Krivda SJ

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.

Birt-Hogg-Dubé syndrome (BHDS) is a rare genodermatosis with cutaneous and systemic findings. We report the case of a 47-year-old woman with BHDS who presented with numerous facial papules and the more recently associated finding of pulmonary cysts. We review recent genetic discoveries and the cutaneous and systemic findings associated with this rare syndrome.

Case Report

A 47-year-old otherwise healthy white woman presented for evaluation of numerous asymptomatic facial papules that had gradually developed over the previous 2 years. Physical examination results revealed multiple white to flesh-colored, smooth, 1- to 3-mm papules over the central face, most prominently on the cheeks (Figure 1), with no other mucocutaneous findings. The patient had a history of an eyelid acrochordon that had been removed.

Results of renal computed tomography scan with and without contrast were within reference range. Colonoscopy results revealed two 1- to 2-mm polyps located 10 cm from the anal verge that were normal on biopsy. A chest radiograph also showed normal results. A noncontrast spiral computed tomography scan of the chest with lung windows and 5-mm slice thickness demonstrated multiple, 1.0- to 2.3-mm, primarily peripheral, pulmonary bullae (Figure 2).

The patient reported that her parents had no facial lesions. Her father had a history of pulmonary adenocarcinoma, melanoma, and colonic polyposis. The patient's only 2 children had complete mucocutaneous examinations and renal ultrasounds performed. Her 16-year-old son was noted to have 2 axillary acrochordons that were confirmed histologically and large but otherwise normal kidneys. Her 15-year-old son's mucocutaneous examination had normal results; however, renal ultrasound revealed a congenital absence of the right kidney and a hypertrophic left kidney with mild left upper pole pelviectasis. There is no family history of renal neoplasia or pneumothorax. The patient had smoked one pack of cigarettes a day for the previous 30 years. Shave biopsy results of a right cheek papule revealed an adnexal structure with radiating epithelial strands and surrounding fibrous stroma consistent with a fibrofolliculoma (Figure 3). Shave biopsy of a left alar papule demonstrated a well- circumscribed proliferation of small blood vessels embedded in a fibrous stroma with a hair follicle located in the periphery consistent with a trichodiscoma (Figure 4). A diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was confirmed.

Comment

In 1977, Birt, Hogg, and Dubé1 reported small, papular skin lesions in 15 members of 70 kindred studied. The asymptomatic lesions appeared in each patient after he or she reached 25 years of age and were distributed over the scalp, forehead, face, neck, and trunk. Histologically, these heritable lesions were confirmed to be fibrofolliculomas and trichodiscomas. Small, globoid acrochordons intermingled with these lesions but also were present on the upper eyelids, in the axillary folds, and on the antecubital fossae.1 This triad of fibrofolliculomas, trichodiscomas, and acrochordons has become known as BHDS. An autosomal-dominant pattern of transmission has been identified.1 Schmidt et al2 recently demonstrated that BHDS maps to chromosome 17p11.2. In a recent study of families with BHDS, Nickerson et al3 used recombination mapping, which delineated the susceptibility locus to 700 kb on chromosome 17p11.2. They also discovered protein-truncating mutations in a novel candidate gene and a novel BHDS protein named folliculin.3

Ubogy-Rainey et al4 reviewed the differential diagnosis of genetic disorders involving multiple firm papules of the face and categorized the diagnoses according to the histogenetic origin of the lesions. Lesions of epithelial origin include trichoepitheliomas and trichilemmomas. Mesodermal-originating lesions consist of trichodiscomas, perifollicular fibromas, and adenoma sebaceum. Fibrofolliculomas represent lesions of mixed epithelial and mesodermal origins.4

