endemic form occurs mainly in Africa and has a more aggressive course, especially the lymphadenopathic type that affects children younger than 10 years.³ Iatrogenic KS develops in immunosuppressed patients, such as transplant recipients, and may regress if the immunosuppressive agent is stopped.¹ Kaposi sarcoma is an AIDS-defining illness and is the most common malignancy in AIDS patients. It is strongly associated with a low CD4 count, which accounts for the notable decline in its incidence after the widespread introduction of HAART.¹ Among HIV patients, KS has the highest incidence in men who have sex with men. This population has a higher seroprevalence of HHV-8, which suggests possible sexual transmission of HHV-8. AIDS-associated KS most commonly involves the lower extremities, face, and oral mucosa. It may have visceral involvement, particularly of the gastrointestinal and respiratory systems, which carries a poor prognosis.^4,5 

Approximately 40% of patients presenting with KS have gastrointestinal tract involvement.⁶ Of these patients, up to 80% are asymptomatic, with diagnosis usually being made on endoscopy.⁷ In contrast, pulmonary KS is less common and typically is symptomatic. It can involve the lung parenchyma, airways, or pleura and is diagnosed by chest radiography or CT scans. Glucocorticoid therapy is a known trigger for pulmonary KS exacerbation.⁸  

All 4 subtypes share the same histopathologic findings consisting of spindled endothelial cell proliferation, inflammation, and angiogenesis. Immunohistochemistry reveals tumor cells that are CD34 and CD31 positive but are factor VIII negative. Staining for HHV-8 antigen is used to confirm the diagnosis. The inflammatory infiltrate predominantly is lymphocytic with scattered plasma cells.⁹  

The laboratory results and histopathologic findings clearly indicated a diagnosis of KS in our patient. Other entities in the clinical differential would have shown notably different histopathologic findings and laboratory results. Lichen planus pigmentosus displays a lichenoid infiltrate and pigment dropout on histology. Histologic findings of psoriasis include psoriasiform acanthosis, dilated vessels in the dermal papillae, thinning of suprapapillary plates, and neutrophilic microabscesses. Sarcoidosis would demonstrate naked granulomas on histopathology. Syphilis displays variable but often psoriasiform or lichenoid findings on histology, and a positive rapid plasma reagin also would be noted.  

First-line treatment of AIDS-related KS is HAART. For patients with severe and rapidly progressive KS or with visceral involvement, cytotoxic chemotherapy with doxorubicin or taxanes often is required. Additional therapies include radiotherapy, topical alitretinoin, and cryotherapy.^1,10 

The Diagnosis: Kaposi Sarcoma 

On initial presentation, the differential diagnosis included secondary syphilis, Kaposi sarcoma (KS), lichen planus pigmentosus, sarcoidosis, and psoriasis. A laboratory workup was ordered, which included complete blood cell count, comprehensive metabolic panel, antinuclear antibodies, anti-Ro/Sjögren syndrome antigen A and anti-La/Sjögren syndrome antigen B autoantibodies, angiotensin-converting enzyme, rapid plasma reagin, and human immunodeficiency virus (HIV) antibodies. A 4-mm punch biopsy of the rash also was performed from the right upper back. Histology revealed a vascular proliferation that was diffusely positive for human herpesvirus 8 (HHV-8)(Figure 1). The patient was informed of the diagnosis, at which time he revealed he had a history of homosexual relationships, with his last sexual contact being more than 1 year prior to presentation. The laboratory workup confirmed a diagnosis of HIV, and the remainder of the tests were unremarkable. 

He was referred to our university's HIV clinic where he was started on highly active antiretroviral therapy (HAART). His facial swelling worsened, leading to hospital admission. Computed tomography (CT) of the chest, abdomen, and pelvis showed diffuse lymphadenopathy and lung nodules concerning for visceral involvement of KS. Hematology and oncology was consulted for further evaluation, and he was treated with 6 cycles of doxorubicin 20 mg/m², which led to resolution of the lung nodules on CT and improvement of the rash burden. He was then started on alitretinoin gel 0.1% twice daily, which led to continued slow improvement (Figure 2). 

Kaposi sarcoma is a vascular neoplasm that occurs from infection with HHV-8. It typically presents as painless, reddish to violaceous macules or patches involving the skin and mucosa that often progress to plaques or nodules with possible visceral involvement. Kaposi sarcoma is classified into 4 subtypes based on epidemiology and clinical presentation: classic, endemic, iatrogenic, and AIDS associated.^1,2  

Classic KS primarily affects elderly males of Mediterranean or Eastern European descent, with a mean age of 64.¹ years and a male to female ratio of 3 to 1. It has an indolent course and a strong predilection for the skin of the lower extremities. The endemic form occurs mainly in Africa and has a more aggressive course, especially the lymphadenopathic type that affects children younger than 10 years.³ Iatrogenic KS develops in immunosuppressed patients, such as transplant recipients, and may regress if the immunosuppressive agent is stopped.¹ Kaposi sarcoma is an AIDS-defining illness and is the most common malignancy in AIDS patients. It is strongly associated with a low CD4 count, which accounts for the notable decline in its incidence after the widespread introduction of HAART.¹ Among HIV patients, KS has the highest incidence in men who have sex with men. This population has a higher seroprevalence of HHV-8, which suggests possible sexual transmission of HHV-8. AIDS-associated KS most commonly involves the lower extremities, face, and oral mucosa. It may have visceral involvement, particularly of the gastrointestinal and respiratory systems, which carries a poor prognosis.^4,5 

Approximately 40% of patients presenting with KS have gastrointestinal tract involvement.⁶ Of these patients, up to 80% are asymptomatic, with diagnosis usually being made on endoscopy.⁷ In contrast, pulmonary KS is less common and typically is symptomatic. It can involve the lung parenchyma, airways, or pleura and is diagnosed by chest radiography or CT scans. Glucocorticoid therapy is a known trigger for pulmonary KS exacerbation.⁸  

All 4 subtypes share the same histopathologic findings consisting of spindled endothelial cell proliferation, inflammation, and angiogenesis. Immunohistochemistry reveals tumor cells that are CD34 and CD31 positive but are factor VIII negative. Staining for HHV-8 antigen is used to confirm the diagnosis. The inflammatory infiltrate predominantly is lymphocytic with scattered plasma cells.⁹  

The laboratory results and histopathologic findings clearly indicated a diagnosis of KS in our patient. Other entities in the clinical differential would have shown notably different histopathologic findings and laboratory results. Lichen planus pigmentosus displays a lichenoid infiltrate and pigment dropout on histology. Histologic findings of psoriasis include psoriasiform acanthosis, dilated vessels in the dermal papillae, thinning of suprapapillary plates, and neutrophilic microabscesses. Sarcoidosis would demonstrate naked granulomas on histopathology. Syphilis displays variable but often psoriasiform or lichenoid findings on histology, and a positive rapid plasma reagin also would be noted.  

First-line treatment of AIDS-related KS is HAART. For patients with severe and rapidly progressive KS or with visceral involvement, cytotoxic chemotherapy with doxorubicin or taxanes often is required. Additional therapies include radiotherapy, topical alitretinoin, and cryotherapy.^1,10 

The Diagnosis: Kaposi Sarcoma 

On initial presentation, the differential diagnosis included secondary syphilis, Kaposi sarcoma (KS), lichen planus pigmentosus, sarcoidosis, and psoriasis. A laboratory workup was ordered, which included complete blood cell count, comprehensive metabolic panel, antinuclear antibodies, anti-Ro/Sjögren syndrome antigen A and anti-La/Sjögren syndrome antigen B autoantibodies, angiotensin-converting enzyme, rapid plasma reagin, and human immunodeficiency virus (HIV) antibodies. A 4-mm punch biopsy of the rash also was performed from the right upper back. Histology revealed a vascular proliferation that was diffusely positive for human herpesvirus 8 (HHV-8)(Figure 1). The patient was informed of the diagnosis, at which time he revealed he had a history of homosexual relationships, with his last sexual contact being more than 1 year prior to presentation. The laboratory workup confirmed a diagnosis of HIV, and the remainder of the tests were unremarkable. 

He was referred to our university's HIV clinic where he was started on highly active antiretroviral therapy (HAART). His facial swelling worsened, leading to hospital admission. Computed tomography (CT) of the chest, abdomen, and pelvis showed diffuse lymphadenopathy and lung nodules concerning for visceral involvement of KS. Hematology and oncology was consulted for further evaluation, and he was treated with 6 cycles of doxorubicin 20 mg/m², which led to resolution of the lung nodules on CT and improvement of the rash burden. He was then started on alitretinoin gel 0.1% twice daily, which led to continued slow improvement (Figure 2). 

