Birt-Hogg-Dubé syndrome

INTRODUCTION — Birt-Hogg-Dubé syndrome (BHD; MIM #135150) is an autosomal dominant condition first described in 1977, characterized by benign skin hamartomas, most commonly located on the head and neck; pulmonary cysts and spontaneous pneumothorax; and an increased risk of renal cancer. BHD syndrome is caused by germline variants in the folliculin gene (FLCN), which encodes the protein folliculin, a putative tumor suppressor gene whose function is still under investigation.

This topic review will discuss the pathogenesis, clinical features, diagnosis, and management of BHD syndrome. Renal tumors and other inherited renal cancer syndromes are discussed separately. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma" and "Hereditary kidney cancer syndromes".)

EPIDEMIOLOGY — The incidence of Birt-Hogg-Dubé (BHD) syndrome is unknown. Approximately 200 families have been identified worldwide [1]. The overall penetrance of folliculin (FLCN) variants in affected families is high; however, the presence of cutaneous, pulmonary, and renal manifestations varies significantly, even within families. Although the penetrance of renal cancer is relatively low, patients with BHD syndrome have a sevenfold increased risk of kidney tumors compared with the general population [2].

In a review of 89 patients with BHD syndrome from 51 families from the National Institutes of Health (NIH), cutaneous lesions were found in 90 percent of patients, pulmonary cysts in 84 percent, and history of pneumothorax in 38 percent [3]. Renal tumors were found in 30 patients from 25 families, indicating that most families with renal tumors had only one member affected, even after screening all carriers of FLCN variants for renal tumors with abdominal computed tomography (CT) or magnetic resonance imaging (MRI) of the kidneys.

PATHOGENESIS — Birt-Hogg-Dubé (BHD) syndrome is caused by germline autosomal dominant pathogenic variants in the folliculin (FLCN) gene, located on chromosome 17p11.2. These variants include small insertion/deletions, splice-site, and nonsense variants, which lead, in most cases, to premature truncation and loss of function of the folliculin protein [4]. Over 180 unique FLCN germline disease variants spanning all 14 exons have been identified in families with BHD syndrome and catalogued in the Leiden Open Variation Database (version 3.0).

Although folliculin is thought to function as a tumor suppressor, its exact mechanism of action remains unknown [5]. Loss of heterozygosity due to somatic "second hit" mutations has been demonstrated in 53 percent of BHD syndrome renal tumors [6]. Protein-protein interaction studies led to the identification of folliculin-interacting proteins 1 and 2 (FNIP1 and FNIP2, respectively) [7]. FLCN and FNIP1 interact with 5'-AMP-activated protein kinase (AMPK), a negative regulator of mechanistic target of rapamycin (mTOR). This finding suggests that FLCN may act as a tumor suppressor by controlling the interactions between FNIP1/FNIP2 and the mTOR signaling pathway [5].

Studies on FNIP knockout mouse models support the hypothesis that these interacting proteins play a key role in kidney tumorigenesis [8]. Loss of heterozygosity has not been detected in fibrofolliculomas, which demonstrate a strong expression of FLCN messenger ribonucleic acid (mRNA) [9,10]. These findings suggest that haploinsufficiency of folliculin is sufficient to initiate the development of these skin tumors.

CLINICAL MANIFESTATIONS — The phenotype of Birt-Hogg-Dubé (BHD) syndrome is highly heterogeneous within families and between families sharing the same folliculin (FLCN) variant. No clear correlations have been identified between the type of variant in FLCN and the extent of skin involvement and lung or kidney manifestations [5]. Some patients may develop cutaneous lesions only; others may present with cutaneous lesions and pulmonary manifestations or cutaneous lesions and kidney tumors. In some patients, pulmonary cysts or renal tumors may be the only manifestation of the disease.

