Birt-Hogg-Dubé syndrome

Actionability Pediatric Summary Report

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

• Gene: FLCN (HGNC:27310)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/22/2023
• Curation Status: Released (1.0.1)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
FLCN	Birt-Hogg-Dube syndrome 1 (0800445)	135150	Limited Actionability

Actionability Assertion Rationale

• Although the suggested assertion based on consensus score was moderate, the majority of experts agreed on an assertion of limited. Reasons include the intervention does not prevent pneumothorax, there is limited evidence that anticipatory guidance reduces morbitity related to pneumothorax, and it is unclear how many individuals with pulmonary cysts go on to develop pneumothorax in the pediatric age range.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from pneumothorax / Anticipatory guidance regarding risk of pneumothorax including need for prompt intervention and imaging before anesthesia	1	2A	2C	3	8AC

Severity of Outcome

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 400 families from various populations affected by BHDS.

Clinical Features (Signs / symptoms)

BHDS is a rare condition characterized by renal tumors of varying histologic subtypes, cutaneous manifestations (cutaneous collagenomas and fibrofolliculomas, oral papules, and epidermal cysts), and pulmonary cysts (most often located in the basal lung regions), which can manifest as spontaneous pneumothoraces (with a clinical presentation ranging from asymptomatic to dyspnea and chest pain). Cutaneous perifollicular fibromas, acrochordons, and angiofibromas have also been associated with BHDS, but only fibrofolliculomas are specific for BHDS. Other findings reported in a small number of individuals includes thyroid nodules and cysts, thyroid cancer, colon polyps, colorectal cancer, parotid tumors, cutaneous-type oral papules, cutaneous melanomas, and various other tumor types.

Natural History (Important subgroups & survival / recovery)

Skin lesions typically appear between the second and fourth decades of life, and most often have a distribution on the face, neck, and anterior trunk. Skin lesions typically increase in size and number with age. Cutaneous manifestations are unusual in individuals age <20 years. Later onset correlates with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. Fibrofolliculomas are the most common cutaneous manifestation and are present in more than 80% of individuals with BHDS over age 40 years. While skin lesions usually have an earlier onset than renal tumors, some patients have presented with pulmonary and/or renal involvement without skin lesions. Families with confirmed FLCN pathogenic variants have been described in which pulmonary involvement appears to be the only disease manifestation. Lung cysts occur in over 80% of patients with BHDS, are often bilateral and multifocal, and do not cause pulmonary symptoms. The age when cysts start to appear is unknown; childhood onset is likely. However, lung cysts predispose to a high risk of spontaneous, often recurrent, pneumothorax, which may present without symptoms or with dyspnea and chest pain. With an average age of onset of 30.2 years (females) and 38.4 years (males), spontaneous pneumothorax is often the first symptom in individuals with BHDS (onset range 13-69 years). In most individuals the risk of pneumothorax decreases in later adulthood. However, the probability of a spontaneous pneumothorax is up to 75% by age 50 years. One review of over 1000 individuals with BHDS reported that pneumothorax incidence seemed to differ between individuals of varying ancestries. Individuals with BHDS are at increased risk (approximately 15-35%) for renal tumors, with a wide age range of onset (median age, 48 years; range, 31 to 71). The major cause of morbidity and mortality in BHDS is related to renal lesions. Unusually, BHDS-related renal tumors have different histologic subtypes. While BHDS-associated renal tumors can be aggressive, they are generally indolent. Only renal oncocytoma is considered benign. Most renal tumors associated with BHDS are bilateral, multifocal, and may affect morbidity more than mortality, as metastatic disease is rare (a 7% mortality rate from metastatic renal cell carcinoma has been reported). One study found that men develop renal tumors more often than women. When patients with BHDS are managed with an appropriate surveillance and intervention strategy, life expectancy should not be significantly different from that of individuals in the general population.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 5000

FLCN (previously known as BHD) is the only gene known to be associated with BHDS. A study recent of individuals drawn from the general population found pathogenic/likely pathogenic variants in 1 in 3234 unrelated individuals.

Tier 3

>1-2 in 100

FLCN pathogenic variants are detected in up to 96% of clinically diagnosed individuals, depending on the analysis method.