Kaposi sarcoma is a vascular neoplasm that occurs from infection with HHV-8. It typically presents as painless, reddish to violaceous macules or patches involving the skin and mucosa that often progress to plaques or nodules with possible visceral involvement. Kaposi sarcoma is classified into 4 subtypes based on epidemiology and clinical presentation: classic, endemic, iatrogenic, and AIDS associated.^1,2  

Classic KS primarily affects elderly males of Mediterranean or Eastern European descent, with a mean age of 64.¹ years and a male to female ratio of 3 to 1. It has an indolent course and a strong predilection for the skin of the lower extremities. The endemic form occurs mainly in Africa and has a more aggressive course, especially the lymphadenopathic type that affects children younger than 10 years.³ Iatrogenic KS develops in immunosuppressed patients, such as transplant recipients, and may regress if the immunosuppressive agent is stopped.¹ Kaposi sarcoma is an AIDS-defining illness and is the most common malignancy in AIDS patients. It is strongly associated with a low CD4 count, which accounts for the notable decline in its incidence after the widespread introduction of HAART.¹ Among HIV patients, KS has the highest incidence in men who have sex with men. This population has a higher seroprevalence of HHV-8, which suggests possible sexual transmission of HHV-8. AIDS-associated KS most commonly involves the lower extremities, face, and oral mucosa. It may have visceral involvement, particularly of the gastrointestinal and respiratory systems, which carries a poor prognosis.^4,5 

Approximately 40% of patients presenting with KS have gastrointestinal tract involvement.⁶ Of these patients, up to 80% are asymptomatic, with diagnosis usually being made on endoscopy.⁷ In contrast, pulmonary KS is less common and typically is symptomatic. It can involve the lung parenchyma, airways, or pleura and is diagnosed by chest radiography or CT scans. Glucocorticoid therapy is a known trigger for pulmonary KS exacerbation.⁸  

All 4 subtypes share the same histopathologic findings consisting of spindled endothelial cell proliferation, inflammation, and angiogenesis. Immunohistochemistry reveals tumor cells that are CD34 and CD31 positive but are factor VIII negative. Staining for HHV-8 antigen is used to confirm the diagnosis. The inflammatory infiltrate predominantly is lymphocytic with scattered plasma cells.⁹  

The laboratory results and histopathologic findings clearly indicated a diagnosis of KS in our patient. Other entities in the clinical differential would have shown notably different histopathologic findings and laboratory results. Lichen planus pigmentosus displays a lichenoid infiltrate and pigment dropout on histology. Histologic findings of psoriasis include psoriasiform acanthosis, dilated vessels in the dermal papillae, thinning of suprapapillary plates, and neutrophilic microabscesses. Sarcoidosis would demonstrate naked granulomas on histopathology. Syphilis displays variable but often psoriasiform or lichenoid findings on histology, and a positive rapid plasma reagin also would be noted.  

First-line treatment of AIDS-related KS is HAART. For patients with severe and rapidly progressive KS or with visceral involvement, cytotoxic chemotherapy with doxorubicin or taxanes often is required. Additional therapies include radiotherapy, topical alitretinoin, and cryotherapy.^1,10 

The Diagnosis: Warty Dyskeratoma 

Warty dyskeratoma (WD) is a benign cutaneous tumor that was first described in 1954 as isolated Darier disease (DD). In 1957, Szymanski¹ renamed it warty dyskeratoma as a distinct condition from DD. Warty dyskeratoma typically presents as a flesh-colored to brownish, round, well-demarcated, and slightly elevated papule or nodule accompanied by an umbilical invagination at the center. It most commonly arises on the scalp, face, or neck.² In contrast to DD, familial occurrence is uncommon. It usually is difficult to distinguish WD from other conditions such as seborrheic keratosis, verruca vulgaris, or keratoacanthoma due to its macroscopic features. Therefore, histopathologic investigation is necessary for a precise diagnosis. 

In our case, histologic investigation revealed a symmetric cup-shaped invagination filled with acantholytic and dyskeratotic keratinocytes with no atypia or mitotic figures (Figure, A). The bottom of the invagination was occupied with numerous villi covered by a single layer of basal cells (Figure, B). At the edge of the invagination, corps ronds and grains were observed in the granular and cornified layers, respectively (Figure, C).

The hallmark histopathologic findings are acantholysis and dyskeratosis just above the basal cell layer, called focal acantholytic dyskeratosis. The differential diagnosis includes other disorders associated with focal acantholytic dyskeratosis, such as DD and acantholytic squamous cell carcinoma.³ Distinguishing WD from DD may be difficult in rare cases with multiple lesions.⁴ In such cases, an autosomal-dominant inheritance pattern and younger age of onset should prompt clinicians to seek for mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2, for the diagnosis of DD.⁵ Additionally, the presence of atypia or mitotic figures will rule out malignant disorders such as squamous cell carcinoma.  

Although the pathogenesis of WD is not fully understood, most clinicians consider it a follicular adnexal neoplasm because the lesions often are connected to the pilosebaceous unit on microscopic observation.⁶ Although WD-like lesions arising from the oral mucosa have been reported,⁷ their etiology may be different from WD because the oral mucosa lacks hair follicles.⁸ The term warty leads to speculation of the contribution of human papillomavirus to the pathogenesis of WD, but this has been questioned due to the negative result of viral DNA detection from WD lesions by polymerase chain reaction analysis.² Therefore, the term follicular dyskeratoma has been suggested as a novel denomination that reflects its etiology more precisely.²  

The efficacy of topical treatment has not yet been established. Cryosurgery is another therapeutic option, but it sometimes fails.⁹ As performed in our patient, excisional biopsy is the most reasonable treatment option to obtain both complete removal and precise diagnosis.  
 

The Diagnosis: Warty Dyskeratoma 

Warty dyskeratoma (WD) is a benign cutaneous tumor that was first described in 1954 as isolated Darier disease (DD). In 1957, Szymanski¹ renamed it warty dyskeratoma as a distinct condition from DD. Warty dyskeratoma typically presents as a flesh-colored to brownish, round, well-demarcated, and slightly elevated papule or nodule accompanied by an umbilical invagination at the center. It most commonly arises on the scalp, face, or neck.² In contrast to DD, familial occurrence is uncommon. It usually is difficult to distinguish WD from other conditions such as seborrheic keratosis, verruca vulgaris, or keratoacanthoma due to its macroscopic features. Therefore, histopathologic investigation is necessary for a precise diagnosis. 

In our case, histologic investigation revealed a symmetric cup-shaped invagination filled with acantholytic and dyskeratotic keratinocytes with no atypia or mitotic figures (Figure, A). The bottom of the invagination was occupied with numerous villi covered by a single layer of basal cells (Figure, B). At the edge of the invagination, corps ronds and grains were observed in the granular and cornified layers, respectively (Figure, C).

The hallmark histopathologic findings are acantholysis and dyskeratosis just above the basal cell layer, called focal acantholytic dyskeratosis. The differential diagnosis includes other disorders associated with focal acantholytic dyskeratosis, such as DD and acantholytic squamous cell carcinoma.³ Distinguishing WD from DD may be difficult in rare cases with multiple lesions.⁴ In such cases, an autosomal-dominant inheritance pattern and younger age of onset should prompt clinicians to seek for mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2, for the diagnosis of DD.⁵ Additionally, the presence of atypia or mitotic figures will rule out malignant disorders such as squamous cell carcinoma.  

Although the pathogenesis of WD is not fully understood, most clinicians consider it a follicular adnexal neoplasm because the lesions often are connected to the pilosebaceous unit on microscopic observation.⁶ Although WD-like lesions arising from the oral mucosa have been reported,⁷ their etiology may be different from WD because the oral mucosa lacks hair follicles.⁸ The term warty leads to speculation of the contribution of human papillomavirus to the pathogenesis of WD, but this has been questioned due to the negative result of viral DNA detection from WD lesions by polymerase chain reaction analysis.² Therefore, the term follicular dyskeratoma has been suggested as a novel denomination that reflects its etiology more precisely.²  

The efficacy of topical treatment has not yet been established. Cryosurgery is another therapeutic option, but it sometimes fails.⁹ As performed in our patient, excisional biopsy is the most reasonable treatment option to obtain both complete removal and precise diagnosis.  
 

The Diagnosis: Warty Dyskeratoma 

Warty dyskeratoma (WD) is a benign cutaneous tumor that was first described in 1954 as isolated Darier disease (DD). In 1957, Szymanski¹ renamed it warty dyskeratoma as a distinct condition from DD. Warty dyskeratoma typically presents as a flesh-colored to brownish, round, well-demarcated, and slightly elevated papule or nodule accompanied by an umbilical invagination at the center. It most commonly arises on the scalp, face, or neck.² In contrast to DD, familial occurrence is uncommon. It usually is difficult to distinguish WD from other conditions such as seborrheic keratosis, verruca vulgaris, or keratoacanthoma due to its macroscopic features. Therefore, histopathologic investigation is necessary for a precise diagnosis. 

In our case, histologic investigation revealed a symmetric cup-shaped invagination filled with acantholytic and dyskeratotic keratinocytes with no atypia or mitotic figures (Figure, A). The bottom of the invagination was occupied with numerous villi covered by a single layer of basal cells (Figure, B). At the edge of the invagination, corps ronds and grains were observed in the granular and cornified layers, respectively (Figure, C).

The hallmark histopathologic findings are acantholysis and dyskeratosis just above the basal cell layer, called focal acantholytic dyskeratosis. The differential diagnosis includes other disorders associated with focal acantholytic dyskeratosis, such as DD and acantholytic squamous cell carcinoma.³ Distinguishing WD from DD may be difficult in rare cases with multiple lesions.⁴ In such cases, an autosomal-dominant inheritance pattern and younger age of onset should prompt clinicians to seek for mutations in the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2, for the diagnosis of DD.⁵ Additionally, the presence of atypia or mitotic figures will rule out malignant disorders such as squamous cell carcinoma.  

Although the pathogenesis of WD is not fully understood, most clinicians consider it a follicular adnexal neoplasm because the lesions often are connected to the pilosebaceous unit on microscopic observation.⁶ Although WD-like lesions arising from the oral mucosa have been reported,⁷ their etiology may be different from WD because the oral mucosa lacks hair follicles.⁸ The term warty leads to speculation of the contribution of human papillomavirus to the pathogenesis of WD, but this has been questioned due to the negative result of viral DNA detection from WD lesions by polymerase chain reaction analysis.² Therefore, the term follicular dyskeratoma has been suggested as a novel denomination that reflects its etiology more precisely.²  

The efficacy of topical treatment has not yet been established. Cryosurgery is another therapeutic option, but it sometimes fails.⁹ As performed in our patient, excisional biopsy is the most reasonable treatment option to obtain both complete removal and precise diagnosis.  
 

Punch biopsies from the right axilla (Figure) and right abdomen as well as a tangential biopsy from the left volar wrist papule showed an interstitial histiocytic infiltrate with focal palisading of histiocytes around central regions with collagen alteration and increased mucin. Grocott-Gomori methenamine-silver stain and acid-fast bacilli smear both were negative for organisms; these findings were consistent with a diagnosis of granuloma annulare (GA).

Granuloma annulare is a noninfectious granulomatous disease of unknown etiology. It most commonly appears as asymptomatic, flesh-colored, pink or violaceous annular patches or thin plaques favoring the trunk and extremities. Granuloma annulare has many documented presentations including generalized, patch, subcutaneous, and perforating forms. It can present as macules, papules, nodules, patches, or plaques. Reported associations include diabetes mellitus, hyperlipidemia, solid organ tumors, systemic infection, and thyroid disease.¹ Granuloma annulare can occur in any age group but is most common between the ages of 20 and 40 years.²

Diagnosis most often is made clinically and can be confirmed by histopathology. Histologic examination most commonly shows histiocytes within the dermis that palisade around a central area of mucin deposition between degenerating collagen fibers. The histiocytes of GA stain positive with vimentin, lysozyme, and CD68. The increased mucin stains with colloidal iron and Alcian blue. Multinucleated giant cells and perivascular lymphocytic infiltrate also are commonly seen.³

Cutaneous B-cell lymphoma has a wide range of presentations but usually occurs as hyperpigmented plaques and patches with dermal atrophy. Psoriasis can present in an inverse distribution but will show epidermal changes including scale. Sarcoidosis presents as multiple erythematous plaques and papules and also can be accompanied by erythema nodosum. Tinea corporis likely would have resolved with antifungal treatment.

Many different treatments have been described as effective, including cryosurgery, topical and intralesional corticosteroids, antibiotics, immune modulators, phototherapy, and oral corticosteroids.¹ We started our patient on triple-antibiotic therapy with rifampin 600 mg, minocycline 100 mg, and ofloxacin 400 mg all once monthly for 6 months, which has been shown to be efficacious in treating GA.⁴ The patient returned for follow-up 1 year after the initial presentation. At that time, she had faint pink patches on the waist and medial upper thighs, and the axillary lesions had cleared. In the interim, she developed more classic GA lesions—pink to violaceous smooth papules with no overlying epidermal changes—on the volar wrists and dorsal feet. These lesions were asymptomatic, and she currently is not undergoing any further treatment.

Punch biopsies from the right axilla (Figure) and right abdomen as well as a tangential biopsy from the left volar wrist papule showed an interstitial histiocytic infiltrate with focal palisading of histiocytes around central regions with collagen alteration and increased mucin. Grocott-Gomori methenamine-silver stain and acid-fast bacilli smear both were negative for organisms; these findings were consistent with a diagnosis of granuloma annulare (GA).

Granuloma annulare is a noninfectious granulomatous disease of unknown etiology. It most commonly appears as asymptomatic, flesh-colored, pink or violaceous annular patches or thin plaques favoring the trunk and extremities. Granuloma annulare has many documented presentations including generalized, patch, subcutaneous, and perforating forms. It can present as macules, papules, nodules, patches, or plaques. Reported associations include diabetes mellitus, hyperlipidemia, solid organ tumors, systemic infection, and thyroid disease.¹ Granuloma annulare can occur in any age group but is most common between the ages of 20 and 40 years.²

Diagnosis most often is made clinically and can be confirmed by histopathology. Histologic examination most commonly shows histiocytes within the dermis that palisade around a central area of mucin deposition between degenerating collagen fibers. The histiocytes of GA stain positive with vimentin, lysozyme, and CD68. The increased mucin stains with colloidal iron and Alcian blue. Multinucleated giant cells and perivascular lymphocytic infiltrate also are commonly seen.³

Cutaneous B-cell lymphoma has a wide range of presentations but usually occurs as hyperpigmented plaques and patches with dermal atrophy. Psoriasis can present in an inverse distribution but will show epidermal changes including scale. Sarcoidosis presents as multiple erythematous plaques and papules and also can be accompanied by erythema nodosum. Tinea corporis likely would have resolved with antifungal treatment.

Many different treatments have been described as effective, including cryosurgery, topical and intralesional corticosteroids, antibiotics, immune modulators, phototherapy, and oral corticosteroids.¹ We started our patient on triple-antibiotic therapy with rifampin 600 mg, minocycline 100 mg, and ofloxacin 400 mg all once monthly for 6 months, which has been shown to be efficacious in treating GA.⁴ The patient returned for follow-up 1 year after the initial presentation. At that time, she had faint pink patches on the waist and medial upper thighs, and the axillary lesions had cleared. In the interim, she developed more classic GA lesions—pink to violaceous smooth papules with no overlying epidermal changes—on the volar wrists and dorsal feet. These lesions were asymptomatic, and she currently is not undergoing any further treatment.

Punch biopsies from the right axilla (Figure) and right abdomen as well as a tangential biopsy from the left volar wrist papule showed an interstitial histiocytic infiltrate with focal palisading of histiocytes around central regions with collagen alteration and increased mucin. Grocott-Gomori methenamine-silver stain and acid-fast bacilli smear both were negative for organisms; these findings were consistent with a diagnosis of granuloma annulare (GA).

Granuloma annulare is a noninfectious granulomatous disease of unknown etiology. It most commonly appears as asymptomatic, flesh-colored, pink or violaceous annular patches or thin plaques favoring the trunk and extremities. Granuloma annulare has many documented presentations including generalized, patch, subcutaneous, and perforating forms. It can present as macules, papules, nodules, patches, or plaques. Reported associations include diabetes mellitus, hyperlipidemia, solid organ tumors, systemic infection, and thyroid disease.¹ Granuloma annulare can occur in any age group but is most common between the ages of 20 and 40 years.²

Diagnosis most often is made clinically and can be confirmed by histopathology. Histologic examination most commonly shows histiocytes within the dermis that palisade around a central area of mucin deposition between degenerating collagen fibers. The histiocytes of GA stain positive with vimentin, lysozyme, and CD68. The increased mucin stains with colloidal iron and Alcian blue. Multinucleated giant cells and perivascular lymphocytic infiltrate also are commonly seen.³

Cutaneous B-cell lymphoma has a wide range of presentations but usually occurs as hyperpigmented plaques and patches with dermal atrophy. Psoriasis can present in an inverse distribution but will show epidermal changes including scale. Sarcoidosis presents as multiple erythematous plaques and papules and also can be accompanied by erythema nodosum. Tinea corporis likely would have resolved with antifungal treatment.

Many different treatments have been described as effective, including cryosurgery, topical and intralesional corticosteroids, antibiotics, immune modulators, phototherapy, and oral corticosteroids.¹ We started our patient on triple-antibiotic therapy with rifampin 600 mg, minocycline 100 mg, and ofloxacin 400 mg all once monthly for 6 months, which has been shown to be efficacious in treating GA.⁴ The patient returned for follow-up 1 year after the initial presentation. At that time, she had faint pink patches on the waist and medial upper thighs, and the axillary lesions had cleared. In the interim, she developed more classic GA lesions—pink to violaceous smooth papules with no overlying epidermal changes—on the volar wrists and dorsal feet. These lesions were asymptomatic, and she currently is not undergoing any further treatment.

Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

The Diagnosis: Monilethrix

Trichoscopy showed a beaded appearance of the hair shafts (Figure, A). Light microscopy demonstrated normal medullated nodes of hair coupled with internodal, thin, nonmedullated hair at regular intervals (Figure, B). Clinical and trichoscopic findings led to a diagnosis of monilethrix.

Monilethrix is a genetic hair disorder characterized by regular periodic thinning of the hair shafts, giving the strands a beaded appearance. The hair tends to break at these constricted parts, resulting in short hairs. Nodosities represent the normal hair shaft, whereas the constricted points are the site of the defect. The hair tends to be normal at birth and then becomes short, fragile, and brittle within months, leading to hypotrichosis, particularly on the occipital scalp.¹ Monilethrix also may involve the eyebrows and eyelashes in addition to scalp hair. Follicular hyperkeratotic papules with perifollicular erythema frequently are noted on the occipital area. Monilethrix can be inherited in an autosomal-dominant fashion with mutations involving KRT81, KRT83, and KRT86, which code for the type II hair keratins Hb1, Hb3, and Hb6, respectively. The autosomal-recessive form is caused by mutations in the DSG4 gene, coding for the desmoglein 4 protein.2 Trichoscopy or light microscopy is essential to establish a diagnosis of monilethrix. Trichoscopy is an easy and rapid tool that is utilized to illustrate the beaded appearance of the hair shafts.³ Light microscopy shows the distinctive nodes that are medullated, with a normal hair diameter alternating with the internodes, or constrictions, that are nonmedullated and represent the sites of fracture.¹ Monilethrix can improve by puberty. There is no definitive treatment; however, some patients show considerable improvement on minoxidil.⁴ Treatment with minoxidil was initiated in this patient; however, she was lost to follow-up.