Cutaneous lesions — Fibrofolliculomas are typically the earliest and most frequent manifestation of BHD syndrome. They begin to appear in the third decade of life in approximately 90 percent of patients and present as round, white-gray papules 1 to 4 mm in size, some of which show a dell in the center corresponding to the follicular opening. Lesions as large as 8 mm and cystic or comedonal lesions may also occur [11]. (See "Cutaneous adnexal tumors", section on 'Follicular tumors'.)

The midface (cheeks, nose) is most densely affected, and the papules are also often most prominent at this location (picture 1), particularly in fair-skinned individuals with a rosaceiform complexion (picture 2A). Lesions may develop anywhere on the head/neck, including the posterior ears (picture 3). Isolated papules on the neck may be difficult to differentiate from acrochordons (skin tags) or small seborrheic keratoses (picture 2B).

Affected patients will continue to slowly accumulate new lesions and experience enlargement of pre-existing lesions throughout life. However, some patients have only a small number of lesions by late adulthood, whereas others may develop hundreds, at times near confluent, in the head/neck area (picture 4).

Other skin lesions initially described in BHD syndrome along with fibrofolliculomas include trichodiscomas and acrochordons. Trichodiscomas are clinically indistinguishable from fibrofolliculomas and may represent a histologic variant of the same tumor (picture 5). Acrochordons (skin tags) are common in the general population, and their presence or absence is not helpful in making/excluding a diagnosis of BHD syndrome. Angiofibromas (also known as fibrous papules) may occasionally be seen in the setting of BHD syndrome but are also common in the general population [12]. The presence of multiple facial angiofibromata should raise suspicion of tuberous sclerosis complex (TSC) (picture 6). (See 'Differential diagnosis' below.)

Small, mucosa-colored or whitish papules on the gingiva, tongue, mucosal lips (picture 7), or buccal mucosa have been reported in some patients with BHD syndrome [13]. However, similar lesions may be seen in a variety of hamartoma syndromes, such as multiple endocrine neoplasia I, TSC, and Cowden disease [14,15].

Pulmonary manifestations — Multiple, bilateral pulmonary cysts develop in 70 to 80 percent of affected members of families with BHD syndrome and may be the only manifestation of the disease [5,16]. Approximately 30 percent of patients with pulmonary cysts develop single or more often multiple episodes of spontaneous pneumothorax, usually before the age of 40 years [3,17]. Despite the high frequency of pulmonary involvement, most patients with BHD syndrome have normal pulmonary function or mild obstructive pulmonary disease [5]. (See "Diagnostic approach to the adult with cystic lung disease".)

Radiologic findings — High-resolution chest computed tomography (HRCT) scans show numerous, irregularly shaped, thin-walled pulmonary cysts, most of which are <1 cm in size [18]. In contrast with the typical apical location of air blebs seen in patients with spontaneous primary pneumothorax or pneumothorax secondary to chronic obstructive pulmonary disease (COPD), the majority of cysts in patients with BHD syndrome are located in the basilar medial regions of the lungs [18]. (See "Pneumothorax in adults: Epidemiology and etiology" and "Treatment of secondary spontaneous pneumothorax in adults".)

Kidney tumors — Renal cancer is the most serious manifestation of BHD syndrome, occurring in approximately 12 to 34 percent of patients around the age of 50 years (range 30 to 70 years) [3,17,19,20]. In contrast with other inherited renal cancer syndromes, which are usually associated with a single histologic tumor type, BHD syndrome is associated with a wide range of tumor histologies, most commonly chromophobe tumors and hybrid chromophobe/oncocytic tumors. Clear cell carcinoma, papillary carcinoma, and mixed-type carcinoma may infrequently be seen [1]. Renal oncocytosis, consisting of diffuse microscopic nodules of oncocytes, which are large, well-differentiated neoplastic cells, have also been observed in kidney parenchyma in the majority of patients with BHD syndrome and renal tumors.

