BIRT-HOGG-DUBÉ SYNDROME

Birt-Hogg-Dubé Syndrome — a hereditary syndrome where spontaneous pneumothorax, skin fibrofolliculomas, and renal cell carcinoma occur together, frequently misattributed to separate unrelated conditions for years.

Whole genome sequencing identifies all FLCN pathogenic variants, establishing the diagnosis that transforms three seemingly unrelated conditions — lung cysts, skin tumors, and kidney cancer — into a single manageable hereditary syndrome.

FLCN

About this condition

Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant hereditary tumor syndrome caused by germline pathogenic variants in FLCN (folliculin) on chromosome 17p11.2. FLCN encodes folliculin, a tumor suppressor that regulates the mTOR signaling pathway. BHD is characterized by three cardinal features: multiple skin fibrofolliculomas (benign hair follicle hamartomas, appearing as small white papules on the face, neck, and upper trunk), pulmonary cysts with risk of spontaneous pneumothorax, and renal cell carcinoma — most commonly a distinctive hybrid oncocytic/chromophobe histologic hybrid unique to BHD, though clear cell and other subtypes also occur.

Renal cell carcinoma develops in approximately 27-34% of FLCN pathogenic variant carriers, with a median onset age of 48 years — substantially younger than sporadic RCC. The distinctive histological features of BHD-associated RCC — chromophobe, oncocytoma, and hybrid variants — differ from most common sporadic clear cell RCC and may prompt the pathologist to raise BHD consideration after nephrectomy. Spontaneous pneumothorax occurs in approximately 24% of BHD carriers, approximately 7-fold more frequently than in the general population, and recurrence rates are high. Pulmonary cysts are present on chest CT in the vast majority of FLCN carriers even without symptomatic pneumothorax.

The diagnostic challenge of BHD lies in the presentation pattern. Patients presenting with spontaneous pneumothorax — particularly those under 40, with recurrent episodes, or with a family history of pneumothorax — may have BHD evaluated only as 'idiopathic spontaneous pneumothorax' without genomic testing. These patients then receive no renal surveillance and develop RCC without preventive monitoring. Similarly, patients with characteristic fibrofolliculomas who do not have a dermatologist familiar with BHD may receive biopsies with a generic fibromatosis or angiofibromatosis diagnosis. FLCN pathogenic variants include mononucleotide C-insert deletions in exon 11 (a hotspot accounting for approximately 50% of pathogenic variants), missense variants, nonsense variants, and large genomic deletions.

Gene locus: FLCN (17p11.2)

Large FLCN genomic deletions are missed by standard sequencing panels. The exon 11 hotspot accounts for 50% of variants, leaving the other 50% requiring complete gene analysis to detect.

Large FLCN deletions explain a significant fraction of BHD — and require copy number analysis to detect

Approximately 10-15% of FLCN pathogenic variants are large genomic deletions spanning one or more exons. These are not detected by standard Sanger or next-generation sequencing panel approaches that do not include dedicated copy number variant analysis. In the BHD context, a missed large FLCN deletion in a patient with recurrent pneumothorax means they never receive the renal surveillance that would detect RCC at a surgically curable stage. Whole genome sequencing simultaneously sequences all FLCN exons, detects copy number variants across the FLCN locus, and resolves the complete variant landscape — providing the definitive molecular diagnosis in a single test.

Confirming BHD converts three alarming diagnoses into one manageable hereditary syndrome

A BHD patient without a diagnosis may be followed by a pulmonologist for 'recurrent idiopathic pneumothorax,' a dermatologist for 'fibrofolliculomas of uncertain significance,' and a urologist for 'incidentally discovered renal mass' — three separate clinical pathways with no coordination. After FLCN molecular confirmation, these three findings are unified into one hereditary syndrome with a single coordinated surveillance protocol: annual renal ultrasound or alternating MRI/CT every 3 years (NCCN recommendation), dermatological review, pulmonary evaluation, and cascade family testing. This integration of care is only possible after the molecular diagnosis is established.

Birt-Hogg-Dubé Syndrome — a hereditary syndrome where spontaneous pneumothorax, skin fibrofolliculomas, and renal cell carcinoma occur together, frequently misattributed to separate unrelated conditions for years.

Birt-Hogg-Dubé Syndrome

Large FLCN genomic deletions are missed by standard sequencing panels. The exon 11 hotspot accounts for 50% of variants, leaving the other 50% requiring complete gene analysis to detect.

Large FLCN deletions explain a significant fraction of BHD — and require copy number analysis to detect

Confirming BHD converts three alarming diagnoses into one manageable hereditary syndrome

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