Genetic hair disorders are rare and can be an isolated phenomenon or part of concurrent genetic syndromes. Therefore, thorough clinical examination of other ectodermal structures such as the nails and teeth is crucial as well as obtaining a detailed family history and review of systems to exclude other syndromes.² Hypotrichosis simplex is characterized by hair loss exclusively on the scalp, sparing other ectodermal structures and with no systemic abnormalities. Ectodermal dysplasia is a heterogeneous group of disorders affecting not only the hair but also the teeth, nails, and sweat glands.² Pili torti is another rare genetic hair disorder that is characterized by twisting of the hair fiber on its own axis. It presents clinically as sparse, depigmented, lusterless hair that is easily broken. Light microscopy demonstrates twists of hair at irregular intervals. Pili annulati is characterized by bright and dark bands when viewed with reflected light. Unlike monilethrix, there is no fragility, and the hair can grow long.⁵

The Diagnosis: Monilethrix

Trichoscopy showed a beaded appearance of the hair shafts (Figure, A). Light microscopy demonstrated normal medullated nodes of hair coupled with internodal, thin, nonmedullated hair at regular intervals (Figure, B). Clinical and trichoscopic findings led to a diagnosis of monilethrix.

Monilethrix is a genetic hair disorder characterized by regular periodic thinning of the hair shafts, giving the strands a beaded appearance. The hair tends to break at these constricted parts, resulting in short hairs. Nodosities represent the normal hair shaft, whereas the constricted points are the site of the defect. The hair tends to be normal at birth and then becomes short, fragile, and brittle within months, leading to hypotrichosis, particularly on the occipital scalp.¹ Monilethrix also may involve the eyebrows and eyelashes in addition to scalp hair. Follicular hyperkeratotic papules with perifollicular erythema frequently are noted on the occipital area. Monilethrix can be inherited in an autosomal-dominant fashion with mutations involving KRT81, KRT83, and KRT86, which code for the type II hair keratins Hb1, Hb3, and Hb6, respectively. The autosomal-recessive form is caused by mutations in the DSG4 gene, coding for the desmoglein 4 protein.2 Trichoscopy or light microscopy is essential to establish a diagnosis of monilethrix. Trichoscopy is an easy and rapid tool that is utilized to illustrate the beaded appearance of the hair shafts.³ Light microscopy shows the distinctive nodes that are medullated, with a normal hair diameter alternating with the internodes, or constrictions, that are nonmedullated and represent the sites of fracture.¹ Monilethrix can improve by puberty. There is no definitive treatment; however, some patients show considerable improvement on minoxidil.⁴ Treatment with minoxidil was initiated in this patient; however, she was lost to follow-up.

Genetic hair disorders are rare and can be an isolated phenomenon or part of concurrent genetic syndromes. Therefore, thorough clinical examination of other ectodermal structures such as the nails and teeth is crucial as well as obtaining a detailed family history and review of systems to exclude other syndromes.² Hypotrichosis simplex is characterized by hair loss exclusively on the scalp, sparing other ectodermal structures and with no systemic abnormalities. Ectodermal dysplasia is a heterogeneous group of disorders affecting not only the hair but also the teeth, nails, and sweat glands.² Pili torti is another rare genetic hair disorder that is characterized by twisting of the hair fiber on its own axis. It presents clinically as sparse, depigmented, lusterless hair that is easily broken. Light microscopy demonstrates twists of hair at irregular intervals. Pili annulati is characterized by bright and dark bands when viewed with reflected light. Unlike monilethrix, there is no fragility, and the hair can grow long.⁵

The Diagnosis: Monilethrix

Trichoscopy showed a beaded appearance of the hair shafts (Figure, A). Light microscopy demonstrated normal medullated nodes of hair coupled with internodal, thin, nonmedullated hair at regular intervals (Figure, B). Clinical and trichoscopic findings led to a diagnosis of monilethrix.

Monilethrix is a genetic hair disorder characterized by regular periodic thinning of the hair shafts, giving the strands a beaded appearance. The hair tends to break at these constricted parts, resulting in short hairs. Nodosities represent the normal hair shaft, whereas the constricted points are the site of the defect. The hair tends to be normal at birth and then becomes short, fragile, and brittle within months, leading to hypotrichosis, particularly on the occipital scalp.¹ Monilethrix also may involve the eyebrows and eyelashes in addition to scalp hair. Follicular hyperkeratotic papules with perifollicular erythema frequently are noted on the occipital area. Monilethrix can be inherited in an autosomal-dominant fashion with mutations involving KRT81, KRT83, and KRT86, which code for the type II hair keratins Hb1, Hb3, and Hb6, respectively. The autosomal-recessive form is caused by mutations in the DSG4 gene, coding for the desmoglein 4 protein.2 Trichoscopy or light microscopy is essential to establish a diagnosis of monilethrix. Trichoscopy is an easy and rapid tool that is utilized to illustrate the beaded appearance of the hair shafts.³ Light microscopy shows the distinctive nodes that are medullated, with a normal hair diameter alternating with the internodes, or constrictions, that are nonmedullated and represent the sites of fracture.¹ Monilethrix can improve by puberty. There is no definitive treatment; however, some patients show considerable improvement on minoxidil.⁴ Treatment with minoxidil was initiated in this patient; however, she was lost to follow-up.

Genetic hair disorders are rare and can be an isolated phenomenon or part of concurrent genetic syndromes. Therefore, thorough clinical examination of other ectodermal structures such as the nails and teeth is crucial as well as obtaining a detailed family history and review of systems to exclude other syndromes.² Hypotrichosis simplex is characterized by hair loss exclusively on the scalp, sparing other ectodermal structures and with no systemic abnormalities. Ectodermal dysplasia is a heterogeneous group of disorders affecting not only the hair but also the teeth, nails, and sweat glands.² Pili torti is another rare genetic hair disorder that is characterized by twisting of the hair fiber on its own axis. It presents clinically as sparse, depigmented, lusterless hair that is easily broken. Light microscopy demonstrates twists of hair at irregular intervals. Pili annulati is characterized by bright and dark bands when viewed with reflected light. Unlike monilethrix, there is no fragility, and the hair can grow long.⁵

The Diagnosis: Heparin-Induced Bullous Hemorrhagic Dermatosis

Results of a punch biopsy of one of the hemorrhagic papules revealed a subcorneal hemorrhagic vesicle without underlying vasculitis, vasculopathy, inflammation, or viral changes (Figure). Tissue and blood cultures were sterile. Heparin and platelet factor 4 antibody testing was negative. The patient was diagnosed with heparin induced bullous hemorrhagic dermatosis (BHD). After chest imaging ruled out a pulmonary embolism, anticoagulation therapy was discontinued. Respiratory symptoms improved on antibiotics, and the skin lesions resolved completely within 2 weeks.

Bullous hemorrhagic dermatosis is an uncommon and underrecognized reaction to various anticoagulants. Bullous hemorrhagic dermatosis presents with painless, noninflammatory, hemorrhagic vesicles and bullae occurring at sites distant from anticoagulant administration. The condition was first characterized in 2006 by Perrinaud et al,¹ who presented 3 cases in patients treated with heparin and low-molecular-weight heparin. Since then, there have been at least 90 cases reported in the international literature, with elderly men found to be the more affected demographic (male to female ratio, 1.9:1).² Typically, BHD presents within 1 week of administration of an anticoagulant, but delayed onset has been reported.² Bullous hemorrhagic dermatosis is most commonly observed with enoxaparin use but also has been described in association with unfractionated heparin, low-molecular-weight heparin products, and warfarin.²

The noninflammatory-appearing hemorrhagic papules and small plaques of BHD generally are seen on the extremities but can occur anywhere on the body including the oral mucosa.³ The differential diagnosis of BHD may include autoimmune vesiculobullous conditions, bullous drug eruptions, herpetic infection, supratherapeutic anticoagulation, porphyria cutanea tarda, amyloidosis, leukocytoclastic vasculitis, angioinvasive infections, and heparin necrosis. Diagnosis of BHD can be made clinically, but a biopsy is useful to exclude other conditions.

Histologically, BHD is characterized by the presence of intraepidermal hemorrhagic bullae without thrombotic, inflammatory, or vasculitic changes. Although heparinrelated skin lesions have been attributed to various mechanisms, including immune-mediated thrombocytopenia, type IV hypersensitivity reactions, type I allergic hypersensitivity reactions, pustulosis, and skin necrosis, the pathogenesis of BHD remains poorly understood.⁴ The condition has demonstrated koebnerization in some cases.⁵

In our patient, the absence of histologic inflammation, viral changes, vasculitis, and amyloid deposition helped rule out the other entities in the differential. The absence of heparin and platelet factor 4 antibodies helped exclude heparin necrosis. Direct immunofluorescence testing was not obtained in our patient but may be used to evaluate for an immunobullous etiology.

Management strategies for BHD are variable, and associated evidence is lacking. Treatment of BHD should be considered in the clinical context based on the necessity for anticoagulation and the severity of the eruption. Discontinuation of anticoagulation therapy, if possible, may prevent morbidity in some cases.⁶ If it is necessary to continue anticoagulation therapy, changing the drug or decreasing the dose are reasonable options. Skin lesions may resolve even if anticoagulation therapy is continued at the same dose.^7,8 Concurrent supportive wound care is beneficial.

The Diagnosis: Heparin-Induced Bullous Hemorrhagic Dermatosis

Results of a punch biopsy of one of the hemorrhagic papules revealed a subcorneal hemorrhagic vesicle without underlying vasculitis, vasculopathy, inflammation, or viral changes (Figure). Tissue and blood cultures were sterile. Heparin and platelet factor 4 antibody testing was negative. The patient was diagnosed with heparin induced bullous hemorrhagic dermatosis (BHD). After chest imaging ruled out a pulmonary embolism, anticoagulation therapy was discontinued. Respiratory symptoms improved on antibiotics, and the skin lesions resolved completely within 2 weeks.