Other neoplasms — Although early reports suggested an association between BHD syndrome and colon polyposis and colorectal carcinoma [21], the analysis of a United States-based cohort including 223 members of 33 families with BHD syndrome did not find an increased risk of colon polyps or colorectal cancer [2]. However, a United Kingdom study of 51 families with BHD syndrome identified an elevated risk of colorectal cancer in patients with BHD syndrome and a specific c.1285dupC variant in the FLCN gene [22]. A German study of 256 BHD syndrome patients from 83 families found a prevalence rate of colon cancer of 5.1 percent [23].

There are isolated reports of a variety of cutaneous and internal tumors in patients with BHD syndrome, including lipomas; cutaneous cysts; melanoma; and parotid, thyroid, and parathyroid tumors [24-28].

Clinical associations — Concurrent features of BHD syndrome (eg, renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas) have been described in a few patients with Smith-Magenis syndrome, a developmental disorder associated with cognitive impairment caused by microdeletion of 17p11.2, with resultant haploinsufficiency of the retinoic acid-induced 1 (RA1) gene as well as of FLCN located in the deleted region [29,30]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion syndrome (Smith-Magenis syndrome)'.)

PATHOLOGY

Skin — Fibrofolliculoma, a benign hamartoma of the hair follicle, is the hallmark skin finding of Birt-Hogg-Dubé (BHD) syndrome. Fibrofolliculoma is typically characterized by thin, epithelial strands two to four cell layers thick that emanate from an adjacent hair follicle. The epithelial strands often anastomose with one another in a background of stromal mucin and fibrocytes (picture 8). In trichodiscomas, the myxoid stroma is the most prominent feature, and the pilosebaceous units, if present, are at the periphery of the lesion (picture 9) [31]. However, it is unclear whether trichodiscomas and fibrofolliculomas in fact represent discrete histopathologic entities. Features of both trichodiscoma and fibrofolliculoma, which are both derived from epithelial and mesenchymal components, can often be identified in a single biopsy. In patients with BHD syndrome, histologic features of fibrofolliculoma have been demonstrated in lesions clinically resembling acrochordons [32]. (See "Cutaneous adnexal tumors", section on 'Trichodiscoma and fibrofolliculoma'.)

Lung — The histopathologic examination of lung specimens of 11 patients with BHD syndrome and history of pulmonary cysts and recurrent pneumothorax showed that the inner surfaces of the pulmonary cysts were lined with cytokeratin-positive, type II pneumocyte-like cells [33]. This finding suggests that, in contrast with nonspecific blebs or bullae, which result from alveolar destruction, the BHD syndrome pulmonary cysts may be considered slowly growing, hamartomatous cysts that may frequently rupture. In all cases, the epithelial cells in the pulmonary cysts stained positive for folliculin (FLCN) expression, suggesting that FLCN exists in a haploinsufficient form in cyst-lining epithelial cells.

Kidney — BHD syndrome is remarkable for the histologic variability of renal tumors. Chromophobe and mixed chromophobe-oncocytic patterns are most common, but papillary and clear cell histologic patterns may also be seen. Patients may have multiple tumors in the same kidney or in the contralateral kidney. In one review of 130 renal tumors from 30 patients with BHD syndrome, 50 percent were hybrid tumors with elements of oncocytoma and chromophobe renal cell carcinoma, 34 percent were chromophobe renal cell carcinoma, 9 percent clear cell renal cell carcinoma, 5 percent oncocytomas, and 2 percent papillary renal cell carcinoma [20]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)

DIAGNOSIS

Clinical suspicion — In approximately 90 percent of patients with Birt-Hogg-Dubé (BHD) syndrome, cutaneous fibrofolliculomas and trichodiscomas are the first and most consistent manifestation of the disease. Thus, the diagnosis of BHD syndrome should be suspected in any patient presenting with multiple facial papules that have been histologically proven to be fibrofolliculomas. A personal or family history of lung cysts, especially if located in the basilar medial regions of the lungs, or pneumothorax, especially if recurrent, and/or a family or personal history of renal cancer at a young age should raise suspicion of BHD syndrome, even in the absence of cutaneous lesions. Patients and family members with suspected BHD syndrome should undergo further clinical evaluation and imaging studies for kidney lesions and be offered genetic testing for diagnostic confirmation.