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

>= 40 %

Approximately 90%-95% of individuals with a heterozygous germline FLCN pathogenic variant develops at least one feature of BHDS.

Tier 4

5-39 %

A recent systematic review used segregation analysis to estimate cumulative risks of BHDS-associated manifestations for carriers of FLCN pathogenic variants. The final dataset contained 204 families informative for at least one manifestation of BHDS.

• Risk to age 20 for the following manifestations of BHDS:

-Skin manifestations (mild and severe): 6.5% (male) and 4.3% (female)

-Lung manifestations (lung cysts and/or pneumothorax): 11% (male) and 5.4% (female)

-Renal tumors: 0.6% (male) and 0.6% (female)

-Colon polyps: 0.4% (male) and 0.2% (female)

• Risk to age 70 for the following manifestations of BHDS:

-Skin manifestations (mild and severe): 87% (male) and 78% (female)

-Lung manifestations (lung cysts and/or pneumothorax): 87% (male) and 82% (female)

-Renal tumors: 19% (male) and 21% (female)

-Colon polyps: 21% (male) and 32% (female)

Tier 1

>= 40 %

A study of penetrance estimates of BHD-associated manifestations based on a health care system population (135,990 participants) reported BHD-related phenotypes identified in 35 individuals found to have pathogenic truncating variants in FLCN. Of the 35 individuals, 68.6% had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). Only 4 (11.4%) of individuals had prior clinical BHD diagnoses.

Tier 5

Unknown

Individuals with a pathogenic variant in FLCN and a family history of spontaneous pneumothorax have a higher risk of spontaneous pneumothorax compared to those without a family history of spontaneous pneumothorax (p=.011)

Tier 3

>= 40 %

One study found that individuals with BHDS had a 6% chance of developing their first spontaneous pneumothorax by age 30 years (95% CI, 3%–10%). This probability increased to 75% by age 50 years (95% CI, 19%–32%).

Tier 3

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

>3

By comparison to unaffected family members, individuals with BHDS have a higher chance of developing renal tumors (odds ratio 6.9 – 95%CI, 1.5-31.6) and spontaneous pneumothorax (odd ratio 50.2 – 95%CI, 6.4-392).

Tier 3

Expressivity

Intra- as well as interfamilial variation in disease severity can be significant. Individuals carrying the same gene variant may have none, some, or all of the major clinical characteristics

Tier 4

No genotype-phenotype correlations for FLCN have been confirmed, and any correlations are preliminary.

Tier 4

Intervention Effectiveness

Patient Management

Initial screening for major clinical manifestations in individuals with BHDS includes screening for renal, lung and skin manifestations. Referral to a cancer genetics professional should be considered.

Tier 2

To establish the extent of disease and needs in an individual diagnosed with BHDS, the following evaluations are recommended:

• Detailed dermatologic examination

• High-resolution computed tomography (HRCT) or CT of the chest for visualization of pulmonary cysts.

• Baseline abdominal/pelvic CT scan with contrast or MRI to screen for renal tumor.

Tier 4

Individuals with BHDS should undergo nephron-sparing surgery for renal tumors whenever possible, with consideration that an individual may have multiple tumors during their lifetime.

Tier 2

In general, fibrofolliculomas are benign lesions for which no treatment is required. However, affected individuals may seek treatment when multiple cutaneous lesions are located on the face. Surgical and laser treatment can lead to temporary improvement, but lesions often recur over time.

Tier 4

Treatment of pneumothorax is the same as in the general population. Therapy is dictated by the underlying lung condition and general health of the patient. Individuals with symptoms/signs of pneumothorax should immediately undergo chest x-ray and CT with appropriate follow-up. Lung CT can also be performed prior to scheduled anesthesia or long-distance flights. One study reported that of 101 patients with spontaneous pneumothoraces, 78 required medical intervention, and 23 were managed by observation alone.

Tier 4

Anesthesia recommendations for patients with BHDS include the following:

• Preoperative pulmonary assessment is indicated

• During pre-procedure time-out, the team should be made aware of hypoxemia or hemodynamic instability due to (tension) pneumothorax

• Neuraxial/peripheral regional anesthesia is preferred over general anesthesia (specifically with necessity for mechanical ventilation)

• For mechanical ventilation, especially in presence of lung cysts, high pressure values and peaks should be avoided due to high risk of cyst rupture and (tension) pneumothorax.

