Birt-Hogg-Dubé Syndrome

Last Literature Review: September 2022 Last Update:

Recommended test to confirm a clinical diagnosis or family history of BHDS

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Birt-Hogg-Dubé syndrome (BHDS), caused by heterozygous germline pathogenic variants in the FLCN gene, is commonly characterized by cutaneous manifestations, pulmonary cysts (typically with history of pneumothorax), and various renal tumors.

Disease Overview

Common Features

Feature % of Patients Comment

Cutaneous manifestations (eg, fibrofolliculoma, acrochordons)


Cutaneous manifestations are unusual in individuals age <20 yrs

Pulmonary cysts


The age when cysts start to appear is unknown; childhood onset is likely

Spontaneous recurrent pneumothorax

Approximately 25 

Renal cell carcinoma


Frequency of specific tumor typesa:

  • Chromophobe:19/49 individuals
  • Clear cell: 15/49
  • Hybrid oncocytic: 5/49
  • Papillary: 4/49

aFrequency of chromophobe or hybrid renal cell carcinoma was higher in studies that focused on renal symptoms.

Sources: Toro, 2008 ; Schmidt, 2015 ; Kunogi, 2010 ; Houweling, 2011 ; Zbar, 2002 ; Sattler, 2018 ; Johannesma, 2019 

Clinical Criteria

BHDS should be suspected in individuals with any of the following major or minor criteria. The diagnosis of BHDS is established in an individual with one major or two minor criteria. 

  • Major criteria
    • Five or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically
    • A single pathogenic FLCN germline variant
  • Minor criteria
    • Multiple lung cysts, with or without spontaneous primary pneumothoraxes
    • Early-onset renal cancer (<50 years of age)
    • Multifocal or bilateral renal cancer
    • Renal cancer of mixed chromophobe and oncocytic histology
    • First-degree relative with BHDS



FLCN (NM_144997)


Approximately two individuals per million in the general population are estimated to have BHDS.  Over 400 families affected by BHDS have been reported. 


Autosomal dominant


High; approximately 90-95% of individuals with a single pathogenic FLCN variant will develop at least one feature of BHDS. 

Recurrent Variants

Twenty to 24% of families with BHDS were found to have either the pathogenic variant c.1285delC or c.1285dupC, located in the polycytosine mutational hotspot in exon 11. 

Test Interpretation

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays
  • Individuals with hematologic malignancy and/or a previous allogeneic bone marrow transplantation should not undergo molecular genetic testing on a peripheral blood specimen.
    • Testing of cultured fibroblasts is required for accurate interpretation of test results.
  • When a relative has a previously identified pathogenic variant, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Sensitivity and Specificity

Clinical Sensitivity

Approximately 96% 

Analytic Sensitivity and Specificity

Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region Analytic Specificity (NPA) Estimate (%)


>99 (96.9-99.4)


Deletions 1-10 bpb

93.8 (84.3-98.2)


Insertions 1-10 bpb

94.8 (86.8-98.5)


Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]


Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]


aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants


Result Variant(s) Detected Clinical Significance


One FLCN pathogenic variant detected

Consistent with a diagnosis of Birt-Hogg-Dubé syndrome


No pathogenic variants detected

Diagnosis of Birt-Hogg-Dubé syndrome is unlikely but not excluded


FLCN variant(s) of uncertain clinical significance detected

Uncertain; it is unknown whether variant is benign or pathogenic


  • A negative result does not exclude a diagnosis of BHDS or FLCN-associated tumors.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the FLCN gene
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions