Birt-Hogg-Dube syndrome

Birt-Hogg-Dube syndrome(birt-hog-doob SIN-drome)

Other Names: BHD syndrome; Fibrofolliculomas with trichodiscomas and acrochordons; BHD; Hornstein-Knickenberg syndrome; Birt Hogg Dube syndrome

Birt-Hogg-Dube syndrome (BHDS) is a rare, complex, genetic disorder with three main clinical findings: non-cancerous (benign) skin tumors; lung cysts and/or history of pneumothorax (collapsed lung); and various types of renal tumors.

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Epidemiology

Birt-Hogg-Dubé syndrome is rare; its exact incidence is unknown. This condition has been reported in more than 400 families.

Cause

Mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome. This gene provides instructions for making a protein called folliculin. The normal function of this protein is unknown, but researchers believe that it may act as a tumor suppressor. Tumor suppressors prevent cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the FLCN gene may interfere with the ability of folliculin to restrain cell growth and division, leading to uncontrolled cell growth and the formation of noncancerous and cancerous tumors. Researchers have not determined how FLCN mutations increase the risk of lung problems, such as pneumothorax.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered FLCN gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one affected parent. Less commonly, the condition results from a new mutation in the gene and occurs in people with no history of the disorder in their family.

Having a single mutated copy of the FLCN gene in each cell is enough to cause the skin tumors and lung problems associated with Birt-Hogg-Dubé syndrome. However, both copies of the FLCN gene are often mutated in the kidney tumors that occur with this condition. One of the mutations is inherited from a parent, while the other occurs by chance in a kidney cell during a person's lifetime. These genetic changes disable both copies of the FLCN gene, which allows kidney cells to divide uncontrollably and form tumors.

Signs and symptoms

Its signs and symptoms vary among affected individuals. Birt-Hogg-Dubé syndrome is characterized by multiple noncancerous (benign) skin tumors, particularly on the face, neck, and upper chest. These growths typically first appear in a person's twenties or thirties and become larger and more numerous over time. Affected individuals also have an increased chance of developing cysts in the lungs and an abnormal accumulation of air in the chest cavity (pneumothorax) that may result in the collapse of a lung. Additionally, Birt-Hogg-Dubé syndrome is associated with an elevated risk of developing cancerous or noncancerous kidney tumors. Other types of cancer have also been reported in affected individuals, but it is unclear whether these tumors are actually a feature of Birt-Hogg-Dubé syndrome.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Emphysema
• Papule
• Skin tags

30%-79% of people have these symptoms

• Abnormality of retinal pigmentation
• Multiple lipomas(Multiple fatty lumps)
• Pulmonary sequestration

5%-29% of people have these symptoms

• Medullary thyroid carcinoma
• Parathyroid adenoma
• Pneumothorax(Collapsed lung)
• Renal cell carcinoma(Cancer starting in small tubes in kidneys)

1%-4% of people have these symptoms

• Colon cancer
• Cutaneous leiomyoma
• Cutaneous leiomyosarcoma
• Fibrofolliculoma
• Sebaceous hyperplasia
• Spontaneous pneumothorax(Spontaneous collapsed lung)
• Trichodiscoma

Diagnosis

BHDS should be suspected in individuals with any of the following major or minor criteria.

Major criteria

Five or more fibrofolliculomas/trichodiscomas with at least one confirmed histologically Note: Identification of a heterozygous pathogenic variant in FLCN was included as a major criterion .

Minor criteria

• Multiple lung cysts. Bilateral basally located lung cysts with no other apparent cause, with or without spontaneous primary pneumothorax
• Early-onset renal cancer (age <50 years)
• Multifocal or bilateral renal cancer
• Renal cancer of mixed chromophobe and oncocytic histology
• First-degree relative with BHDS

Establishing the Diagnosis The diagnosis of BHDS is established in a proband with: One major criteria (Note: Identification of a heterozygous pathogenic variant in FLCN is one of the major criteria); OR Two minor criteria as described in Suggestive Findings.

Molecular ʽgenetic testingʼ approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Treatment

Fibrofolliculomas. In general, fibrofolliculomas are benign lesions for which no treatment is required; however, affected individuals may seek treatment for such lesions for cosmetic purposes, particularly when multiple cutaneous lesions are located on the face. Surgical and laser treatment can lead to temporary improvement, but lesions often recur over time. . Topical treatment of fibrofolliculomas with the mTOR inhibitor rapamycin in individuals with BHDS in a double-blinded placebo-controlled randomized split-face study showed no effect [Gijezen et al 2014].

Pneumothorax. Treatment of pneumothorax is the same as in the general population. Lung cysts are usually not treated and most individuals show normal lung function. Some individuals develop mild signs of airway obstruction, which are treated conservatively.

Renal tumors. Individuals with BHDS are at risk of developing more than one renal tumor. It is therefore crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on the size and location of the tumors . It has been previously reported that renal tumors in BHDS tend to be slow growing and metastasize late. This is most likely not accurate for all tumor subtypes and several individuals with metastatic disease have been reported .

Renal tumors <3.0 cm in diameter are monitored by periodic imaging. When the largest renal tumor reaches 3.0 cm in diameter, evaluation by a urologic surgeon is appropriate with consideration of nephron-sparing surgery . Rapidly growing lesions and/or symptoms including pain, blood in the urine, or atypical presentations require a more individualized approach. PET-CT scan is an option for evaluation of these lesions.

NIH genetic and rare disease info

• NIH info on Birt-Hogg-Dube syndrome

Birt-Hogg-Dube syndrome is a rare disease.

Birt-Hogg-Dube syndrome Resources
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