Skin biopsy — Skin biopsy is indicated in all patients presenting with multiple facial papules suspected to be fibrofolliculomas. A punch biopsy is preferred to a shave biopsy because it allows the visualization of the entire lesion and associated hair follicle.

Imaging studies — Serial baseline chest and abdominal imaging should be obtained in patients suspected to have BHD syndrome. High-resolution chest computed tomography (HRCT) will identify cysts within the lung or occult pneumothoraces (see 'Radiologic findings' above). Abdominal CT or MRI with intravenous contrast provide the best anatomic detail of the kidneys and allow for characterization of any cystic or solid renal lesions.

Genetic testing — Germline pathogenic variants in the folliculin (FLCN) can be detected by sequence analysis of the entire coding region of FLCN and confirm the diagnosis of BHD syndrome. Disease variants in the FLCN gene were detected in 88 percent of families in the National Cancer Institute BHD syndrome cohort by sequence analysis of all 14 exons [3]. If full gene sequence analysis does not identify a pathogenic variant, deletion/duplication analysis (ie, copy number analysis) may be considered [34]. In one study of families with BHD syndrome lacking FLCN sequence alterations, intragenic deletions and/or duplications in FLCN were identified in 11 of 23 patients in whom a pathogenic variant could not be detected by sequence analysis [35].

Diagnostic criteria — The diagnosis of BHD syndrome is made based upon the presence of one or more of the following proposed criteria [5]:

●Presence of ≥2 skin lesions clinically consistent with fibrofolliculoma and/or trichodiscoma and ≥1 histologically confirmed fibrofolliculoma

●Multiple bilateral pulmonary cysts located primarily in the basilar regions of the lung with or without a history of spontaneous pneumothorax before age 40 years, especially if associated with a family history of similar pulmonary manifestations

●Bilateral, multifocal chromophobe renal carcinomas or hybrid oncocytic tumors, especially in patients with a family history of renal tumors at <50 years

●A combination of these cutaneous, pulmonary, or renal manifestations presenting in the patient or family members

●Identification of a germline pathogenic variant in FLCN by deoxyribonucleic acid (DNA) sequencing

Although genetic testing will identify a germline FLCN variant and confirm the diagnosis in approximately 90 percent of cases, in some patients, the diagnosis of BHD syndrome relies upon clinicopathologic findings.

GENETIC COUNSELING — Once a folliculin (FLCN) variant has been demonstrated in a proband, genetic testing and counseling should be offered to at-risk relatives (ie, all first-degree relatives), and carriers of the germline variant should be offered imaging surveillance for renal cancer. Genetic testing of family members at risk of Birt-Hogg-Dubé (BHD) syndrome is recommended starting at age 20 to 21 years [1,36].

DIFFERENTIAL DIAGNOSIS

Skin lesions — Cutaneous neoplasms that mimic clinically the fibrofolliculomas of Birt-Hogg-Dubé (BHD) syndrome may occur sporadically or in other cancer-associated genodermatoses:

●Fibrous papules of the nose – Fibrous papules of the nose (also called fibrous papules of the face or facial angiofibromas) are skin-colored to white, firm, 1 to 3 mm papules that usually occur singly or in small numbers, often on the nose or midface, in late adulthood (picture 10A-B). Histologically, these lesions resemble angiofibromas and show a normal epidermis, sometimes with an increased number of clear cells overlying the lesion, increased dermal collagen with ectatic blood vessels, and increased dermal cellularity composed of mono- and multinucleated cells with a histiocyte-like appearance.

●Sebaceous hyperplasia – Sebaceous hyperplasia presents as 1 to 4 mm lobulated papules with a yellow hue, often on the forehead and cheeks of older individuals (picture 11 and picture 12). Histology shows a dome-shaped lesion with numerous, mature sebaceous lobules composed of mature sebocytes, frequently radiating from a central, dilated hair follicle. (See "Cutaneous adnexal tumors", section on 'Sebaceous hyperplasia'.)