Bullous hemorrhagic dermatosis is an uncommon and underrecognized reaction to various anticoagulants. Bullous hemorrhagic dermatosis presents with painless, noninflammatory, hemorrhagic vesicles and bullae occurring at sites distant from anticoagulant administration. The condition was first characterized in 2006 by Perrinaud et al,¹ who presented 3 cases in patients treated with heparin and low-molecular-weight heparin. Since then, there have been at least 90 cases reported in the international literature, with elderly men found to be the more affected demographic (male to female ratio, 1.9:1).² Typically, BHD presents within 1 week of administration of an anticoagulant, but delayed onset has been reported.² Bullous hemorrhagic dermatosis is most commonly observed with enoxaparin use but also has been described in association with unfractionated heparin, low-molecular-weight heparin products, and warfarin.²

The noninflammatory-appearing hemorrhagic papules and small plaques of BHD generally are seen on the extremities but can occur anywhere on the body including the oral mucosa.³ The differential diagnosis of BHD may include autoimmune vesiculobullous conditions, bullous drug eruptions, herpetic infection, supratherapeutic anticoagulation, porphyria cutanea tarda, amyloidosis, leukocytoclastic vasculitis, angioinvasive infections, and heparin necrosis. Diagnosis of BHD can be made clinically, but a biopsy is useful to exclude other conditions.

Histologically, BHD is characterized by the presence of intraepidermal hemorrhagic bullae without thrombotic, inflammatory, or vasculitic changes. Although heparinrelated skin lesions have been attributed to various mechanisms, including immune-mediated thrombocytopenia, type IV hypersensitivity reactions, type I allergic hypersensitivity reactions, pustulosis, and skin necrosis, the pathogenesis of BHD remains poorly understood.⁴ The condition has demonstrated koebnerization in some cases.⁵

In our patient, the absence of histologic inflammation, viral changes, vasculitis, and amyloid deposition helped rule out the other entities in the differential. The absence of heparin and platelet factor 4 antibodies helped exclude heparin necrosis. Direct immunofluorescence testing was not obtained in our patient but may be used to evaluate for an immunobullous etiology.

Management strategies for BHD are variable, and associated evidence is lacking. Treatment of BHD should be considered in the clinical context based on the necessity for anticoagulation and the severity of the eruption. Discontinuation of anticoagulation therapy, if possible, may prevent morbidity in some cases.⁶ If it is necessary to continue anticoagulation therapy, changing the drug or decreasing the dose are reasonable options. Skin lesions may resolve even if anticoagulation therapy is continued at the same dose.^7,8 Concurrent supportive wound care is beneficial.

The Diagnosis: Heparin-Induced Bullous Hemorrhagic Dermatosis

Results of a punch biopsy of one of the hemorrhagic papules revealed a subcorneal hemorrhagic vesicle without underlying vasculitis, vasculopathy, inflammation, or viral changes (Figure). Tissue and blood cultures were sterile. Heparin and platelet factor 4 antibody testing was negative. The patient was diagnosed with heparin induced bullous hemorrhagic dermatosis (BHD). After chest imaging ruled out a pulmonary embolism, anticoagulation therapy was discontinued. Respiratory symptoms improved on antibiotics, and the skin lesions resolved completely within 2 weeks.

Bullous hemorrhagic dermatosis is an uncommon and underrecognized reaction to various anticoagulants. Bullous hemorrhagic dermatosis presents with painless, noninflammatory, hemorrhagic vesicles and bullae occurring at sites distant from anticoagulant administration. The condition was first characterized in 2006 by Perrinaud et al,¹ who presented 3 cases in patients treated with heparin and low-molecular-weight heparin. Since then, there have been at least 90 cases reported in the international literature, with elderly men found to be the more affected demographic (male to female ratio, 1.9:1).² Typically, BHD presents within 1 week of administration of an anticoagulant, but delayed onset has been reported.² Bullous hemorrhagic dermatosis is most commonly observed with enoxaparin use but also has been described in association with unfractionated heparin, low-molecular-weight heparin products, and warfarin.²

The noninflammatory-appearing hemorrhagic papules and small plaques of BHD generally are seen on the extremities but can occur anywhere on the body including the oral mucosa.³ The differential diagnosis of BHD may include autoimmune vesiculobullous conditions, bullous drug eruptions, herpetic infection, supratherapeutic anticoagulation, porphyria cutanea tarda, amyloidosis, leukocytoclastic vasculitis, angioinvasive infections, and heparin necrosis. Diagnosis of BHD can be made clinically, but a biopsy is useful to exclude other conditions.

Histologically, BHD is characterized by the presence of intraepidermal hemorrhagic bullae without thrombotic, inflammatory, or vasculitic changes. Although heparinrelated skin lesions have been attributed to various mechanisms, including immune-mediated thrombocytopenia, type IV hypersensitivity reactions, type I allergic hypersensitivity reactions, pustulosis, and skin necrosis, the pathogenesis of BHD remains poorly understood.⁴ The condition has demonstrated koebnerization in some cases.⁵

In our patient, the absence of histologic inflammation, viral changes, vasculitis, and amyloid deposition helped rule out the other entities in the differential. The absence of heparin and platelet factor 4 antibodies helped exclude heparin necrosis. Direct immunofluorescence testing was not obtained in our patient but may be used to evaluate for an immunobullous etiology.

Management strategies for BHD are variable, and associated evidence is lacking. Treatment of BHD should be considered in the clinical context based on the necessity for anticoagulation and the severity of the eruption. Discontinuation of anticoagulation therapy, if possible, may prevent morbidity in some cases.⁶ If it is necessary to continue anticoagulation therapy, changing the drug or decreasing the dose are reasonable options. Skin lesions may resolve even if anticoagulation therapy is continued at the same dose.^7,8 Concurrent supportive wound care is beneficial.

The Diagnosis: Relapsing Polychondritis 

Due to suspicion of relapsing polychondritis (RP), we also performed an audiometric evaluation, which demonstrated bilateral sensorineural hearing loss. Echocardiography highlighted mild to moderate mitralic and tricuspidal insufficiency without hemodynamic impairment (ejection fraction, 50%). Corticosteroid therapy was started (prednisone 0.5 mg/kg/d). After 7 days of treatment, inflammation was remarkably reduced, and the patient no longer reported pain. 

Relapsing polychondritis is a rare noninfective condition characterized by focal inflammatory destruction of ear cartilage, followed by fibroblastic regeneration. It often is associated with ocular inflammation, including conjunctivitis, scleritis, and episcleritis; cochlear or vestibular lesions; and seronegative nonerosive inflammatory arthritis.¹ Clinical examination of the affected area shows swelling, redness, and tenderness of the ear, which could lead to a misdiagnosis of cellulitis. A typical and useful differentiating sign is the sparing of the noncartilaginous parts of the ear lobule. If not promptly diagnosed and treated, the destructive process can cause thinning of the cartilage, leading to deformities of the external ear.  

The differential diagnosis includes erysipelas, which presents as a rapidly appearing inflammatory patch with sharply defined borders, accompanied by regional lymphadenopathy or skin streaking as well as fever. Sweet syndrome usually presents with tender erythematous or violaceous skin papules, plaques, or nodules, frequently with a pseudovesicular appearance; patients generally present with a classic fever and peripheral neutrophilia.² The localized cutaneous form of leishmaniasis usually appears with a papule that generally develops into an ulcerative nodular lesion. Our patient did not have a history of exposure to topical substances that could point to photocontact dermatitis.  

Dion et al³ proposed 3 distinct clinical phenotypes of RP: (1) patients with concomitant myelodysplastic syndrome or other hematologic malignancy (<10% of patients), mostly older men with a poor prognosis; (2) patients with tracheobronchial involvement (approximately 25% of patients); and (3) patients who do not have hematologic or tracheobronchial involvement (approximately 65% of patients) with a good prognosis.  

Two sets of diagnostic criteria have been proposed. The criteria from McAdam et al⁴ required the presence of 3 or more of the following clinical features: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation (eg, conjunctivitis, keratitis, scleritis/episcleritis, uveitis), respiratory tract chondritis (laryngeal and/or tracheal cartilages), and cochlear and/or vestibular dysfunction (eg, neurosensory hearing loss, tinnitus, vertigo). These criteria were modified by Damiani and Levine.⁵ According to the latter, all patients were required to have one of the following: at least 4 of the McAdam et al⁴ diagnostic criteria; 1 or more of the clinical findings included in the McAdam et al⁴ criteria with histologic features suggestive for RP; or chondritis at 2 or more separate anatomic locations with a response to glucocorticoids and/or dapsone.  

No laboratory findings are specific for RP, and nonspecific indicators of inflammation--elevated erythrocyte sedimentation rate and C-reactive protein--often are present. 
The cause of RP is unknown. Familial clustering has not been observed. Terao et al⁶ found that HLA-DRB1*1602, -DQB1*0502, and -B*6701, in linkage disequilibrium with each other, are associated with susceptibility to RP. 

