Introduction
Birt-Hogg-Dubé Syndrome is a rare, autosomal dominant, congenital disorder. It is also referred to as Hornstein-Birt-Hogg-Dubé syndrome, Hornstein-Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons. It affects the hair follicles in the skin, the lungs, and the kidneys.
What Is Birt Hogg Dube Syndrome?
Birt-Hogg-Dubé Syndrome is a rare genetic disorder. It causes multiple benign tumors of the hair follicles, called fibrofolliculomas, skin lesions like acrochordons, angiofibroma, oral papules, cutaneous collagenomas, epidermal cysts, renal cancer, renal and lung cysts, pneumothorax. Fibrofolliculomas are commonly found on the face and upper trunk. Pulmonary cysts and kidney tumors are also common.
What Causes Birt Hogg Dube Syndrome?
It is a genetic disorder caused by a mutation in the folliculin (FLCN) gene. This gene produces a protein called folliculin that acts as a tumor suppressor in the skin, kidneys and type I pneumocyte cells of the lungs. It is also seen in the parotid glands, brain, breast, pancreas, prostate, and ovaries. Tumor suppressors prevent abnormal cell growth. Mutation in the FLCN gene interferes with the FLCN’s job of preventing abnormal cell growth and results in cancerous and noncancerous tumors. It is an autosomal dominant disorder in which the mutations are passed from one generation to the next. It can also occur as a new mutation in an individual without any family history. Children born to affected parents have a fifty percent chance of inheriting this disease.
What Are the Effects of Birt Hogg Dube Syndrome?
Birt-Hogg-Dubé Syndrome causes skin lesions, lung cysts, and kidney tumors. It includes:
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Skin Lesions - Multiple small opaque whitish or yellowish dome-shaped papules called fibrofolliculomas are present. These lesions are common and are present in individuals above 40 years of age. They are usually found in the nasal, paranasal, and retro auricular regions. They increase in size and number with age and gradually involve the face, neck, and upper trunk. Women have fewer skin lesions than men. Benign adnexal tumors called acrochordons (skin tags) are also present. They are present on the neck, axillae, and larger skin folds. Angiofibromas are common in individuals with tuberous sclerosis. Cutaneous collagenomas and oral papules are seen on the buccal mucosa, tongue, gums, or lips. Multiple epidermal cysts and cutaneous melanoma, including multiple desmoplastic melanoma and choroidal melanoma, were observed.
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Pulmonary Cysts and Pneumothorax - Lung cysts are usually present in the subpleural and intrapulmonary areas. The cysts are usually irregular in shape, variable in size, and are located in the normal parenchyma. It shows no signs of proliferation, inflammation, or matrix deposition. Recurrent spontaneous pneumothorax is common in adulthood, and lung cysts are common in young individuals.
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Renal Cysts and Tumors - Bilateral and multifocal renal tumors are common in this syndrome. Renal cell carcinoma is seen in adolescents. A hybrid of oncocytoma and chromophobe histological cell types called hybrid oncocytoma or chromophobe tumor is the most commonly associated with this syndrome. Multifocal renal oncocytosis is seen in the renal parenchyma surrounding the tumor.
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Parotid Tumors - Parotid oncocytoma is seen in individuals with this syndrome. Pleomorphic adenoma and Warthin’s tumor have also been observed. Bilateral parotid tumors were also reported.
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Thyroid - Thyroid cancer, multinodular goiter, thyroid nodules, and thyroid cysts were observed in individuals with this syndrome. Thyroid cancers were not detected.
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Other Tumors - Other tumor types are also seen in this syndrome but are less common. this includes:
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Basal cell carcinoma, dermatofibrosarcoma protuberans, Koenen’s tumor, squamous cell carcinoma, and trichoblastoma tumors of the skin.
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Lipoma, angiolipoma, leiomyoma, and leiomyosarcoma of soft tissues.
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Musculoskeletal tumors include cardiac rhabdomyosarcoma, fibrosarcoma, osteoma, rhabdomyoma, and sarcoma.
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Gastrointestinal tumors like gastric cancer, hepatic cysts, hepatic angioma, and peritoneal mesothelioma.
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Head and neck tumors include parathyroid adenoma, squamous cell carcinoma, and throat cancer.
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Endocrine tumors like adrenal adenoma, oncocytic adrenal tumor, and pheochromocytoma.
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Hematologic or lymphatic tumors like Hodgkin’s lymphoma, leukemia, and non-Hodgkin’s lymphoma.
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Astrocytoma, cerebral hemangioma, choroidal melanoma, meningioma, neurothekeoma, oncocytic pituitary adenoma, and schwannoma of the nervous system.
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Renal tumors like neuroendocrine tumors, prostate cancer, and renal angiomyolipoma.
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Tumors of the reproductive system include breast cancer, sarcoma, endometrial carcinoma, fibroadenomatosis, and uterine cancer.
How Is Birt Hogg Dube Syndrome Diagnosed?
The diagnosis depends on the clinical findings and molecular genetic testing. Determination of pathological variants in the FLCN gene is the primary criterion, and clinical findings form the minor criteria in diagnosing this syndrome.
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Clinical Findings - This syndrome is diagnosed if five or more fibrofolliculomas are present. Multiple lung cysts, renal cancer, multifocal or bilateral renal cancer, and relatives with Birt-Hogg-Dubé Syndrome are the clinical findings suggestive of this syndrome.
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Molecular Genetic Testing - Single gene testing, multigene panel, and comprehensive genomic testing are done to identify the pathologic variant in the FLCN gene. Single gene testing is done to detect small changes in the gene. If variants are not detected, gene-targeted analysis is performed. Multipanel testing is performed to determine the genetic cause of the condition. Comprehensive genomic testing includes exome sequencing, exome array, and genome sequencing. Comprehensive genomic testing is performed if the variant is indistinguishable from other inherited disorders. Exome sequencing is commonly performed.
How Is Birt Hogg Dube Syndrome Treated?
The treatment depends on the management of the symptoms.
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Fibrofolliculomas - Fibrofolliculomas are noncancerous skin lesions that do not require treatment. Cosmetic treatments like surgical and laser removal can be performed for cosmetic purposes if multiple lesions are present on the face. However, these lesions can recur at any time. Topical treatment with mTOR (the mammalian target of Rapamycin) is also done.
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Pneumothorax - Needle aspiration, chest tube insertion, nonsurgical repair, or surgery is done to treat pneumothorax. Lung cysts are not treated. Airway obstruction requires treatment. The majority of individuals with this syndrome have normal lung function.
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Renal Tumors - Single or bilateral tumors can be present. Nephron-sparing surgery is performed depending on the size and location of the tumor. Renal cancers require chemotherapy and radiation therapy.
Conclusion
Birt-Hogg-Dubé syndrome is a rare congenital disorder associated with multiple benign skin lesions, kidney diseases, lung disorders, and other disorders. This syndrome is difficult to diagnose because it resembles many other inherited disorders. Molecular genetic testing is a major diagnostic tool for Birt-Hogg-Dubé syndrome. Early diagnosis plays a significant role in determining this syndrome.