The fibrofolliculoma is a benign neoplasm that histologically consists of a characteristic well-formed hair follicle with a dilated infundibulum containing laminated keratin. Anastomosing epithelial strands 2 to 4 mm thick radiate from the epithelium of the hair follicle and are surrounded by a well-circumscribed mantle of loose connective tissue embedded in a mucoid, basophilic, hyaluronic acid–rich ground substance.1,4 Trichodiscomas represent small hamartomatous tumors of the hair disk. A hair follicle is often noted at the periphery of the papule. Histologic features of trichodiscomas include a proliferation of only the fibrovascular component of the hair disk, small melanin granules containing cells in the substance of the tumor, and occasional myelinated nerves at the base of the lesion.1,5,6 Thus, trichodiscomas and fibrofolliculomas differ histologically. However, a recent study demonstrated that they are immunophenotypically similar. The perifollicular stromal cells of both neoplasms stain CD34+, vimentin+, and factor XIII, indicating that they likely are derived from a similar histogenic precursor.7 Acrochordons do not contain hair follicles, rather they consist of flattened, elastic epithelium and loose connective tissue, as well as dilated blood vessels.1,8 Schulz and Hartschuh9 recently concluded that although BHDS and Hornstein-Knickenberg syndrome are characterized by multiple perifollicular fibromas, they are indeed the same syndrome. Both syndromes are transmitted in an autosomal-dominant pattern and are associated with colonic polyposis. The similar-appearing cutaneous lesions are distributed over the head, neck, and upper trunk in each syndrome. Histologic study of these lesions revealed that sectioning techniques may have skewed the interpretation of the lesions in the past. By using vertical and superficial and deeper horizontal sectioning planes and serial sections,

Schulz and Hartschuh9 showed that lesions appearing to be perifollicular fibromas with superficial horizontal sections proved to be fibrofolliculomas on deeper horizontal sections. Thus, the skin lesions in BHDS and Hornstein-Knickenberg syndrome most likely represent a similar pathological process.

Roth et al10 described the first case of renal cell carcinoma in association with BHDS. The patient in their study had bilateral renal cell carcinoma with histopathologic findings demonstrating a chromophobe adenocarcinoma with a mixed population of clear and eosinophilic cells in one tumor and a hypernephroma in the other. Toro et al11 identified 3 extended kindred in whom renal neoplasms (oncocytomas and a variant of papillary renal cell carcinoma) and BHDS appeared to segregate together. In a large study of BHDS-affected and nonaffected family members, Zbar et al12 reported the age-adjusted odds ratio for renal tumor development in patients with BHDS was 6.9 times that of patients who did not have BHDS. Renal tumors in BHDS-affected patients were multiple, and in some patients they were bilateral. Median age for detection was 51 years. The most common type of renal cancer found in BHDS-affected patients was chromophobe renal carcinoma; but chromophobe-oncocytic tumor and clear cell renal carcinoma also were noted. Interestingly, 2 nonaffected family members had single clear cell renal carcinomas.12

Other features of BHDS noted by Toro et al11 were deforming lipomas, collagenomas, and pulmonary cysts and/or pneumothorax. Zbar et al12 also reported the age-adjusted odds ratio for pneumothorax in BHDS-affected individuals to be 50.3 times that of those not affected with BHDS. In addition, pulmonary cysts were present in 83% of BHDS-affected family members compared with 10% of unaffected control members of families with BHDS (P=.0001). These cysts were noted to be well circumscribed and separate from each other, and their location was either basilar, subpleural, or intraparenchymal.12 Other reported associated manifestations of BHDS include: large connective tissue nevus13; oral mucosal papules on the lip, buccal area, and gingivae, which histologically demonstrate parakeratosis, acanthosis, prominent basal cell layer, and a few chronic inflammatory cells in the underlying connective tissue8; multiple spontaneous pneumothoraces, bullous emphysema, lipomas, angiolipomas, parathyroid adenoma, and prostate adenocarcinoma14; flecked chorioretinopathy15; parotid oncocytoma16; and colonic polyps, which are tubular adenomas with mild to marked epithelial dysplasia.17 Colonic neoplasms and colonic polyps have not been found as an associated finding in a large cohort of patients with BHDS.12 Although some of the above associations may be coincidental, screening for renal cancer and pulmonary cysts is recommended.