There is no universal consensus about treatment, but a course of steroids leads to the resolution of the acute phase. Maintenance treatment can include dapsone, azathioprine, methotrexate, cyclophosphamide, and cyclosporine.^7,8 Some studies have described the successful use of anti-tumor necrosis factor α inhibitors and rituximab.^9,10  

The Diagnosis: Relapsing Polychondritis 

Due to suspicion of relapsing polychondritis (RP), we also performed an audiometric evaluation, which demonstrated bilateral sensorineural hearing loss. Echocardiography highlighted mild to moderate mitralic and tricuspidal insufficiency without hemodynamic impairment (ejection fraction, 50%). Corticosteroid therapy was started (prednisone 0.5 mg/kg/d). After 7 days of treatment, inflammation was remarkably reduced, and the patient no longer reported pain. 

Relapsing polychondritis is a rare noninfective condition characterized by focal inflammatory destruction of ear cartilage, followed by fibroblastic regeneration. It often is associated with ocular inflammation, including conjunctivitis, scleritis, and episcleritis; cochlear or vestibular lesions; and seronegative nonerosive inflammatory arthritis.¹ Clinical examination of the affected area shows swelling, redness, and tenderness of the ear, which could lead to a misdiagnosis of cellulitis. A typical and useful differentiating sign is the sparing of the noncartilaginous parts of the ear lobule. If not promptly diagnosed and treated, the destructive process can cause thinning of the cartilage, leading to deformities of the external ear.  

The differential diagnosis includes erysipelas, which presents as a rapidly appearing inflammatory patch with sharply defined borders, accompanied by regional lymphadenopathy or skin streaking as well as fever. Sweet syndrome usually presents with tender erythematous or violaceous skin papules, plaques, or nodules, frequently with a pseudovesicular appearance; patients generally present with a classic fever and peripheral neutrophilia.² The localized cutaneous form of leishmaniasis usually appears with a papule that generally develops into an ulcerative nodular lesion. Our patient did not have a history of exposure to topical substances that could point to photocontact dermatitis.  

Dion et al³ proposed 3 distinct clinical phenotypes of RP: (1) patients with concomitant myelodysplastic syndrome or other hematologic malignancy (<10% of patients), mostly older men with a poor prognosis; (2) patients with tracheobronchial involvement (approximately 25% of patients); and (3) patients who do not have hematologic or tracheobronchial involvement (approximately 65% of patients) with a good prognosis.  

Two sets of diagnostic criteria have been proposed. The criteria from McAdam et al⁴ required the presence of 3 or more of the following clinical features: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation (eg, conjunctivitis, keratitis, scleritis/episcleritis, uveitis), respiratory tract chondritis (laryngeal and/or tracheal cartilages), and cochlear and/or vestibular dysfunction (eg, neurosensory hearing loss, tinnitus, vertigo). These criteria were modified by Damiani and Levine.⁵ According to the latter, all patients were required to have one of the following: at least 4 of the McAdam et al⁴ diagnostic criteria; 1 or more of the clinical findings included in the McAdam et al⁴ criteria with histologic features suggestive for RP; or chondritis at 2 or more separate anatomic locations with a response to glucocorticoids and/or dapsone.  

No laboratory findings are specific for RP, and nonspecific indicators of inflammation--elevated erythrocyte sedimentation rate and C-reactive protein--often are present. 
The cause of RP is unknown. Familial clustering has not been observed. Terao et al⁶ found that HLA-DRB1*1602, -DQB1*0502, and -B*6701, in linkage disequilibrium with each other, are associated with susceptibility to RP. 

There is no universal consensus about treatment, but a course of steroids leads to the resolution of the acute phase. Maintenance treatment can include dapsone, azathioprine, methotrexate, cyclophosphamide, and cyclosporine.^7,8 Some studies have described the successful use of anti-tumor necrosis factor α inhibitors and rituximab.^9,10  

The Diagnosis: Relapsing Polychondritis 

Due to suspicion of relapsing polychondritis (RP), we also performed an audiometric evaluation, which demonstrated bilateral sensorineural hearing loss. Echocardiography highlighted mild to moderate mitralic and tricuspidal insufficiency without hemodynamic impairment (ejection fraction, 50%). Corticosteroid therapy was started (prednisone 0.5 mg/kg/d). After 7 days of treatment, inflammation was remarkably reduced, and the patient no longer reported pain. 

Relapsing polychondritis is a rare noninfective condition characterized by focal inflammatory destruction of ear cartilage, followed by fibroblastic regeneration. It often is associated with ocular inflammation, including conjunctivitis, scleritis, and episcleritis; cochlear or vestibular lesions; and seronegative nonerosive inflammatory arthritis.¹ Clinical examination of the affected area shows swelling, redness, and tenderness of the ear, which could lead to a misdiagnosis of cellulitis. A typical and useful differentiating sign is the sparing of the noncartilaginous parts of the ear lobule. If not promptly diagnosed and treated, the destructive process can cause thinning of the cartilage, leading to deformities of the external ear.  

The differential diagnosis includes erysipelas, which presents as a rapidly appearing inflammatory patch with sharply defined borders, accompanied by regional lymphadenopathy or skin streaking as well as fever. Sweet syndrome usually presents with tender erythematous or violaceous skin papules, plaques, or nodules, frequently with a pseudovesicular appearance; patients generally present with a classic fever and peripheral neutrophilia.² The localized cutaneous form of leishmaniasis usually appears with a papule that generally develops into an ulcerative nodular lesion. Our patient did not have a history of exposure to topical substances that could point to photocontact dermatitis.  

Dion et al³ proposed 3 distinct clinical phenotypes of RP: (1) patients with concomitant myelodysplastic syndrome or other hematologic malignancy (<10% of patients), mostly older men with a poor prognosis; (2) patients with tracheobronchial involvement (approximately 25% of patients); and (3) patients who do not have hematologic or tracheobronchial involvement (approximately 65% of patients) with a good prognosis.  

Two sets of diagnostic criteria have been proposed. The criteria from McAdam et al⁴ required the presence of 3 or more of the following clinical features: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation (eg, conjunctivitis, keratitis, scleritis/episcleritis, uveitis), respiratory tract chondritis (laryngeal and/or tracheal cartilages), and cochlear and/or vestibular dysfunction (eg, neurosensory hearing loss, tinnitus, vertigo). These criteria were modified by Damiani and Levine.⁵ According to the latter, all patients were required to have one of the following: at least 4 of the McAdam et al⁴ diagnostic criteria; 1 or more of the clinical findings included in the McAdam et al⁴ criteria with histologic features suggestive for RP; or chondritis at 2 or more separate anatomic locations with a response to glucocorticoids and/or dapsone.  

No laboratory findings are specific for RP, and nonspecific indicators of inflammation--elevated erythrocyte sedimentation rate and C-reactive protein--often are present. 
The cause of RP is unknown. Familial clustering has not been observed. Terao et al⁶ found that HLA-DRB1*1602, -DQB1*0502, and -B*6701, in linkage disequilibrium with each other, are associated with susceptibility to RP. 

There is no universal consensus about treatment, but a course of steroids leads to the resolution of the acute phase. Maintenance treatment can include dapsone, azathioprine, methotrexate, cyclophosphamide, and cyclosporine.^7,8 Some studies have described the successful use of anti-tumor necrosis factor α inhibitors and rituximab.^9,10  

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

The Diagnosis: Acrodermatitis Enteropathica 

Acrodermatitis enteropathica (AE) was the presumptive diagnosis. Oral supplementation with zinc sulfate 3 mg/kg/d was started immediately after a zinc level was ordered. A low zinc level of 15 µg/dL (reference range, 56-134 µg/dL) eventually was obtained. The lesions began to fade in 2 days along with return of normal feeding and disposition, and the patient was discharged with continued zinc supplementation.  

Acrodermatitis enteropathica is an autosomal-recessive condition resulting in severe zinc deficiency caused by a defect of dietary zinc absorption in the duodenum and jejunum.¹ It occurs in 1 in 500,000 individuals with no gender or racial predilection. It can be acquired or inherited.² Recognition of clinical symptoms is essential due to potential death if untreated. Zinc is an important trace element required for the proper functioning of all cells and plays a large role in the metabolism of protein, carbohydrates, and vitamin A. Zinc deficiency impairs immune function, leading to bacterial infections. It also is a cofactor of numerous metal enzymes such as alkaline phosphatase, RNA polymerase, and numerous digestive enzymes.³  

Our laboratory analysis revealed low alkaline phosphatase and zinc levels, which led to the diagnosis of AE; unfortunately, these levels can be ambiguous.⁴ There are many causes of acquired zinc deficiency, including premature birth, low birth weight, zinc deficiency in maternal milk, exclusive parenteral nutrition, malabsorption syndromes such as Crohn disease and celiac disease, alcoholism, low calcium and phytate (cereal grain) diet, and kwashiorkor.⁵ The hereditary deficiency of zinc classically is known as AE and is caused by an autosomal-recessive mutation of the SLC39A4 gene on chromosome arm 8q24.3, which determines a congenital partial or total deficiency of the zinc transporter protein ZIP4.⁶  

The clinical manifestations of acquired zinc deficiency and AE are similar and consist of 3 essential symptoms: periorificial dermatitis, alopecia, and diarrhea. Unfortunately, this clinical triad is complete in only 20% of patients with AE.³ For example, our patient was too young for an alopecia determination. The disease typically presents with eczematous papules and sometimes vesiculobullous or pustular lesions located around perioral and acral areas (Figure 1) as well as the anogenital region (Figures 2 and 3). The severity of the skin lesions is variable.⁷ Our patient also presented with eczematous truncal papules on the chest (Figure 4). Acrodermatitis enteropathica usually presents during childhood after weaning. Along with the aforementioned skin findings, other symptoms in infancy can include diarrhea, mood changes, and anorexia. In school-aged children and toddlers, zinc deficiency is characterized by growth retardation, alopecia, weight loss, and recurrent infections.  

