FLCN (Birt-Hogg-Dubé) - risk management

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition with a predisposition to benign skin lesions, renal tumours and lung cysts leading to pneumothoraces, caused by a pathogenic variant in the folliculin (FLCN) gene.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant tumour. The care of affected individuals should be individualised based on their clinical situation and the monitoring they need as part of their treatment and post-treatment follow up. 

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised. 

• Known or obligate FLCN gene pathogenic variant carrier who has not been diagnosed with a renal tumour
• Those at 50% risk of inheriting a FLCN gene pathogenic variant
• Individuals with a clinical diagnosis of BHD syndrome^r with uninformative genetic testing.

* BHD-associated renal cancers are often, but not exclusively, bilateral and multifocal. Chromophobe or mixed oncocytic-chromophobe histology is characteristic, but clear cell and papillary cancers also occur.^rr
**Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2016 data)

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

***The impact of lifestyle on general cancer risks should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Pulmonary manifestations

Pulmonary cysts

Approximately 80-90% of patients with Birt-Hogg-Dubé syndrome have lung cysts.^rr BHD-associated lung cysts likely develop in early to mid-adulthood. In sporadic primary pneumothorax, pulmonary cysts are typically found in the apical zones, while in BHD, the lung cysts are most often located in the basal regions.   

Consequences of BHD-associated cystic lung disease appear worse in smokers.^r

Avoid smoking.^r

Pneumothoraces

The documented lifetime risk for incident pneumothorax ranges between 29%^r and 76%.^r Ascertainment bias is suspected to account for this variation with rates expected to be underestimated when recruitment was through a dermatology clinic and overestimated when recruitment was through a respiratory clinic. Risk factors for pneumothorax in this population include family history of pneumothorax, past history of pneumothorax, presence of lung cysts, cyst size and volume; while age and smoking status have not been consistently found to be associated with pneumothorax.^rr

Facilitate patient education about the risk of future pneumothoraces. Refer to a respiratory physician prior to any high-risk activity e.g. scuba diving, high altitude mountain climbing.

Strongly recommend: medical alert bracelet, action plan for pneumothorax.

The reported recurrence rate of pneumothorax in BHD varies from 30% - 80%.^rr The management of BHD-associated pneumothorax is similar to that for the general population.

Skin manifestations

Fibrofolliculomas, which are benign, are the most common skin manifestation occurring on the central face, neck and upper aspect of the trunk. They are present in the majority of BHD patients, and typically appear after age 20 years. If no lesions are present at age 40, they are unlikely to develop. Multiple biopsies and careful sectioning are often required for correct diagnosis. Other skin lesions associated with BHD include angiofibromas, trichodiscomas, perifollicular fibromas and epidermoid cysts.

Currently available treatments only remove cutaneous lesions temporarily; at the present time there does not appear to be a treatment that works permanently.

Renal cell carcinoma

Management depends on the lesion size, location, growth rate, number of tumours, and the patient’s comorbidities. In general, surgical resection with renal sparing surgery whenever possible is recommended once a solid lesion exceeds the 3 cm threshold.^r

Ablation methods, such as radiofrequency ablation (RFA) or cryoablation therapy, are not recommended in patients who are good surgical candidates as previous ablation may complicate subsequent surgical procedures and can also make post-ablation imaging difficult to interpret.^r

Kidney

Surveillance

There is only expert opinion to support the use of renal imaging, as the effectiveness of screening in Birt-Hogg-Dubé syndrome has not been evaluated to date. To reduce the cumulative radiation exposure, MRI (gold standard) and high-resolution renal ultrasound are preferred over CT with contrast. There is concern that renal ultrasound is inadequate in identifying small renal tumours, and may miss some forms of BHD-associated renal cancers.^r A recent paper reported 178 individuals affected with BHD syndrome of whom 34 developed renal cancers, with age at diagnosis ranging from 30 to 80.^r However, because there are now several reports of individuals with BHD who have developed renal cancer <30 years,^rrr  surveillance commencing at 20 years is deemed to be appropriate.

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Bibliography

Currow D, Thomson W. 2009, Cancer in NSW:Incidence Report 2009. Sydney: Cancer Institute NSW, February 2014.

