FLCN

Professionals

Birt, Hogg and Dubé syndrome (BHDS) is a disease caused by mutations in the folliculin (FLCN) gene with autosomal dominant transmission.
It manifests with skin, pulmonary and renal symptoms.
Cutaneous manifestations of BHDS are benign proliferations derived from hair follicle cells of the following types: follicular fibromas(fibrofolliculoma), hamartoma-type nodules derived from skin stem cells (trichodiscoma), and soft fibromas (acrochordons).
In the lungs, various s and shapes cysts have developed, which cause pneumothorax.
Renal involvement is manifested by various types of benign and malignant neoplasms, sometimes of mixed origin, often bilateral and multifocal.
The presence of skin and renal lesions was first described in 1975 by Hornstein and Knickenberg. However, the name of the disease has become accepted in the literature, derived from the names of Canadian dermatologists Britt, Hogg and Dubé, who in 1977 described in a family with multiple cases of thyroid cancer and the presence of fibrofolliculoma-like skin lesions. The association appeared to be coincidental, and it was not until several years later that the skin lesions were linked to renal tumors and pulmonary cysts.

Epidemiology
The incidence of BHDS is not established and is probably greatly underestimated. This is due to the sparse and nonspecific symptoms, which are often underestimated. More than 600 affected families have been identified worldwide. Symptomatic cases of the disease are most often diagnosed in the fourth to fifth decade of life. In young people, BHDS is diagnosed in the course of a study of families burdened with the disease.

Etiology and pathogenesis
The genetic locus involved in BHDS was mapped to chromosome 17p11.2 in 2001, and a year later an impairment of the FLCN gene, which encodes a protein called folliculin, was identified. The FLCN gene consists of 14 exons and more than 200 of its pathogenic variants have been identified. Most FLCN mutations result in a shift in the reading frame (small deletions or insertions). In addition, nonsense or splice mutations are detected that lead to loss of folliculin function. The most common so-called "hot spot" mutation site is exon 11. About 40% of families are burdened with a defect located in this area. Mutations are often inherited from a single affected parent, but can also occur de novo, in individuals without previous disease in relatives.
Penetration of FLCN pathogenic mutations is high, but disease expression varies widely among family members and between families. The FLCN gene belongs to a group of oncogenes. To date, no clear genotype-phenotype correlations have been demonstrated in BHDS patients. Nevertheless, Toro et al. observed an association between mutations in exon 9 and the presence of cysts in the lungs. The study showed a significantly increased risk of pneumothorax in carriers of c.1300G >C (59%) or c.250-2A>G (77%) mutations compared to the hot-spot c.1285dupC mutation. In addition, the c.1285dupC variant was associated with a significantly higher risk of colorectal cancer than the c.610delGGinsTA variant.
The function of folliculin is not fully understood. Expression of this protein is found in most tissues, including lung, skin and kidney. It exhibits cytoplasmic guanine exchange factor (GEF, guanine nucleotide exchange factor) activity and interreacts with various signaling pathways that are important for normal cellular metabolism as well as tumorigenesis. It influences the function of mTOR and AMPK kinases, as well as EGFR and HIF1α signaling. Folliculin is involved in ciliogenesis, autophagy, lysosomal biogenesis, control of cell adhesion mechanisms, proper functioning of intercellular junctions, and influences extracellular metalloproteinase activity, among others. A suggested mechanism for the formation of cysts is related to insufficient cellular adhesion and stress induced by stretching during respiration. "Stretching hypothesis" explains the localization of cystic lesions mainly in the basal and subpleural areas. In addition, the inhibitory effect of the transcription factor TFE3 on the activity of the WNT signaling pathway has been demonstrated in the folliculin-deficient cells. The WNT pathway plays roles in lung development by affecting cell-to-cell communication, which could contribute to the formation of lung cysts in BHDS patients.
Renal neoplasms developing in the course of BHDS differ from sporadic forms in their differentiated histologic pattern (chromophobe and mixed oncocytic-chromophobe neoplasms) and are sometimes multifocal and bilateral. Sporadic clear cell renal cell carcinomas usually arise from proximal renal tubule cells, while chromophobe and oncocytic neoplasms observed in BHDS. The loss of heterozygosity for the FLCN gene is necessary for renal carcinogenesis.

Clinical picture
BHDS is characterized by a highly variable clinical picture. Depending on the population, pulmonary lesions are observed in 30-100% of patients, cutaneous lesions in 50-80%, and the rarest renal lesions in about 30% of patients.
Fibrofolliculomas and trichodiscomas are small, benign, soft, skin-colored nodules with thin necks and occur mainly on the face and neck and upper trunk. Soft fibroadenomas occurring in BHDS patients are not disease-specific and are detected with equal frequency in the non-defective population.
More than 80% of patients with BHDS have multiple bilateral thin-walled lung cysts of various s and shapes. The presenting pulmonary lesions in BHDS patients are usually pneumothoraces, often recurrent (75-82%). On average, patients experience about four episodes of pneumothorax during their lifetime. Many of them are small, sparse or asymptomatic, detected on incidental or follow-up radiography. The risk of pneumothorax in patients with BHDS is estimated to be 50 times higher than in the general population. There are differences in the incidence of spontaneous pneumothorax depending on the analyzed cohorts. The highest rate is noted in the pulmonary cohorts (42-100%) compared to the renal and dermatologic cohorts (23-38%).
Pulmonary cysts and/or pneumothorax have no sex predilection and are not associated with smoking or the presence and/or severity of skin and renal lesions.
Renal lesions include cysts, various types of benign and malignant tumors, often occurring bilaterally or multifocal. They are observed seven times more often in BHDS patients than in healthy family members. Neoplastic lesions in the kidneys are most often diagnosed in the fifth decade of life, but incidences in the 20s have been reported. The malignancy potential of renal tumors associated with BHDS also varies, ranging from benign oncocytoma-type lesions (about 5% of cases) to malignant clear cell renal cell carcinoma (about 9%).