In the differential diagnosis, the clinical presentation of biotin deficiency involves abnormalities of the hair, skin, nails, and central nervous system (eg, seizures, ataxia, deafness).⁸ Cystic fibrosis presentation depends on the multiorgan involvement, but neonates often present with failure to thrive.⁹ Essential fatty acid deficiency presents clinically as dermatitis, alopecia, and thrombocytopenia, but a complete blood cell count with platelets was within reference range in our patient.¹⁰ Langerhans cell histiocytosis presents with perineal and postauricular lesions, but the skin biopsy did not confirm this diagnosis in our patient.¹¹ Histopathologic examination of the buttock biopsy in our patient revealed nonspecific epidermal hyperplasia with acanthosis as well as clustered necrotic keratinocytes with vacuolization and parakeratosis.  

Most clinicians who suspect AE treat with a therapeutic supplementation of zinc sulfate 3 mg/kg/d while awaiting laboratory results. Acrodermatitis enteropathica is a rare condition, and early recognition of skin findings is important because misdiagnosis can lead to infections, malnutrition, and possibly death.  

The Diagnosis: Fusariosis 

A periodic acid-Schiff stain of the seropurulent drainage from a skin nodule revealed neutrophils and scarce branching hyaline hyphae. Skin and blood cultures grew a white cottony colony. Microscopic examination showed sickle-shaped macroconidia and septate hyaline hyphae with branching acute angles (Figure). Molecular analysis by polymerase chain reaction yielded Fusarium solani species complex. Histopathology as well as culture and molecular findings were consistent with a diagnosis of disseminated fusariosis. Amphotericin B was started with rapid clinical improvement. The patient was asymptomatic upon discharge with voriconazole 200 mg twice daily. 

Fusariosis is an emerging, opportunistic, and life-threatening mycosis. In immunocompetent patients it may cause onychomycosis and keratitis.¹ Invasive fusariosis predominantly is caused by the F solani species complex and affects immunocompromised patients, especially those with neutropenia or acute leukemia or hematopoietic stem cell transplant recipients.² 

Before invasion, the infection frequently may begin by affecting the nail apparatus as onychomycosis or paronychia of the skin. As in our case, trauma or manipulation of the nail favors dissemination.³ Skin manifestations include erythematous to violaceous papules, macules, and nodules with central necrosis or crust; some may exhibit target morphology. Other organs may be affected, including the sinuses, lungs, liver, spleen, and kidneys. A comprehensive clinical examination before hematopoietic cell transplant and during fever and neutropenia may opportunely identify these potential infective foci.^3,4 

The differential diagnosis of disseminated fusariosis includes bacterial infections, especially Staphylococcus aureus and Pseudomonas aeruginosa, and other invasive fungal infections, particularly aspergillosis, mucormycosis, and candidiasis.⁵ Symptom persistence after broad-spectrum antibiotic initiation should raise diagnostic suspicion of systemic mycosis or mycobacterial infection. Mucormycosis and candidiasis have histopathologic profiles that differ from fusariosis, presenting with broad ribbonlike hyphae with 90° angulation and pseudohyphae with budding yeast cells, respectively. Differentiation of disseminated fusariosis and aspergillosis in neutropenic patients is difficult. Hyphae cannot be differentiated from those of Aspergillus species on histology.⁶ Furthermore, serologic assays, such as galactomannan and (1,3)-β-D-glucan, cross-react with both genera. Clinically, Fusarium species exhibit metastatic skin lesions, cellulitis, and positive blood cultures due to adventitious sporulation more frequently than Aspergillus species. Patients with aspergillosis more commonly present with sinusitis, pneumonia, and pulmonary macronodules with the halo sign.⁶ Although nocardiosis presents with disseminated subcutaneous nodules with pulmonary affection in immunocompromised patients, its morphology is very different from fusariosis. Nocardia presents with a gram-positive bacillus with the microscopic appearance of branching filaments. Yeastlike microorganisms with morphology ranging from oval to sausagelike are found in talaromycosis, an uncommon fungal infection predominantly caused by Talaromyces marneffei. Fusarium species culture reveals white cottony colonies with characteristic hyaline, canoe-shaped or sickle-shaped (banana-shaped), multicellular macroconidia, and microconidia. Precise species identification requires molecular analyses such as polymerase chain reaction. 

Mortality is high, ranging from 50% to 70% of cases.⁵ Voriconazole or lipid-based amphotericin B are considered first-line treatments. Posaconazole may be employed as a second-line alternative. Surgical debridement of infected tissues and removal of colonized venous catheters is recommended. Secondary prophylaxis should be considered with agents such as voriconazole, posaconazole, or amphotericin B.⁵ Resolution of immunosuppression and neutropenia is an important factor to reduce the mortality rate. 

The Diagnosis: Fusariosis 

A periodic acid-Schiff stain of the seropurulent drainage from a skin nodule revealed neutrophils and scarce branching hyaline hyphae. Skin and blood cultures grew a white cottony colony. Microscopic examination showed sickle-shaped macroconidia and septate hyaline hyphae with branching acute angles (Figure). Molecular analysis by polymerase chain reaction yielded Fusarium solani species complex. Histopathology as well as culture and molecular findings were consistent with a diagnosis of disseminated fusariosis. Amphotericin B was started with rapid clinical improvement. The patient was asymptomatic upon discharge with voriconazole 200 mg twice daily. 

Fusariosis is an emerging, opportunistic, and life-threatening mycosis. In immunocompetent patients it may cause onychomycosis and keratitis.¹ Invasive fusariosis predominantly is caused by the F solani species complex and affects immunocompromised patients, especially those with neutropenia or acute leukemia or hematopoietic stem cell transplant recipients.² 

Before invasion, the infection frequently may begin by affecting the nail apparatus as onychomycosis or paronychia of the skin. As in our case, trauma or manipulation of the nail favors dissemination.³ Skin manifestations include erythematous to violaceous papules, macules, and nodules with central necrosis or crust; some may exhibit target morphology. Other organs may be affected, including the sinuses, lungs, liver, spleen, and kidneys. A comprehensive clinical examination before hematopoietic cell transplant and during fever and neutropenia may opportunely identify these potential infective foci.^3,4 

The differential diagnosis of disseminated fusariosis includes bacterial infections, especially Staphylococcus aureus and Pseudomonas aeruginosa, and other invasive fungal infections, particularly aspergillosis, mucormycosis, and candidiasis.⁵ Symptom persistence after broad-spectrum antibiotic initiation should raise diagnostic suspicion of systemic mycosis or mycobacterial infection. Mucormycosis and candidiasis have histopathologic profiles that differ from fusariosis, presenting with broad ribbonlike hyphae with 90° angulation and pseudohyphae with budding yeast cells, respectively. Differentiation of disseminated fusariosis and aspergillosis in neutropenic patients is difficult. Hyphae cannot be differentiated from those of Aspergillus species on histology.⁶ Furthermore, serologic assays, such as galactomannan and (1,3)-β-D-glucan, cross-react with both genera. Clinically, Fusarium species exhibit metastatic skin lesions, cellulitis, and positive blood cultures due to adventitious sporulation more frequently than Aspergillus species. Patients with aspergillosis more commonly present with sinusitis, pneumonia, and pulmonary macronodules with the halo sign.⁶ Although nocardiosis presents with disseminated subcutaneous nodules with pulmonary affection in immunocompromised patients, its morphology is very different from fusariosis. Nocardia presents with a gram-positive bacillus with the microscopic appearance of branching filaments. Yeastlike microorganisms with morphology ranging from oval to sausagelike are found in talaromycosis, an uncommon fungal infection predominantly caused by Talaromyces marneffei. Fusarium species culture reveals white cottony colonies with characteristic hyaline, canoe-shaped or sickle-shaped (banana-shaped), multicellular macroconidia, and microconidia. Precise species identification requires molecular analyses such as polymerase chain reaction. 

Mortality is high, ranging from 50% to 70% of cases.⁵ Voriconazole or lipid-based amphotericin B are considered first-line treatments. Posaconazole may be employed as a second-line alternative. Surgical debridement of infected tissues and removal of colonized venous catheters is recommended. Secondary prophylaxis should be considered with agents such as voriconazole, posaconazole, or amphotericin B.⁵ Resolution of immunosuppression and neutropenia is an important factor to reduce the mortality rate. 

The Diagnosis: Fusariosis 

A periodic acid-Schiff stain of the seropurulent drainage from a skin nodule revealed neutrophils and scarce branching hyaline hyphae. Skin and blood cultures grew a white cottony colony. Microscopic examination showed sickle-shaped macroconidia and septate hyaline hyphae with branching acute angles (Figure). Molecular analysis by polymerase chain reaction yielded Fusarium solani species complex. Histopathology as well as culture and molecular findings were consistent with a diagnosis of disseminated fusariosis. Amphotericin B was started with rapid clinical improvement. The patient was asymptomatic upon discharge with voriconazole 200 mg twice daily. 

