Birt-Hogg-Dubé (BHD) syndrome also known as Hornstein–Knickenberg syndrome is a rare, autosomal dominantly inherited genodermatosis complex genetic monogenic skin disorder (genodermatosis) characterized by multiple cutaneous hamartomas (namely fibrofolliculomas and trichodiscomas) and increased susceptibility to renal neoplasms, pulmonary cysts, and spontaneous pneumothoraces that development of skin papules generally located on the head, face, and upper torso. These benign (noncancerous) tumors (hamartomas) of the hair follicle are called fibrofolliculomas. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs, repeated episodes of a collapsed lung (pneumothorax), and an increased risk of developing kidney neoplasia. BHD syndrome is caused by alterations (mutations) in the FLCN gene (alias BHD) and is inherited as an autosomal dominant trait.
Symptoms
The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax), and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary among affected members of a single BHD family who inherit the same FLCN mutation, and patients may develop one, two, or all three of the characteristic features in any combination.
Birt-Hogg-Dubé syndrome (BHDS) includes cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibroma, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are often bilateral and multifocal; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Multiple, small, skin-colored papules on the head and neck
The skin papules known as fibrofolliculomas that are associated with BHD syndrome commonly occur on the scalp, face, and neck, but can also be found on the ear lobes and in the oral mucosa. They are generally 2-3mm in size, dome-shaped, flesh-colored, and are not associated with any pain or discomfort. The onset is usually after the age of 20. Skin lesions may increase in number as affected individuals age. The number of skin lesions can vary dramatically; some individuals may only have a few skin lesions, while others may have a hundred or more.
In the original description of BHD syndrome, two other skin lesions were noted: trichodiscomas, benign tumors of the hair disc, and acrochordons or skin tags that appear as soft small growths that hang off the skin and are common in the general population. Some researchers believe that trichodiscomas and fibrofolliculomas are the same lesions despite different surface appearances.
Individuals with BHD syndrome may also develop multiple lung (pulmonary) cysts in both lungs, which occur in greater than 80% of individuals affected with BHD. These cysts usually do not cause symptoms (asymptomatic) and lung function is generally normal, but up to one-third of affected individuals may experience repeated occurrences of a collapsed lung (spontaneous pneumothorax). A collapsed lung occurs when air or gas is trapped in the space surrounding the lungs. When the cause is not known (e.g., trauma, injury), it is referred to as spontaneous. Pneumothorax in BHD syndrome occurs more often in younger individuals and has been reported in children as young as 7 and 16 years old. Individuals in a BHD family who inherit the FLCN mutation have a 50-fold greater risk of developing spontaneous pneumothorax than their unaffected siblings.
Approximately 15-30 % of individuals with BHD syndrome may develop multiple kidneys (renal) neoplasms. These are usually slow-growing and affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50. The most common tumor types are the hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), and chromophobe renal cell carcinoma, both of which are malignant (cancerous). Renal oncocytomas, which are benign tumors, can also develop but occur only rarely. Individuals affected with BHD have a 7-fold greater risk of developing renal neoplasia than siblings who do not inherit the FLCN mutation.
In 1975, two researchers reported on a disorder that became known as Hornstein-Knickenberg syndrome. This disorder is now considered to be the same as BHD syndrome. Affected individuals with Hornstein-Knickenberg syndrome had polyps in the colon in addition to skin lesions. Some researchers believe that colonic polyps are a coincidental finding in individuals with BHD syndrome and not part of the disorder; more family studies are needed to determine whether or not colon polyps are an additional symptom of BHD.
Other findings have been reported in a few cases of BHD syndrome including oral papules in the mouth, benign tumors consisting of fatty tissue (lipomas), benign tumors consisting of fatty tissue and an abnormally large number of blood vessels (angiolipomas), a benign tumor of the parathyroid glands (parathyroid adenoma), a benign tumor of the salivary gland (parotid oncocytoma) and a lesion or birthmark consisting of thickened, abnormally firm connective tissue (connective tissue nevus). Research does not know whether these findings are incidental or true manifestations of BHD syndrome.
Causes
A germline mutation of FLCN, which encodes the tumor-suppressor folliculin, is responsible and is located on chromosome 17p11.2. Multiple distinct mutations have been identified. Folliculin is thought to be a tumor suppressor, but its exact function is unknown. FLCN has been linked to the mTOR pathway.[rx] BHDS is an autosomal dominant monogenic disorder caused by constitutional mutations in the FLCN gene.[rx] FLCN is a tumor suppressor gene,[rx] and codes for the protein folliculin.[rx–rx]
Birt-Hogg-Dubé syndrome is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
BHD syndrome is caused by disruptions or alterations (mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production, and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often predispose individuals to develop cancer.