●Tuberous sclerosis complex – Tuberous sclerosis complex (TSC) presents in childhood with multiple fibrous papules with an erythematous appearance known as angiofibromas. These lesions, also referred to as "adenoma sebaceum," cluster on the midface (picture 6). Other skin features of TSC, including periungual fibromas, shagreen patch, confetti spots, and ash leaf macules, are not present in BHD syndrome. (See "Tuberous sclerosis complex: Clinical features".)

●Brooke-Spiegler syndrome – Brooke-Spiegler syndrome (multiple hereditary trichoepitheliomas) presents with multiple, skin-colored papules located on the face (picture 13) and particularly in the nasolabial sulcus, leading to a "heaped up" appearance (picture 14). Histology can differentiate trichoepithelioma from fibrofolliculoma. (See "Brooke-Spiegler syndrome (CYLD cutaneous syndrome)".)

●Adenoma sebaceum – Sebaceous adenomas present as yellowish or brownish papules, usually <1 cm in diameter, almost exclusively located on the head and neck (picture 15). Histologically, sebaceous adenoma is composed of well-circumscribed, round aggregations of predominantly mature, lipid-filled sebocytes. The presence of multiple sebaceous adenomas should prompt evaluation for Muir-Torre syndrome, a subtype of hereditary nonpolyposis colorectal cancer syndrome. (See "Muir-Torre syndrome".)

●Cowden syndrome – Cowden syndrome is an autosomal dominant disorder characterized by hamartomatous tumors in multiple organ systems, including the skin, and an increased risk for malignancy. The facial trichilemmomas in Cowden syndrome are more keratotic in appearance than fibrofolliculomas seen in BHD syndrome (picture 16). Macrocephaly, acral keratoses, and oral papillomas (picture 17) are found in Cowden syndrome but not in BHD syndrome [37]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cowden syndrome'.)

●Generalized basaloid follicular hamartoma syndrome – Generalized basaloid follicular hamartoma syndrome is a rare, autosomal dominant disorder characterized by numerous, small, skin-colored and hyperpigmented facial and upper trunk papules with milia and comedo-like lesions; alopecia or hypotrichosis; and hypohidrosis [38]. Histologically, the papular lesions are follicular hamartomas that mimic infundibulocystic basal cell carcinoma, a subtype of basal cell carcinoma with follicular differentiation.

●Familial multiple discoid fibromas – Familial multiple discoid fibromas is characterized by the development of multiple trichodiscoma-like lesions at an early age (birth to 25 years) on the face, with predominant involvement on the ears. Because typical histology of fibrofolliculoma is not seen, the term "discoid fibromas" was proposed to denote their distinct pathologic appearance. Folliculin (FLCN) variants, pulmonary cysts, or renal neoplasms have not been reported in this syndrome [39,40]. A locus on chromosome 5 containing FNIP1 has been implicated in the syndrome [41]. (See "Cutaneous adnexal tumors".)

●Lipomatosis, fibrofolliculomas, and renal cell carcinoma – A report described a family with overlapping features of BHD syndrome, specifically oral mucosal lesions, fibrofolliculomas, and renal cell carcinoma [42]. In contrast to BHD syndrome, most patients exhibited prominent cutaneous lipomatosis, and all patients lacked pulmonary cysts. A missense variant in PRDM10 was identified that cosegregated with the phenotype [42].

Lung cysts and recurrent pneumothorax — The differential diagnosis of lung manifestations associated with BHD syndrome includes:

●Lymphangioleiomyomatosis – Lymphangioleiomyomatosis (LAM) is a rare lung disease that may be sporadic or associated with the TSC. It predominantly affects young women and is characterized by the presence of diffuse, small, thin-walled cysts scattered throughout both lung fields. The definitive diagnosis requires the demonstration on a lung biopsy of interstitial nodular proliferations of atypical smooth muscle cells. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis".)