Natural Course
The earliest skin nodules appear around age 20 on the face, neck and upper torso. Another manifestation of BHDS is pneumothorax, most often in the fourth and fifth decades of life. In contrast, less than one-third of patients between the ages of 38 and 48 develop renal tumors of various types.
Lung involvement in BHDS usually does not lead to respiratory failure.

Diagnosis
Radiologic examination
A chest radiograph usually fails to detect lesions. Patients presenting with pneumothorax show air in the pleura sometimes with a slight pleural reaction. Rarely, translucency corresponding to cysts is observed.
Computed tomography of the lungs
High-resolution CT imaging reveals variously shaped cysts, with prominent, thin walls and diameters ranging from a few millimeters to several centimeters, localizing subpleurally most often bellow from the tracheal bifurcation. Larger or smaller pneumothoraces and pleural lesions associated with them are visible.
Pulmonary function tests
The disease causes only a slight decrease in ventilation parameters. Most commonly detected are features of increasing of residual volume and impaired diffusing capacity for carbon monoxide.
Histological examination of the lungs
The ruptured cysts visualized on histological examination are in the nature of emphysematous cysts. In contrast, examination of unruptured cysts shows that the inner surface of the cyst is lined with epithelial cells, without abnormal proliferation or atypia and without an inflammatory or fibrotic component. The cysts are located in close proximity to the interlobular septum and/or visceral pleura, usually located in the lung parenchyma without a clear connection to the bronchi, Sometimes they contain intracystic structures composed of interlobular septa.

Criteria for diagnosis
BHDS is diagnosed based on criteria proposed by the European BHDS Consortium. At least one major criterion or two minor criteria are necessary for the diagnosis of BHDS. The major criteria are: 1. at least five perichondrial fibromas or trichodiscomas (at least one histologically confirmed, with onset in adulthood) and 2. pathogenic mutation of the FLCN gene. Minor criteria are: 1. multiple lung cysts (bilateral, localized cysts at the base of the lungs with no other apparent cause, with or without spontaneous primary pneumothorax), 2. renal cell carcinoma (early onset before age 50, multifocal or bilateral, mixed chromophobe and oncocytic form on histology), 3. first-degree relative with BHDS.

Differential diagnosis
The disease should be differentiated from tuberous sclerosis (TSC). This is also an autosomal dominant disease, which develops multiple hamartoma-type tumors on the skin, in the kidneys, central nervous system, eye or heart. Lymphangioleiomyomatosis develops in the lungs, also manifested by numerous thin-walled cysts, but with a diameter of no more than 3 cm and uniform distribution. The similarity between the symptoms of BHDS and TSC may be due to the common effect of mutant proteins on signal transduction by mTOR complex 1.
Among the diseases causing thin-walled cystic lesions in the lungs in the differentiation should be considered emphysema, sporadic lymphangioleiomyomatosis, Langerhans cell histiocytosis, lymphoid interstitial pneumonia, amyloidosis, light chain deposition disease.

Prognosis
The prognosis of patients with BHDS is good.
Early diagnosis of the disease, identification and treatment of renal tumors, and prevention of pneumothorax are major aspects of patient care. Family members should be offered screening for lung and kidney involvement.

Recommendations
BHDS patients are advised to stop smoking tobacco and marijuana and to avoid sports or occupations involving pressure fluctuations, such as scuba diving.
Since the risk of emphysema during and after air travel ranges from 0.12% to 0.63% per flight, there are no significant contraindications to using this form of travel. It is recommended that this travel take place a minimum of 30 days after an episode of pneumothorax.
The increased risk of kidney cancer necessitates initial evaluation of the kidneys with magnetic resonance imaging and annual abdominal ultrasound examinations. Abdominal MRI should be repeated once every 3 years. Abdominal CT is indicated only if renal lesions are detected, prior to planned surgery.
BHDS patients do not have a higher risk of skin malignancies but a follow-up dermatologic examination every 2-3 years is recommended.
Several studies have shown a higher risk of BHDS patients to develop colorectal cancer. However, it is believed that there is no indication for systematic colonoscopies.
Because of the higher likelihood of thyroid disease, BHDS patients are ordered to undergo thyroid testing.
Onset of symptoms in childhood is rare (pneumothorax) hence genetic testing in asymptomatic relatives of BHDS patients is not performed until age 18.
Regular vaccination for influenza, COVID and pneumonia is recommended for all BHDS patients.