Birt-Hogg-Dubé syndrome

Actionability Adult Summary Report

Gene: FLCN (HGNC:27310)
Mode(s) of Inheritance:Autosomal Dominant
Literature Search: 03/30/2016
Curation Status: Released (1.2.2)
Release History

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
FLCN Birt-Hogg-Dube syndrome (0007607) 135150 Assertion Pending

Actionability Assertion Rationale

  • This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Morbidity and mortality from masses / Imaging to detect renal masses when intervention is effective 2 2N 2C 3 9NC
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

Prevalence of the Genetic Condition

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.
View Citations

Birt-Hogg-Dubé syndrome. Orphanet encyclopedia, ORPHA: 122., JR Toro, et al. (2006) NCBI: NBK1522

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.
View Citations

Birt-Hogg-Dubé syndrome. Orphanet encyclopedia, ORPHA: 122., JR Toro, et al. (2006) NCBI: NBK1522

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.
View Citations

Birt-Hogg-Dubé syndrome. Orphanet encyclopedia, ORPHA: 122., JR Toro, et al. (2006) NCBI: NBK1522, Online Medelian Inheritance in Man. (2016) OMIM: 135150

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.

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown
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 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %
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 View Citations

Toro JR, et al. (2008) PMID: 18234728

Relative Risk (Includes any high-risk racial or ethnic subgroups)

>3
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 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

Expressivity

Disease severity can vary significantly among family members and between families.
Tier 4 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

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.

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 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

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 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

Circumstances to Avoid

Cigarette smoking, high ambient pressures, which may precipitate spontaneous pneumothorax, and radiation exposure should be avoided.
Tier 4 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

Total nephrectomy should be avoided in order to decrease morbidity by preserving functioning renal tissue.
Tier 4 View Citations

JR Toro, et al. (2006) NCBI: NBK1522

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.

Nature of Intervention

Interventions are skin exams and non-invasive imaging procedures for surveillance.
Context: Adult

Chance to Escape Clinical Detection

BHDS occurs with great clinical variability, which is probably responsible for its underdiagnosis.
Context: Adult
Tier 5 View Citations

Verine J, et al. (2010) PMID: 20817385

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.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
FLCN 135150 0007607

References List

BIRT-HOGG-DUBE SYNDROME; BHD. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 135150, (2016) World Wide Web URL: http://omim.org/

Birt-Hogg-Dubé syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=122

JR Toro. Birt-Hogg-Dub? Syndrome. (2006) [Updated Aug 07 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1522/

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. (2008) BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics. 45(6):321-31.

Verine J, Pluvinage A, Bousquet G, Lehmann-Che J, de Bazelaire C, Soufir N, Mongiat-Artus P. (2010) Hereditary renal cancer syndromes: an update of a systematic review. European urology. 58(5):701-10.

Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is it actionable in an undiagnosed adult with the condition?
  4. Is this condition an important health problem?
  5. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?