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Conditions

Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé syndrome is a rare autosomal dominant tumour predisposition condition characterised by cutaneous manifestations, pulmonary cysts predisposing to spontaneous pneumothorax, and an increased lifetime risk of renal cell carcinoma. It is caused by constitutional (germline) pathogenic variants in the FLCN gene.

Gene function

FLCN is a tumour suppressor gene that encodes the folliculin protein. Although the function of FLCN is not fully understood, it has been linked to different signalling pathways that are crucial for both tumourigenesis and normal cell metabolism, including mTOR, AMPK, EGFR and HIF1α.

Gene locus and structure

The FLCN gene is located at chromosome 17p11.2. It comprises 14 exons and 579 amino acids.

Prevalence

Birt-Hogg-Dubé syndrome (BHDS) is a rare condition. A recent meta-analysis determined that the population frequency of BHDS is around 1.86 to 1.88 per million in the general population. The rate of de novo variation in FLCN is not certain, but appears to be low: the majority of constitutional (germline) variants in FLCN are inherited, and few de novo cases have been reported.

Pathogenic variant spectrum

Loss-of-function variants in FLCN produce a BHDS phenotype. Common FLCN variants include c.1285delC and c.1285dupC, with variants at this hotspot accounting for approximately 20% of BHDS cases.

Founder FLCN variants have been described in a number of different populations, including c.1062+2T>G in the Danish population and c.779+1G>T in the Swedish population.

There are no confirmed genotype-phenotype correlations, but some authors have reported that those with the common variant c.1285dupC have a lower tendency to develop renal malignancy. In some families with a history of colorectal cancer, there is a slightly increased risk of this particular cancer. However, the protocols for renal screening in individuals with this variant are the same as the protocols for renal screening in individuals with other pathogenic FLCN variants, and colorectal screening is not typically indicated unless there is a strong family history of colorectal cancer.

Disease associations

Associated disease penetrance is high. About 90%–95% of individuals with a heterozygous FLCN variant develop at least one clinical feature of BHDS. These features are listed below.

Cutaneous manifestations

  • Skin manifestations are present in more than 80% of affected individuals over 40 years of age and rare in those below 20 years of age.
  • Fibrofolliculomas (benign tumours of the hair follicle that present as small skin-coloured or white dome-shaped papules) are the hallmark feature.
  • Skin manifestations typically involve the face, neck and upper trunk and cause no symptoms.
  • Significant variability is demonstrated in age of onset and expression, but cutaneous features are nevertheless a useful diagnostic feature if present.
  • Such features can also include acrochordons (skin-tags), multiple epidermal cysts and lipomas, but these are seen frequently in the general population as well as in those with BHDS.

Pulmonary cysts and pneumothorax

  • Cysts are predominantly located in the basal lung regions bilaterally (subpleural and intrapulmonary areas), and are present in more than 80% of adults with BHDS.
  • Cysts are often asymptomatic, but cause a predisposition to spontaneous pneumothorax (sometimes recurrent), which can occur from a young age (youngest reported occurred at seven years of age, but more typically occur in the fourth decade onwards).
  • Lifetime risk of pneumothorax is about 25%–30%.
  • Long-term respiratory function is usually unaffected, even in the presence of multiple lung cysts.

Renal tumours

  • The lifetime risk of an FLCN-associated renal cell carcinoma (RCC) in a person with BHDS is likely to approach 30%–35%.
  • Individuals are at risk of developing bilateral and multifocal tumours, often at younger ages than those seen in the general population (median age of 48 years versus 62 years).
  • The youngest reported diagnosis of RCC in BHDS is 14 years of age.
  • The most common renal tumours in BHDS are hybrid oncocytic tumours, chromophobe and oncocytoma histological sub-types. Other histological types, such as clear cell and papillary, are also described.