●Emphysema – Spontaneous pneumothorax occurs frequently in patients with chronic obstructive pulmonary disease (COPD). The presence of symptoms compatible with COPD, pulmonary function testing revealing airflow obstruction, and the absence of true thin-walled cysts on high-resolution computed tomography (HRCT) lead to the correct diagnosis. (See "Chronic obstructive pulmonary disease: Diagnosis and staging" and "Treatment of secondary spontaneous pneumothorax in adults".)

●Pulmonary Langerhans cell histiocytosis – Pulmonary Langerhans cell histiocytosis is an uncommon interstitial lung disease that primarily affects young adults. The diagnosis is based upon the finding on HRCT of multiple cysts and nodules with upper lobe predominance and interstitial thickening. (See "Pulmonary Langerhans cell histiocytosis".)

Renal tumors

●Sporadic hybrid chromophobe/oncocytic tumors – There are no specific immunohistochemical markers to differentiate chromophobe tumors and hybrid chromophobe/oncocytic tumors associated with BHD syndrome from their sporadic counterpart. However, BHD syndrome-associated tumors and sporadic tumors may present several differences in gene expression and genetic aberrations [43-45]. While FLCN gene variants can be detected in hybrid chromophobe/oncocytic tumors in patients with BHD syndrome, they are absent in sporadic tumors and in tumors associated with renal oncocytosis. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Pathology'.)

●Hereditary leiomyomatosis and renal cell cancer – In hereditary leiomyomatosis and renal cell cancer (HLRCC), renal tumors are typically solitary and unilateral. These tumors are in most cases type 2 papillary renal cell carcinomas and tend to be aggressive, with rapid nodal and distant dissemination. (See "Hereditary leiomyomatosis and renal cell cancer (HLRCC)" and "Hereditary kidney cancer syndromes".)

●Von Hippel-Lindau disease – Von Hippel-Lindau (VHL) disease is an inherited, autosomal dominant syndrome characterized by a variety of benign and malignant tumors, including renal cancer. In contrast with BHD syndrome, virtually all VHL-associated renal cancers are clear cell tumors. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

MANAGEMENT

Skin lesions — Fibrofolliculomas and trichodiscomas are benign lesions that usually do not require treatment. However, some patients with numerous facial lesions may seek treatment because of cosmetic concerns. Destructive therapies, including shave removal, electrodessication with or without curettage, and carbon dioxide (CO₂) or erbium-doped yttrium aluminum garnet (Er:YAG) laser ablation, have been used in a few patients with good results, although recurrence is commonplace [46-49].

In a randomized, split-face trial including 19 patients, topical rapamycin (sirolimus) 0.1% solution did not result in reduction in size or number of fibrofolliculoma lesions compared with placebo [50]. However, a split-face case report found superior benefit to fractional 1540 nm nonablative laser resurfacing on the side treated concurrently with 1% topical rapamycin ointment, suggesting that drug delivery may be improved by combination therapy [51].

Pneumothorax — Treatment of pneumothorax in patients with Birt-Hogg-Dubé (BHD) syndrome is the same as in patients with secondary pneumothorax (see "Treatment of secondary spontaneous pneumothorax in adults"). To limit recurrence (eg, in the contralateral lung), patients should avoid tobacco use and SCUBA (self-contained underwater breathing apparatus) diving [52]. Risks of pneumothorax during air travel are discussed elsewhere. (See "Pneumothorax and air travel".)

Pulmonary assessment is recommended for patients with BHD syndrome undergoing surgery, and excessive positive pressure ventilation should be avoided intraoperatively to avoid rupture of a pulmonary cyst and pneumothorax [36].