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Khoo, S. K., S. Giraud, K. Kahnoski, et al. 2002. "Clinical and genetic studies of Birt-Hogg-Dube syndrome." J Med Genet 39(12):906-912.

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Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.

Kluijt, I., D. de Jong, H. J. Teertstra, et al. 2009. "Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome." Clin Genet 75(6):537-543.

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Birt-Hogg-Dube syndrome is a hereditary syndrome characterized by benign disease of skin and lungs and a risk of malignant renal tumors. We describe a clinical and genetic study of a large Dutch family with a novel mutation in the FLCN gene. Renal cancer at very young age occurred in one branch of this family, while in other branches, cutaneous and pulmonary symptoms predominated. A variety of congenital anomalies and connective tissue abnormalities were observed, possibly associated with the gene mutation.

Pavlovich, C. P., R. L. Grubb, 3rd, K. Hurley, et al. 2005. "Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome." J Urol 173(5):1482-1486.

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PURPOSE: Herein we describe the evaluation and management of renal tumors in Birt-Hogg-Dube (BHD), an autosomal dominant disorder predisposing to cutaneous fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax and renal tumors. MATERIALS AND METHODS: A total of 124 affected individuals underwent comprehensive clinical evaluation, including body computerized tomography, to determine cutaneous, pulmonary and renal manifestations of BHD. Of these individuals 14 had their renal tumors managed at our institution. RESULTS: Of the 124 BHD affected individuals 34 (27%) had renal tumors of various histologies, most commonly hybrid oncocytic tumor and chromophobe renal carcinoma. Average age at renal tumor detection was 50.4 years and multiple tumors were found in a majority of patients. Some patients with renal tumors were identified that did not have the characteristic cutaneous hallmarks of BHD. In 4 of the 14 patients treated at our institution small (less than 3 cm) renal tumors were observed, while 10 others underwent a total of 12 renal procedures, including 4 radical and 8 partial nephrectomies. At a median of 38 months of followup 5 of these 10 patients remained free of disease, 3 had small renal tumors and 2 died of metastatic renal cancer. CONCLUSIONS: Patients with BHD are at risk for multiple renal tumors that are often malignant and can metastasize. Individuals at risk or affected by BHD should be radiographically screened for renal tumors at periodic intervals and they are best treated with nephron sparing surgical approaches. Genetic testing for this syndrome is now available.

Schneider, M., K. Dinkelborg, X. Xiao, et al. 2018. "Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion." Fam Cancer 17(1):135-139.

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Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.

Tracey E, Kerr T, Dobrovic A, Currow D. 2010 “Cancer in New South Wales: Incidence and Mortality Report 2008”. Sydney: Cancer Institute NSW, August 2010

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Welsch, M. J., A. Krunic and M. M. Medenica. 2005. "Birt-Hogg-Dube Syndrome." Int J Dermatol 44(8):668-673.

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Birt-Hogg-Dube Syndrome is an autosomal dominant condition characterized by a triad of fibrofolliculomas, trichodiscomas, and acrochordons. Since the first description in 1977, many conditions have been described in association with its clinical triad. Recent epidemiological studies have shown a significant association between the occurrence of lesions in the fibrofolliculoma/trichodiscoma category with renal neoplasms and pneumothoracies. The BHD protein folliculin had recently been identified. The histological findings of the clinical lesions are distinctive. We report a patient with a history of melanoma who presented for routine surveillance. Facial lesions in the fibrofolliculoma/trichodiscoma category were identified. Diagnostic work-up revealed concomitant multinodular goiter, pulmonary cyst, and renal mass. The patient later developed pneumothorax. Clinical manifestations, histological findings, associations, management, and a review of the Birt-Hogg-Dube Syndrome are discussed.

Zbar, B., W. G. Alvord, G. Glenn, et al. 2002. "Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome." Cancer Epidemiol Biomarkers Prev 11(4):393-400.

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The Birt-Hogg-Dube syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dube syndrome, in 13 Birt-Hogg-Dube haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dube syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5-31.6) and approximately 9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dube syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4-392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dube syndrome. The Birt-Hogg-Dube syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.

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