Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: FLCN
Condition: Birt-Hogg-Dubé syndrome
GENEDISEASE PAIRS: FLCN135150
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of Birt-Hogg-Dubé syndrome (BHDS) is estimated at 1 in 200,000 but the exact incidence is unknown. There have been more than 100 families from various populations affected by BHDS.
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Clinical Features
(Signs / symptoms)
BHDS is a rare condition characterized by renal tumors of varying histologic subtypes, cutaneous benign tumors of the hair follicle (fibrofolliculomas), and pulmonary cysts, which can manifest as spontaneous pneumothoraces. Cutaneous perifollicular fibromas, acrochordons, and angiofibromas have also been associated with BHDS, but only fibrofolliculomas are specific for BHDS. Other findings have included thyroid nodules and cysts, a few cases of thyroid cancer, colorectal cancer, benign parotic oncocytoma, cutaneous-type oral papules, and various other tumor types. BHDS has been reported to be associated with cutaneous melanoma, but whether the risk in individuals with BHDS is increased compared to the general population is unclear.
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Natural History
(Important subgroups & survival / recovery)
Skin lesions typically develop during the third or fourth decade of life, and most often have a distribution on the face, neck, and anterior trunk. Fibrofolliculomas increase in size and number with age but are not malignant. Later onset correlates with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. While skin lesions usually have an earlier onset than renal tumors, some patients have presented with pulmonary and/or renal involvement without skin lesions.
 
Lung cysts are mostly bilateral and multifocal, and do not cause pulmonary symptoms. However, lung cysts predispose to a high risk of spontaneous, often recurrent, pneumothorax, which may present without symptoms or with dyspnea and chest pain. Families with confirmed FLCN mutations have been described in which pulmonary involvement appears to be the only disease manifestation.
 
Renal cell tumors occur in a significant proportion of clinically-diagnosed BHDS patients with a wide age range of onset (median age, 48 years; range, 31 to 71). Unusually, BHDS-related renal tumors have different histologic subtypes. For example, in one study of 130 tumors from 30 BHDS patients, the renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, and 2% papillary. Only renal oncocytoma is considered benign. Most renal tumors associated with BHDS are bilateral, multifocal, and slow growing, and may affect morbidity more than mortality.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with BHDS, the following evaluations are recommended:
 
• Detailed dermatologic examination; punch biopsy of suspected cutaneous lesion
 
• High-resolution computed tomography (HRCT) or CT of the chest for visualization of pulmonary cysts. Individuals with symptoms/signs of pneumothorax should immediately undergo chest x-ray and CT with appropriate followup.
 
• Baseline abdominal/pelvic CT scan with contrast or MRI to screen for renal tumor. Renal ultrasound examination may distinguish cystic from solid renal lesions.
 
• Medical genetics consultation (Tier 4)
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Surveillance
There is no consensus on clinical surveillance; current recommendations are provisional:
 
•Beginning at age 18 years, or later when a BHDS diagnosis is established, annual MRI of the kidneys is optimal to assess for lesions (unless family history suggests earlier testing). FLCN-confirmed individuals without a family history of kidney tumors who have had 2-3 consecutive tumor-free MRI examinations may be screened every 2 years. Discovery of any suspicious lesion <1 cm in diameter should result in a return to an annual interval for screening.
 
- Renal lesions <3 cm in diameter are monitored by periodic imaging. Rapidly growing lesions and/or those with potentially associated symptoms require a more individualized approach. Once the largest tumor reaches 3 cm in maximal diameter, referral to a urologic surgeon is appropriate in order to evaluate the need for nephron-sparing surgery.
 
- In a prospective study, 124 clinically or genetically diagnosed individuals with BHDS were followed by surveillance. Of these, 34 (27%) had renal tumors detected at an average age of 50 years. Of 10 with tumors >3cm and treated surgically at one institution, 5 remained disease-free, 3 had small renal tumors (2 in the non-operated kidney), and 2 died of metastatic renal cancer (predominantly clear cell) at a median of 38 months. No other patients have had metastatic disease since.
 
•Full body skin examination at routine intervals to evaluate any suspicious pigmented lesions for melanoma should be considered. (Tier 3)
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Family Management
When the family-specific pathogenic variant is known, genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces unnecessary surveillance of members who have not inherited the pathogenic variant. (Tier 4)
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Early recognition of clinical manifestations may allow timely intervention and improve outcome. Therefore, clinical surveillance of asymptomatic at-risk relatives for early detection is appropriate. (Tier 4)
2
Circumstances to Avoid
Cigarette smoking, high ambient pressures, which may precipitate spontaneous pneumothorax, and radiation exposure should be avoided. (Tier 4)
2
Total nephrectomy should be avoided in order to decrease morbidity by preserving functioning renal tissue. (Tier 4)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
FLCN (previously known as BHD) is the only gene known to be associated with BHDS. Population prevalence of FLCN mutations was not reported. FLCN mutations are found in 88-93% of clinically diagnosed individuals, depending on the analysis method. (Tier 3)
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Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
In one study of 89 individuals (from 51 families; median age 54 years) with an FLCN germline pathogenic variant:
 
• 84% had fibrofolliculoma
 
• 84% had pulmonary cysts on chest CT
 
• 38% had a history of spontaneous pneumothorax
 
• 34% had renal tumors.
 
In a separate review of published cases with FLCN germline mutations:
 
• 85% (122 of 143) had fibrofolliculoma
 
• 87% (95 of 109) had lung cysts
 
• 33% (57 of 171) reported a history of spontaneous pneumothorax
 
• 20% (35 of 177) had renal tumors.
 
Excluding reports from the National Cancer Institute Clinical Center from this series:
 
• 73% had fibrofolliculoma,
 
• 77% had lung cysts
 
• 40% had spontaneous penumothorax
 
• 6.5% (5 of 77) had renal tumors. (Tier 5)
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By comparison to unaffected family members, individuals with BHDS have risks of developing renal tumors and spontaneous pneumothorax that are 7- and 50-fold higher, respectively. (Tier 3)
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Expressivity
Disease severity can vary significantly among family members and between families. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Interventions are skin exams and non-invasive imaging procedures for surveillance.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
BHDS occurs with great clinical variability, which is probably responsible for its underdiagnosis. (Tier 5)
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Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Morbidity and mortality from masses / Imaging to detect renal masses when intervention is effective
2
2N
2C
3
9NC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Birt-Hogg-Dubé syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=122
2. JR Toro. Birt-hogg-dub? syndrome. 2006 Feb 27 [Updated 2014 Aug 07]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1522
3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Birt-hogg-dube syndrome; bhd. MIM: 135150: 2016 Aug 29. World Wide Web URL: http://omim.org.
4. Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. Bhd mutations, clinical and molecular genetic investigations of birt-hogg-dube syndrome: a new series of 50 families and a review of published reports. J Med Genet. (2008) 45(6):321-31.
5. Verine J, Pluvinage A, Bousquet G, Lehmann-Che J, de Bazelaire C, Soufir N, Mongiat-Artus P. Hereditary renal cancer syndromes: an update of a systematic review. Eur Urol. (2010) 58(5):701-10.
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