• Adequate postoperative nausea and vomiting prophylaxis (pneumothorax due to vomiting).

Tier 4

Individuals capable of childbearing who are planning conception should consider renal imaging prior to pregnancy.

Tier 2

Surveillance

Individuals with BHDS who do not yet have a radiographic or pathologic diagnosis of renal cell carcinoma should undergo abdominal MRI (preferred) or CT every 3 years starting at age 20 years. 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 of follow-up. No other patients developed metastatic disease.

Tier 2

Clinical surveillance for asymptomatic genetically confirmed individuals with BHDS should include dermatologic examinations to identify characteristic cutaneous lesions. Full body skin examination every 6-12 months to evaluate any suspicious pigmented lesions for melanoma.

Tier 4

Signs/symptoms of parotid tumors should be discussed annually.

Tier 4

One guideline recommends beginning at age 40 for those without a family history of colorectal cancer. This recommendation is based on a possible association of BHDS with colorectal cancer, though another guideline states that this association has more recently not been supported. Screening can start earlier in patients with a family history of colorectal cancer before age 40 years.

Tier 4

Circumstances to Avoid

Patients with BHDS—especially those with multiple lung cysts—should be advised to avoid or be cautious with scuba diving, air travel, and mechanical ventilation because each exposure increases the risk of spontaneous pneumothorax.

Tier 3

Cigarette smoking, which may precipitate spontaneous pneumothorax, and radiation exposure should be avoided

Tier 4

Nature of Intervention

Nature of Intervention

Clinical surveillance for individuals at risk of BHDS includes dermatologic, radiological, and histological examinations. Decisions regarding the use of lifelong surveillance for renal tumors must consider both risks and benefit, and a surveillance schedule that minimizes the lifetime dose of radiation is advised.

Context: Adult Pediatric

Chance to Escape Clinical Detection

BHDS is probably underdiagnosed due to its clinically varying appearance. BHDS can be indistinguishable from many other inherited conditions characterized by facial papules and renal tumors.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			FLCN			135150	0800445	0800444

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

Bruinsma FJ, Dowty JG, Win AK, Goddard LC, Agrawal P, Attina' D, Bissada N, De Luise M, Eisen DB, Furuya M, Gasparre G, Genuardi M, Gerdes AM, Hansen TVO, Houweling AC, Johannesma PC, Lencastre A, Lim D, Lindor NM, Luzzi V, Lynch M, Maffé A, Menko FH, Michels G, Pulido JS, Ryu JH, Sattler EC, Steinlein OK, Tomassetti S, Tucker K, Turchetti D, van de Beek I, van Riel L, van Steensel M, Zenone T, Zompatori M, Walsh J, Bondavalli D, Maher ER, Winship IM, Genetic Susceptibility Working Group I-CONFIRM. (2023) Update of penetrance estimates in Birt-Hogg-Dubé syndrome. Journal of medical genetics. 60(1468-6244):317-326.

Campbell SC, Uzzo RG, Karam JA, Chang SS, Clark PE, Souter L. (2021) Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-up: AUA Guideline: Part II. The Journal of urology. 206(1527-3792):209-218.

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/

National Comprehensive Cancer Network (NCCN) Guidelines Version 4.2023 Kidney Cancer. (2023) URL: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

OrphanAnesthesia. Anaesthesia recommendations for Birt-Hogg-Dubé syndrome.. (2008) URL: https://www.orphananesthesia.eu/en/rare-diseases/published-guidelines/birt-hogg-dube-syndrome/1702-birt-hogg-dube-syndrome-2/file.html

PDQ Cancer Genetics Editorial Board. (2002) Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. PDQ Cancer Information Summaries.

Savatt JM, Shimelis H, Moreno-De-Luca A, Strande NT, Oetjens MT, Ledbetter DH, Martin CL, Myers SM, Finucane BM. (2022) Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population. Genetics in medicine : official journal of the American College of Medical Genetics. 24(1530-0366):1857-1866.

Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W. (2013) Diagnosis and management of BHD-associated kidney cancer. Familial cancer. 12(1573-7292):397-402.