Renal tumors — Surgery is the only treatment option for BHD syndrome-associated renal tumors. The most common BHD syndrome tumors, chromophobe and hybrid oncocytic tumors, tend to be indolent. Experts recommend active surveillance, as long as the dominant lesion is less than 3 cm in diameter, and nephron-sparing surgery for tumors that are ≥3 cm in size, along with the removal of all lesions detected intraoperatively [36]. Renal preservation is particularly important for patients with BHD syndrome, given the potential for multiple renal tumors and the risk of developing chronic renal failure following surgery. (See "Hereditary kidney cancer syndromes", section on 'Birt-Hogg-Dubé syndrome'.)

Surveillance — Lifelong surveillance for renal cancer is needed for patients with BHD syndrome. However, there is no clinical consensus on the optimal surveillance interval. Some experts recommend abdominal imaging starting at age 21 (or following diagnosis) and at least every 36 months until a mass is identified, at which time interval imaging is determined in the individual patient based upon the size and growth rate of the tumor [36]. Ultrasonography may miss small isoechoic renal masses, and therefore, CT imaging or MRI to minimize radiation exposure should be used when possible [53]. Regular skin cancer screening is reasonable given the possible association with melanoma. Repeat pulmonary screening after initial diagnosis is recommended if new respiratory symptoms develop.

PROGNOSIS — The prognosis of Birt-Hogg-Dubé (BHD) syndrome depends primarily upon the penetrance of renal cancer and histologic type of renal tumors that develop. Deaths from renal cancer in BHD syndrome undergoing routine surveillance are uncommon, and the majority of deaths from metastatic disease are due to clear cell carcinoma tumors [54,55]. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)

Patients should be reassured that BHD syndrome cystic lung disease typically does not result in compromised respiratory function [18].

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by benign skin hamartomas, most commonly located on the head and neck, pulmonary cysts and spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline pathogenic variants in the folliculin (FLCN) gene, located on chromosome 17p11.2. (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical manifestations – The phenotype of BHD syndrome is highly heterogeneous:

•Skin lesions – Fibrofolliculomas, presenting as round, white-gray papules 1 to 4 mm in size located on the head and neck region, are typically the earliest and most frequent manifestation of BHD syndrome (picture 2A-B). (See 'Cutaneous lesions' above.)

•Pulmonary manifestations – Pulmonary manifestations include multiple bilateral pulmonary cysts and spontaneous pneumothorax before age 40 years. (See 'Pulmonary manifestations' above.)

•Kidney tumors – Renal cancer is the most serious manifestation of BHD syndrome, occurring in approximately one-third of affected patients at a mean age of 50 years. The histology of renal tumors varies, with chromophobe tumors and hybrid chromophobe/oncocytic tumors occurring in most cases. (See 'Kidney tumors' above.)

●Diagnosis – The diagnosis of BHD syndrome is made based upon a combination of cutaneous, pulmonary, or renal manifestations presenting in the patient or family members and the identification of a germline pathogenic variant in FLCN by DNA sequencing. (See 'Diagnosis' above and 'Diagnostic criteria' above.)

●Management – The management of patients with BHD syndrome is primarily directed at the detection and treatment of renal tumors and pulmonary manifestations. Treatment of pneumothorax in patients with BHD syndrome is the same as in patients with secondary pneumothorax. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Surgery is the only treatment option for BHD syndrome-associated renal tumors (see "Overview of the treatment of renal cell carcinoma"). Because of the indolent behavior of the most common BHD syndrome tumors, chromophobe and hybrid oncocytic tumors, some experts recommend active surveillance, as long as the dominant lesion is less than 3 cm in diameter, and nephron-sparing surgery for tumors that are ≥3 cm in size, along with the removal of all lesions detected intraoperatively. (See 'Renal tumors' above.)

●Surveillance for kidney cancer – Lifelong surveillance for renal cancer is needed for patients with BHD syndrome. Some experts recommend abdominal imaging with CT or MRI after diagnosis and at least every 36 months thereafter, unless a mass is identified, at which time interval imaging is determined in the individual patient based upon the size and growth rate of the tumor. (See 'Surveillance' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the National Institutes of Health or the United States Government or its components.