Other tumor types have been reported rarely in individuals with BHDS [modified from Tong et al 2018]:
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Skin. Basal cell carcinoma, dermatofibrosarcoma protuberans, Koenen’s tumor, squamous cell carcinoma, trichoblastoma
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Soft tissue. Angiolipoma, leiomyoma, leiomyosarcoma, lipoma
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Musculoskeletal. Cardiac rhabdomyoma, fibrosarcoma, osteoma, rhabdomyoma, sarcoma
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Gastrointestinal. Gastric cancer, hepatic cysts, hepatic angioma, peritoneal mesothelioma
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Head and neck. Parathyroid adenoma, squamous cell carcinoma, throat cancer
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Endocrine. Adrenal adenoma, oncocytic adrenal tumor, pheochromocytoma
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Hematologic/lymphatic. Hodgkin’s lymphoma, leukemia, and non-Hodgkin’s lymphoma
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Nervous system. Astrocytoma, cerebral hemangioma, choroidal melanoma, meningioma, neurothekeoma, oncocytic pituitary adenoma, schwannoma
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Lung. Adenocarcinoma, bronchoalveolar carcinoma, clear cell sugar tumor, histiocytoma
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Renal/urinary tract. Neuroendocrine tumor, prostate cancer, renal angiomyolipoma
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Reproductive system. Breast cancer including sarcoma, endometrial carcinoma, fibroadenomatosis, uterine cancer
Related Disorders
Diagnosis
A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic manifestations (symptoms) including 2 or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophores, or hybrid oncocytic renal tumors. Surgical removal and microscopic evaluation (biopsy) of affected skin tissue are performed to determine the type of skin lesion present. Detection of a pathogenic (disease-causing) FLCN mutation in a DNA-based genetic test confirms the definitive diagnosis of BHD. Since renal neoplasia has been reported in BHD-affected individuals as young as 14, genetic testing is recommended starting at age 21 in at-risk family members.
If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs are recommended to detect pulmonary cysts/pneumothorax. Individuals with BHD have a lifelong risk for developing renal tumors and therefore, should undergo periodic surveillance by abdominal imaging (CT or magnetic resonance imaging to reduce radiation exposure is recommended) for early detection of renal tumors.
Treatment
Due to the risk of malignancies later in life, these patients are best managed by an interprofessional team that includes a geneticist, pulmonologist, thoracic surgeon, dermatologist, nurse practitioners in dermatology, urologist, and primary care providers including internists, family physicians, and nurse practitioners.
The treatment of BHD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may include the use of a laser beam to destroy affected skin tissue (laser ablation). This treatment is highly successful in treating the skin lesions associated with BHD syndrome, but the lesions often return (relapse).
Treatment for BHDS skin lesions includes destruction by electrocautery, curettage, and laser ablation, but is often followed by recurrence. Because folliculin has been implicated in the mTOR pathway, medications such as rapamycin, an mTOR inhibitor, have theoretical application in the treatment of Birt-Hogg-Dube lesions.
Some instances of a lung collapse do not require treatment and the air is absorbed over several days. In some cases, treatment is necessary. Treatment of a collapsed lung is intended to remove the air surrounding the lungs, allowing the lungs to re-inflate. A tube is inserted into the chest to allow the air or gas to escape (aspiration). In cases where repeated lung collapses occur, surgery may be necessary.
Surgery may also be necessary for individuals with renal neoplasia. Surgeons need to remove the kidney neoplasm so it does not grow larger and spread (metastasis). They may also remove part or all of a kidney (nephrectomy) if the tumor burden is extensive. The main objective of surgery in individuals with renal neoplasia is to preserve as much kidney tissue as possible, thereby preserving as much of the kidney function as possible. Since BHD-affected individuals may have multiple surgeries for multiple tumors over their lifetime, one effective management practice has been to wait and remove the largest tumor when it reaches 3cm in diameter by nephron-sparing surgery.
Individuals with BHD syndrome without renal neoplasia should be periodically imaged to monitor tumor development. Genetic counseling may be of benefit for affected individuals and their families.
BHDS is a hereditary syndrome with an increased risk of fibrofolliculomas in the skin, multiple lung cysts predisposing to recurrent pneumothorax, and increased risk of renal cancer. Lung cysts are common, but they are usually asymptomatic unless a pneumothorax is present. The predisposition to RCC is the most feared complication, and it is important to diagnose and treat the patients before metastatic disease develops. The clinical expression of BHDS is variable. No genotype-phenotype correlations have been found, which makes early diagnosis and management of BHDS complex.
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