Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHDS) is characterized by an increased risk of unique benign skin tumors, pulmonary cysts, spontaneous pneumothorax, and various types of renal tumors and renal cell carcinoma (RCC).

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Birt-Hogg-Dubé syndrome (BHDS) is characterized by an increased risk of unique benign skin tumors, pulmonary cysts, spontaneous pneumothorax, and various types of renal tumors and renal cell carcinoma (RCC).

BHDS is caused by mutations in the FLCN gene.  It is a rare condition with autosomal dominant inheritance and variable expressivity.  The lifetime risk for RCC in those with BHDS may be as high as 34%.

Disease Name 
Birt-Hogg-Dubé syndrome (BHDS)
Pneumothorax, Primary Spontaneous (PSP)
Kidney cancer
Disease Information 

Renal cell carcinoma (RCC), a type of kidney cancer, is a complex and heterogeneous disease with a diverse spectrum of malignant subtypes with varied clinical characteristics, genetic causes, and therapeutic responses. RCC tumor subtypes include clear cell or conventional (70-80%); papillary type 1 and type 2 (10-15%); chromophobe (3-5%) and collecting duct (1%).1, 2 The general population lifetime risk to develop RCC is about 1.6%.3 It is the eighth most common cancer in both men and women.3  The majority of RCC cases are sporadic, but approximately 3-8% are due to an inherited cause.2, 4, 5 Unlike sporadic RCC cases, hereditary RCC is often characterized by earlier disease onset and/or multifocal or bilateral tumors.1, 4

FLCN is one of several genes associated with a hereditary predisposition to RCC. Specifically, FLCN mutations are associated with Birt-Hogg-Dubé syndrome (BHDS). BHDS is characterized by benign and cancerous kidney tumors, benign cutaneous (skin) findings, and pulmonary (lung) cysts which can lead to pneumothorax. 

BHDS-associated renal tumors are typically bilateral and multifocal. The histology of the tumor types varies widely within the same individual and within a family. Tumor types include hybrid oncocytic RCC, chromophobe RCC, oncocytoma (benign tumor), and a minority of clear cell and papillary RCC.6-8 The lifetime risk of RCC in those with BHDS has been reported as high as 34%, with a median age at diagnosis of 48 years (range 31-71 years).9, 10

Benign cutaneous tumors seen in those with BHDS include fibrofolliculomas (yellowish dome-shaped tumors of the hair follicle), trichodiscomas/angiofibromas (multiple small papules of the hair disc), and acrochordons (skin tags). Perifollicular fibromas (proliferations of fibrous and vascular stroma around a hair follicle) can also be seen. Cutaneous tumors in BHDS, which appear on the face, neck and upper trunk, typically appear in the 20s-30s and continually grow in size and number with age.6, 8

Nearly 90% of individuals with BHDS develop multiple pulmonary cysts that may be bilateral and multifocal, and typically develop in the 30s-40s.6, 10, 11 The presence of lung cysts is strongly associated with pneumothorax, which has been reported in 38% of individuals with BHDS.6, 10, 11

Various types of parotid tumors have been linked to BHDS including: parotid oncocytoma, pleomorphic adenomas, Warthin parotid tumors, and tumors that are bilateral or multifocal.6, 12-15

Primary spontaneous pneumothorax (PSP), commonly referred to as collapsed lung, typically occurs in the general population due to trauma or lung disease. While it is usually isolated, it can rarely be seen in multiple family members. Isolated familial PSP has been associated with mutations in the FLCN gene in a small number of families.16

 

Testing Benefits & Indication 

Genetic testing for FLCN mutations can identify individuals who have an increased risk of kidney cancer and can help differentiate BHDS from other hereditary causes of kidney cancer. This helps target increased medical surveillance, which may help reduce morbidity and mortality associated with RCC. 

Testing is indicated for those with any of the following findings.6

  • Five or more facial or truncal papules with at least one histologically confirmed fibrofolliculoma, with or without a family history of BHDS
  • Facial papules histologically confirmed to be angiofibroma in someone that does not fit the clinical criteria of tuberous sclerosis complex (TSC) or multiple endocrine neoplasia type 1 (MEN1)
  • Multiple and bilateral chromophobe, oncocytic, and/or hybrid renal tumors
  • A single oncocytic, chromophobe, or oncocytic hybrid renal tumor and a family history of renal cancer with any of the above renal cell tumor types
  • A family history of autosomal dominant primary spontaneous pneumothorax (PSP) without a history of smoking or chronic obstructive pulmonary disease (COPD).
  • FLCN mutation
Test Description 

FLCN coding exons 1-11 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-11. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.17  Gross deletion/duplication analysis of FLCN using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Ambry's FLCN analysis can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
Technique CALENDAR DAYS
FLCN Gene Sequence and Deletion/Duplication Analyses 14-21

 

Specialty 
Genes 
FLCN
References 
  1. Rosner I, et al. The clinical implications of the genetics of renal cell carcinoma. Urol Oncol. 2009. 27(2): p. 131-6.
  2. Barrisford GW, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011. 2011: p. 658767.
  3. SEER Stat Fact Sheets: Kidney and Renal Pelvis Cancer. Surveillance, Epidemiology, and End Results Program; Available from: http://seer.cancer.gov/statfacts/html/kidrp.html#risks.
  4. Haas NB and Nathanson KL. Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis. 2014. 21(1): p. 81-90.
  5. Shuch B, et al. Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol. 2014. 32(5): p. 431-7.
  6. JR T. Birt-Hogg-Dubé syndrome. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
  7. Pavlovich CP, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome. J Urol. 2005. 173(5): p. 1482-6.
  8. Dal Sasso AA, et al. Birt-Hogg-Dube syndrome. State-of-the-art review with emphasis on pulmonary involvement. Respir Med. 2014.
  9. Schmidt LS, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet. 2005. 76(6): p. 1023-33.
  10. Toro JR, et al. 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): p. 321-31.
  11. Gupta N, Seyama K, and McCormack FX. Pulmonary manifestations of Birt-Hogg-Dube syndrome. Fam Cancer. 2013. 12(3): p. 387-96.
  12. Liu V, Kwan T, and Page EH. Parotid oncocytoma in the Birt-Hogg-Dube syndrome. J Am Acad Dermatol. 2000. 43(6): p. 1120-2.
  13. Palmirotta R, et al. Birt-Hogg-Dube (BHD) syndrome: report of two novel germline mutations in the folliculin (FLCN) gene. Eur J Dermatol. 2008. 18(4): p. 382-6.
  14. Maffe A, et al. Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations. Clin Genet. 2011. 79(4): p. 345-54.
  15. Lindor NM, et al. Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors. Hered Cancer Clin Pract. 2012. 10(1): p. 13.
  16. Gunji Y, et al. Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet. 2007. 44(9): p. 588-93.
  17. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.