Birt-Hogg-Dubé syndrome

Synonym: fibrofolliculomas with trichodiscomas and acrochordons

What is Birt-Hogg-Dubé syndrome?

Birt-Hogg-Dubé syndrome is named after the three authors of a paper that described family members with papular skin lesions on their face, forehead, scalp and neck.¹

When these lesions were examined, the following were found:²

• Fibrofolliculomas (benign tumours of the hair follicle).

• Trichodiscomas (hamartomatous tumours of the hair disc).

• Acrochordons ('wart with a thin neck' skin tags).

This triad of features became known as Birt-Hogg-Dubé syndrome. Later reports identified the presence of multiple lung cysts in patients with Birt-Hogg-Dubé syndrome (leading to spontaneous pneumothoraces), as well as an elevated risk of renal cancers.³

It has also been suggested that trichodischomas and fibrofolliculomas are the same lesions, but sectioned in different planes, leading to differing histological interpretations.⁴

Genetics

• Birt-Hogg-Dubé syndrome is a rare inherited genodermatosis.²

• The condition is caused by a mutation in the folliculin (FLCN) gene, a tumour suppressor gene.³

• The mutation is at gene map locus 17p11.2.

• An autosomal dominant inheritance pattern has been identified.⁵

How common is Birt-Hogg-Dubé syndrome? (Epidemiology)

• The actual prevalence is unknown, but it is likely to be underdiagnosed.⁶ One meta-analysis, using a Bayesian approach, estimated a prevalence of 2 per million people.⁷

• About 600 affected families have been described to date in the medical literature.⁸

Symptoms of Birt-Hogg-Dubé syndrome (presentation)

• Onset tends to be in adulthood with skin lesions:²
  

  • These develop in the 20s or 30s and remain throughout life.

  • They are typically small, dome-shaped, papular skin lesions, about 2 mm to 4 mm in diameter, that develop over the scalp, face, neck and upper trunk. They may also be seen in the mouth.

  • They cause no symptoms and the reason for presentation is usually cosmetic.

  • Acrochordons are warty-like skin tags that may be found on the eyelids, neck, axilla and upper half of the trunk. Skin tags are very common in the general population, and therefore not diagnostic for Birt-Hogg-Dubé syndrome.

• Presentation may also be with renal carcinoma, spontaneous pneumothorax or other possible associated conditions - see below.

Associations

There are a number of conditions associated with Birt-Hogg-Dubé syndrome, including:³

• Renal carcinomas (may be multifocal and/or bilateral; most commonly chromophobe renal carcinoma and oncocytic hybrid tumours).⁹

• Pulmonary cysts: these occur frequently, affecting about 70-84% of people with the syndrome.³

• Spontaneous pneumothorax.

These are thought to result from a mutation in the FLCN gene. The conditions below are other possible associations.¹⁰

• Connective tissue naevi.

• Parathyroid adenomas.

• Flecked chorioretinopathy.

• Lipomas and angiolipomas.

• Parotid oncocytomas.

• Multiple oral mucosal papules.

• Neural tissue tumours.

• Multiple facial angiofibromas.

• Colonic polyps and colonic adenocarcinoma.

• Multinodular goiters.

• Medullary thyroid carcinoma.

Diagnosing Birt-Hogg-Dubé syndrome (investigations)

• Skin biopsy will confirm the nature of the lesions.

• Molecular genetic testing is available, and demonstrating a germline FLCN mutation gives definitive diagnostic confirmation.³

• CXR or CT chest (may show pulmonary cysts, bullous emphysema or pneumothorax).

• Renal ultrasound and CT scan of the abdomen/pelvis should be performed to screen for renal tumours. Relatives should also be screened for renal cancer.

• Consider colonoscopy because of the possible association with colonic polyps/carcinoma, although this is debated.^{12 13}

Management of Birt-Hogg-Dubé syndrome

• There is no specific therapy.

• Skin lesions may be treated by surgical removal. Dermabrasion, electrodesiccation and laser treatment have been used but the lesions may recur.

• There should be long-term follow-up for malignant change, especially renal carcinoma. Abdominal CT or MRI is generally recommended for surveillance in these patients, as ultrasound may not detect small or isoechoic hybrid oncocytic and chromophobe tumours.³

  • Enhanced screening for colorectal cancer may also be useful, although this is disputed, as the link between Birt-Hogg-Dubé syndrome and colorectal malignancy is not clear.

• Monitoring and screening for associated chest conditions should be carried out.

• Smoking is a strong risk factor for both spontaneous pneumothorax and renal cancer. There are limited data on how smoking interacts with the existing risks in Birt-Hogg-Dubé syndrome, but it seems prudent to recommend smoking cessation and avoidance in these patients.

• Associated conditions should be managed appropriately.

• Genetic counselling should be offered.

Prognosis

• This depends on the development of associated conditions, especially renal carcinoma.

• The tendency for associated malignancy seems variable between families.

• Specific mutations in the folliculin gene may predispose to cancer development in Birt-Hogg-Dubé syndrome.¹⁴

• Malignancy is not an invariable part of the disease.

Prevention of Birt-Hogg-Dubé syndrome

There are no specific preventative measures for Birt-Hogg-Dubé syndrome, other than smoking cessation and enhanced surveillance (as above) to detect complications early.

Genetic counselling may help people with Birt-Hogg-Dubé syndrome understand their options for family planning. Prenatal diagnosis (for at-risk pregnancies) and preimplantation genetic testing are possible if the FLCN pathogenic variant has been identified in a family member.¹⁵