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Birt-Hogg-Dubé Syndrome, Genetic Testing

Birt-Hogg-Dubé syndrome (BHDS) is a rare genetic disorder that primarily affects the skin, lungs, and kidneys. It is caused by mutations in the FLCN gene, which provides instructions for producing the protein folliculin. The exact function of folliculin is not completely understood, but it is thought to play a role in regulating cell growth and division. BHDS is inherited in an autosomal dominant manner, meaning an individual with a mutation in one copy of the FLCN gene is affected. In many cases, affected individuals have an affected parent. Birt-Hogg-Dubé syndrome is a rare clinicopathologic condition with an estimated prevalence of 1 in 200.000 people, but the exact incidence is unknown.

Birt-Hogg-Dubé syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Key features and aspects of Birt-Hogg-Dubé syndrome include:

  • Skin Manifestations: Individuals with BHDS may develop abnormalities, including multiple benign skin tumors called fibrofolliculomas. These often appear on the face, neck, and upper trunk.
  • Lung Involvement: BHDS is associated with an increased risk of developing lung cysts. In some cases, these cysts can lead to pneumothorax (collapsed lung), recurrent episodes of which may occur.
  • Renal (Kidney) Tumors: The syndrome is also linked to an elevated risk of kidney tumors, particularly oncocytomas and chromophobe renal cell carcinomas. These tumors are typically noncancerous but can occasionally become cancerous.
  • Variable Presentation: The severity and specific manifestations of BHDS can vary widely among affected individuals, even within the same family.
  • Screening and Management: Periodic monitoring and screening for lung cysts and kidney tumors are recommended for individuals with BHDS. Management strategies may include surveillance for early detection and intervention in case of complications.
  • Treatment: Treatment options for BHDS depend on the specific manifestations and complications present in everyone. Surgical interventions may be considered for lung cysts and kidney tumors if necessary.

Due to the potential for various manifestations in multiple organ systems, individuals with Birt-Hogg-Dubé syndrome often benefit from a multidisciplinary approach involving dermatologists, pulmonologists, nephrologists, and other specialists. Early detection and appropriate management are essential for optimizing outcomes in individuals with BHDS. Genetic counseling is important for individuals with BHDS and their families to understand the genetic basis of the condition and assess the risk for future generations.

Diagnosis is confirmed through genetic testing to identify mutations in the FLCN gene. Imaging studies, such as computed tomography (CT) scans, may also be used to assess lung and kidney involvement.

Birt-Hogg-Dub syndrome is an autosomal dominant disorder that is caused by the presence of mutations in the FLCN tumor suppressor gene. This gene encodes for folliculin, and although its function is still unknown, it is believed to be a component of the mTOR pathway, which is implicated in the development of renal tumors and, eventually, in the development of other associated lesions.

The c.1285dupC variant (p.His429fs) causes an alteration of the read-through pattern that changes a histidine to a proline, generating an early stop codon. Consequently, a loss of functionality of the protein responsible for tumor suppression occurs. This mutation is common in patients with BHD, reported in up to 44% of patients. Another common variant is c.1285delC (p.His429fs). In this case, the deletion has a similar effect to the previous variant, i.e., it generates a truncated non-functional or absent protein. A study by Sattler et al. observed that patients with either of the two most common pathogenic variants (c.1285delC and c.1285dupC) had a lower frequency of renal tumors.

The variant c.1285delC was found to have a lower frequency of renal tumors.

Another variant, identified in several BHD patients, is c.250-2A>G, which causes an alteration in the gene sequence that results in a significantly altered protein. One study observed a markedly increased risk of pneumothorax in carriers of this variant compared to other patients carrying the c.1285dupC mutation.

The genetic test of Birt-Hogg-Dubé syndrome analyzes the 25 most frequent pathogenic mutations of the FLCN gene.

With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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