Additional tumour risks

Although colorectal cancer has been reported in association with BHDS, evidence is conflicting in the scientific literature. Colorectal cancer and colonic polyps have been observed in some families, particularly those with the common hotspot variant c.1285dupC, but this is not a confirmed genotype–phenotype correlation.

It may be appropriate to consider additional colon cancer surveillance in BHDS families in which there is a colon cancer history, but this is best advised on by clinical genetics services. Parotid tumours and thyroid cancer have also been reported in BHDS families but a strong association has not been proven.

Genomic testing

Kidney cancer predisposition can be tested for using the National Genomic Test Directory code R224 (Inherited renal cancer) if an individual fulfils one of the following criteria:

  • renal cancer ≤40 years;
  • type 2 papillary renal cancer ≤50 years;
  • bilateral or multifocal renal cancer (any age);
  • renal cancer and a first- or second-degree relative with renal cancer (with both cases diagnosed under 50 years of age); or
  • renal cancer and features of an inherited cancer syndrome.

Familial pneumothorax can be tested for using the test directory code R190 (Pneumothorax – familial) in individuals who have had:

  • primary spontaneous pneumothorax with no identifiable cause; and either
  • a first-degree relative with primary spontaneous pneumothorax; or
  • characteristic radiological features of BHDS on chest imaging.

The test directory code R230 (Multiple monogenic benign skin tumours) can be used for those with three or more benign skin tumours, suggesting a diagnosis of any of the following conditions (with at least two histologically confirmed):

  • familial cylindromatosis;
  • Brooke-Spiegler syndrome;
  • multiple familial trichoepithelioma;
  • Muir-Torre syndrome;
  • Buschke-Ollendorff syndrome (note: one skin biopsy may be sufficient to make a confident diagnosis); or
  • BHDS.

Genomic counselling

  • BHDS is inherited in an autosomal dominant pattern. This means that an affected individual’s first-degree relatives have a 50% chance of having the familial FLCN variant.
  • Referral to clinical genetics should be arranged for newly identified individuals with pathogenic or likely pathogenic variants in FLCN to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Risk-reducing strategies

  • Screening strategies should be considered for individuals with an FLCN pathogenic variant, including:
    • renal surveillance imaging, preferably by annual MRI, recommended from around 18 years of age (renal ultrasound scan may also be an appropriate screening modality if performed by an experienced ultrasonographer);
    • colon screening, which may be appropriate if there is a significant family history of colon cancer; and
    • a dermatology review, as required.
    • Note that pulmonary cysts do not necessarily need to be screened for, as they do not usually affect lung function. Baseline imaging (for example, with lung CT) may be advisable if an individual is likely to be exposed to high ambient pressures, which might increase their risk of pneumothorax.
  • BHDS-related renal tumours exceeding 3cm in diameter are often treated conservatively with nephron-sparing surgery. This is because individuals with BHDS are at risk of developing multiple renal tumours over their lifetime. Traditionally, lesions under 3cm are monitored by a urologist, but earlier intervention may be required if there is evidence of tumour growth or other atypical features.
  • Fibrofolliculoma are benign, and often do not require treatment. Some individuals may wish to pursue treatment for cosmetic purposes, for example with laser therapy, but this should be guided by a dermatologist as lesions can recur over time.
  • Treatment of pneumothorax in affected individuals is the same as that in the general population.
  • Risk-reducing surgery can be considered in individuals who develop recurrent pneumothoraces or who have a significant occupational risk of developing pneumothoraces (for example, pilots).

Family planning implications

The Human Fertilisation and Embryology Authority has approved the use of preimplantation genetic testing for monogenic disorders (PGT-M) (previously known as preimplantation genetic diagnosis) for couples in whom one parent has a likely pathogenic or pathogenic variant in FLCN. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father has the variant) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children later in life.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 27/12/2023
  • Next review due: 27/12/2025
  • Authors: Dr Claire Forde
  • Reviewers: Dr Ellen Copson, Dr Derek Lim, Dr Terri McVeigh