Fusariosis is an emerging, opportunistic, and life-threatening mycosis. In immunocompetent patients it may cause onychomycosis and keratitis.¹ Invasive fusariosis predominantly is caused by the F solani species complex and affects immunocompromised patients, especially those with neutropenia or acute leukemia or hematopoietic stem cell transplant recipients.² 

Before invasion, the infection frequently may begin by affecting the nail apparatus as onychomycosis or paronychia of the skin. As in our case, trauma or manipulation of the nail favors dissemination.³ Skin manifestations include erythematous to violaceous papules, macules, and nodules with central necrosis or crust; some may exhibit target morphology. Other organs may be affected, including the sinuses, lungs, liver, spleen, and kidneys. A comprehensive clinical examination before hematopoietic cell transplant and during fever and neutropenia may opportunely identify these potential infective foci.^3,4 

The differential diagnosis of disseminated fusariosis includes bacterial infections, especially Staphylococcus aureus and Pseudomonas aeruginosa, and other invasive fungal infections, particularly aspergillosis, mucormycosis, and candidiasis.⁵ Symptom persistence after broad-spectrum antibiotic initiation should raise diagnostic suspicion of systemic mycosis or mycobacterial infection. Mucormycosis and candidiasis have histopathologic profiles that differ from fusariosis, presenting with broad ribbonlike hyphae with 90° angulation and pseudohyphae with budding yeast cells, respectively. Differentiation of disseminated fusariosis and aspergillosis in neutropenic patients is difficult. Hyphae cannot be differentiated from those of Aspergillus species on histology.⁶ Furthermore, serologic assays, such as galactomannan and (1,3)-β-D-glucan, cross-react with both genera. Clinically, Fusarium species exhibit metastatic skin lesions, cellulitis, and positive blood cultures due to adventitious sporulation more frequently than Aspergillus species. Patients with aspergillosis more commonly present with sinusitis, pneumonia, and pulmonary macronodules with the halo sign.⁶ Although nocardiosis presents with disseminated subcutaneous nodules with pulmonary affection in immunocompromised patients, its morphology is very different from fusariosis. Nocardia presents with a gram-positive bacillus with the microscopic appearance of branching filaments. Yeastlike microorganisms with morphology ranging from oval to sausagelike are found in talaromycosis, an uncommon fungal infection predominantly caused by Talaromyces marneffei. Fusarium species culture reveals white cottony colonies with characteristic hyaline, canoe-shaped or sickle-shaped (banana-shaped), multicellular macroconidia, and microconidia. Precise species identification requires molecular analyses such as polymerase chain reaction. 

Mortality is high, ranging from 50% to 70% of cases.⁵ Voriconazole or lipid-based amphotericin B are considered first-line treatments. Posaconazole may be employed as a second-line alternative. Surgical debridement of infected tissues and removal of colonized venous catheters is recommended. Secondary prophylaxis should be considered with agents such as voriconazole, posaconazole, or amphotericin B.⁵ Resolution of immunosuppression and neutropenia is an important factor to reduce the mortality rate. 

The Diagnosis: Foreign Body Reaction With Sinus Tract  

A delayed foreign body reaction is a rare complication of retained temporary pacing wires following cardiovascular surgery. These epicardial pacing wires are important for the management of postoperative arrhythmia and normally are removed by external traction after normal rhythm has been re-established. However, it is not uncommon for these wires to be cut at the skin surface in the setting of difficult removal, as retained pacing wires generally are viewed as benign.¹ These reactions often take years after placement of the pacing wire to present themselves and most often resolve with either complete removal of the wire or resection of the distal end.²  

Our patient was referred to dermatology and underwent a shave biopsy. Results were consistent with chronic inflammatory granulation tissue. Bacterial tissue culture grew Staphylococcus epidermidis. Cultures for acid-fast bacilli and fungi were negative. The patient was referred to cardiothoracic surgery. Computed tomography identified a retained temporary pacing wire extending to the base of the lesion. The lesion was excised and the distal aspect of the pacing wire was removed, which resulted in resolution of the nodule.  

The differential diagnosis includes pyoderma gangrenosum, nodular basal cell carcinoma, Sister Mary Joseph nodule, and pyogenic granuloma. Pyoderma gangrenosum is a neutrophilic dermatosis that presents as a rapidly progressing, painful, necrotic ulcer. It is classically associated with inflammatory bowel disease and other systemic diseases but also can occur in isolation.³  

Nodular basal cell carcinomas often develop in chronically sun-exposed areas of the body. Morphologically, they present as pink, pearl appearing papules with rolled borders and overlying arborizing telangiectasia. Nodular basal cell carcinomas may present with recurrent bleeding but typically do not have continuous drainage.⁴  

Sister Mary Joseph nodule represents a periumbilical lymphatic metastasis from an underlying (usually intra-abdominal) malignancy. It typically presents as an umbilical or periumbilical nodule measuring 0.5 to 15 cm in diameter. The nodules often are painful and discharge a serous fluid. It is estimated that they are present in 1% to 3% of cases of abdominopelvic malignancy, but Sister Mary Joseph nodules also have been reported in several other types of solid organ tumors.⁵  

Pyogenic granuloma is a benign vascular lesion that classically develops rapidly over the course of a few weeks. It often presents as a single red, moist, friable papule with a collarette of scale and frequently is associated with pain, bleeding, and ulceration. Keratinized skin or mucosa can be affected, and pyogenic granuloma is most common in children and young adults.⁶  

The Diagnosis: Foreign Body Reaction With Sinus Tract  

A delayed foreign body reaction is a rare complication of retained temporary pacing wires following cardiovascular surgery. These epicardial pacing wires are important for the management of postoperative arrhythmia and normally are removed by external traction after normal rhythm has been re-established. However, it is not uncommon for these wires to be cut at the skin surface in the setting of difficult removal, as retained pacing wires generally are viewed as benign.¹ These reactions often take years after placement of the pacing wire to present themselves and most often resolve with either complete removal of the wire or resection of the distal end.²  

Our patient was referred to dermatology and underwent a shave biopsy. Results were consistent with chronic inflammatory granulation tissue. Bacterial tissue culture grew Staphylococcus epidermidis. Cultures for acid-fast bacilli and fungi were negative. The patient was referred to cardiothoracic surgery. Computed tomography identified a retained temporary pacing wire extending to the base of the lesion. The lesion was excised and the distal aspect of the pacing wire was removed, which resulted in resolution of the nodule.  

The differential diagnosis includes pyoderma gangrenosum, nodular basal cell carcinoma, Sister Mary Joseph nodule, and pyogenic granuloma. Pyoderma gangrenosum is a neutrophilic dermatosis that presents as a rapidly progressing, painful, necrotic ulcer. It is classically associated with inflammatory bowel disease and other systemic diseases but also can occur in isolation.³  

Nodular basal cell carcinomas often develop in chronically sun-exposed areas of the body. Morphologically, they present as pink, pearl appearing papules with rolled borders and overlying arborizing telangiectasia. Nodular basal cell carcinomas may present with recurrent bleeding but typically do not have continuous drainage.⁴  

Sister Mary Joseph nodule represents a periumbilical lymphatic metastasis from an underlying (usually intra-abdominal) malignancy. It typically presents as an umbilical or periumbilical nodule measuring 0.5 to 15 cm in diameter. The nodules often are painful and discharge a serous fluid. It is estimated that they are present in 1% to 3% of cases of abdominopelvic malignancy, but Sister Mary Joseph nodules also have been reported in several other types of solid organ tumors.⁵  

Pyogenic granuloma is a benign vascular lesion that classically develops rapidly over the course of a few weeks. It often presents as a single red, moist, friable papule with a collarette of scale and frequently is associated with pain, bleeding, and ulceration. Keratinized skin or mucosa can be affected, and pyogenic granuloma is most common in children and young adults.⁶  

The Diagnosis: Foreign Body Reaction With Sinus Tract  

A delayed foreign body reaction is a rare complication of retained temporary pacing wires following cardiovascular surgery. These epicardial pacing wires are important for the management of postoperative arrhythmia and normally are removed by external traction after normal rhythm has been re-established. However, it is not uncommon for these wires to be cut at the skin surface in the setting of difficult removal, as retained pacing wires generally are viewed as benign.¹ These reactions often take years after placement of the pacing wire to present themselves and most often resolve with either complete removal of the wire or resection of the distal end.²  

Our patient was referred to dermatology and underwent a shave biopsy. Results were consistent with chronic inflammatory granulation tissue. Bacterial tissue culture grew Staphylococcus epidermidis. Cultures for acid-fast bacilli and fungi were negative. The patient was referred to cardiothoracic surgery. Computed tomography identified a retained temporary pacing wire extending to the base of the lesion. The lesion was excised and the distal aspect of the pacing wire was removed, which resulted in resolution of the nodule.  

The differential diagnosis includes pyoderma gangrenosum, nodular basal cell carcinoma, Sister Mary Joseph nodule, and pyogenic granuloma. Pyoderma gangrenosum is a neutrophilic dermatosis that presents as a rapidly progressing, painful, necrotic ulcer. It is classically associated with inflammatory bowel disease and other systemic diseases but also can occur in isolation.³  

Nodular basal cell carcinomas often develop in chronically sun-exposed areas of the body. Morphologically, they present as pink, pearl appearing papules with rolled borders and overlying arborizing telangiectasia. Nodular basal cell carcinomas may present with recurrent bleeding but typically do not have continuous drainage.⁴  

Sister Mary Joseph nodule represents a periumbilical lymphatic metastasis from an underlying (usually intra-abdominal) malignancy. It typically presents as an umbilical or periumbilical nodule measuring 0.5 to 15 cm in diameter. The nodules often are painful and discharge a serous fluid. It is estimated that they are present in 1% to 3% of cases of abdominopelvic malignancy, but Sister Mary Joseph nodules also have been reported in several other types of solid organ tumors.⁵  

Pyogenic granuloma is a benign vascular lesion that classically develops rapidly over the course of a few weeks. It often presents as a single red, moist, friable papule with a collarette of scale and frequently is associated with pain, bleeding, and ulceration. Keratinized skin or mucosa can be affected, and pyogenic granuloma is most common in children and young adults.⁶