Birt-Hogg-Dubé syndrome
| Birt-Hogg-Dubé syndrome | |
| OMIM | 135150 |
|---|---|
| DiseasesDB | 33274 |
| eMedicine | derm/622 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rithish Nimmagadda,MBBS.[2]
Birt-Hogg-Dubé syndrome (BHD) is a rare human genetic disorder. The disorder has been reported in more than 200 families, and it is inherited in an autosomal dominant pattern.
History
The syndrome was first described in 1977. [1]
Presentation
Birt-Hogg-Dubé syndrome is a rare disorder that affects the skin and increases the risk of certain types of tumors. The condition is characterized by multiple noncancerous tumors of the hair follicles, particularly on the face, neck, and upper chest. These growths typically first appear in a person's twenties or thirties. People with Birt-Hogg-Dubé syndrome also have an increased risk of developing cancerous or noncancerous kidney tumors and possibly tumors in other organs and tissues. Additionally, affected individuals have a higher chance of developing cysts in the lungs and an abnormal collection of air in the chest cavity (pneumothorax) that may result in the collapse of a lung.
Genetics
Mutations in the FLCN gene located on chromosome 17p11.2 cause Birt-Hogg-Dubé syndrome.These variants include small insertion/deletions, splice-site, and nonsense variants, which lead, in most cases, to premature truncation and loss of function of the folliculin protein [2] [3] The FLCN gene makes 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 normally 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 the formation of noncancerous and cancerous tumors.
Researchers believe that two copies (instead of one copy) of the FLCN gene must be altered for a person to develop the kidney tumors often seen in Birt-Hogg-Dubé syndrome. People with this condition are born with one mutated copy of the FLCN gene in each cell. Then, during their lifetime, the other copy of the gene is mutated in kidney cells. These genetic changes result in no functional copies of the FLCN gene in these cells, allowing the cells to divide uncontrollably and form tumors.
CLINICAL MANIFESTATION
Fibrofolliculomas, or cutaneous lesions, are usually the first and most common sign of BHD syndrome. About 90% of patients experience the onset of these lesions in their third decade of life. They manifest as spherical, white-gray papules that range in size from 1 to 4 mm, with some displaying a central dell that corresponds to the follicular opening. There may also be cystic or comedonal lesions, as well as lesions up to 8 mm in size.[4] Together with fibrofolliculomas, other skin lesions that were first identified in BHD syndrome cases were trichodiscomas and acrochordons. Trichodiscomas can be a histologic variation of the same tumor and are clinically indistinguishable from fibrofolliculomas.Angiofibromas, sometimes referred to as fibrous papules, are widespread in the general population but are also occasionally observed in the context of BHD syndrome.[5]
lung manifestations: In 70–80% of afflicted family members with BHD syndrome, multiple, bilateral lung cysts form; these cysts may be the only sign of the illness.[6] Thin-walled, irregularly shaped pulmonary cysts are common on high-resolution chest computed tomography (HRCT) images; the majority of these cysts are less than one centimeter in size.
kidney tumors: Around the age of 50 (range: 30 to 70 years), 12 to 34 percent of individuals will develop renal cancer, the most dangerous symptom of BHD condition. Unlike other hereditary renal cancer syndromes, which are often linked to a specific histologic tumor type, BHD syndrome is linked to a variety of tumor histologies, with chromophobe tumors and hybrid chromophobe/oncocytic tumors being the most prevalent. Rarely, papillary carcinoma, mixed-type carcinoma, and clear cell carcinoma may be seen. [7] [8] [9] [10]
DIAGNOSIS
Skin biopsy: When a patient presents with many face papules that are thought to be fibrofolliculomas, a skin biopsy is recommended. Because a punch biopsy makes the whole tumor and related hair follicle visible, it is recommended above a shave biopsy.
Imaging studies:Patients who may have BHD syndrome should have serial baseline imaging of the chest and abdomen. High-resolution chest computed tomography (HRCT) can detect occult pneumothoraces or lung cysts.
Genetic testing: By sequencing the full coding area of the folliculin (FLCN), germline pathogenic mutations in FLCN may be found, which validates the diagnosis of BHD syndrome. Sequence analysis of all 14 exons in the National Cancer Institute BHD syndrome cohort revealed disease mutations in the FLCN gene in 88% of the families.
Diagnostic criteria: The existence of one or more of the following suggested criteria is used to make the diagnosis of BHD syndrome[11]
- >2 skin lesions that are clinically suggestive of fibrofolliculoma and/or trichodiscoma, and >1 fibrofolliculoma that has been histologically verified
- Many bilateral pulmonary cysts mostly in the lung's basilar areas, with or without a history of spontaneous pneumothorax before to age 40, particularly if connected to a family history of comparable pulmonary symptoms
- Hybrid oncocytic tumors or bilateral, multifocal chromophobe renal carcinomas, particularly in patients with a family history of renal tumors at <50 years of age
- A combination of these pulmonary, renal, or cutaneous manifestations presenting in the patient or family members
- Deoxyribonucleic acid (DNA) sequencing identification of a germline pathogenic variant in FLCN
Management
Skin lesions: Trichodiscomas and fibrofolliculomas are benign lesions that often don't need to be treated. Nonetheless, some individuals may seek therapy for cosmetic reasons if they have a large number of facial abnormalities. While recurrence is common, some individuals have had favorable success via destructive procedures such as shave removal, electrodesication with or without curettage, and carbon dioxide (CO2) or erbium-doped yttrium aluminum garnet (Er:YAG) laser ablation. [12] [13] [14]
Pneumothorax : Treatment of pneumothorax in patients with Birt-Hogg-Dubé (BHD) syndrome is the same as in patients with secondary pneumothorax
Renal tumors: The only available therapy for renal tumors linked to the BHD condition is surgery. Chromophobe and hybrid oncocytic tumors, the most prevalent types of BHD syndrome tumors, are often indolent. Experts advise nephron-sparing surgery for tumors larger than 3 cm in diameter and active surveillance if the dominant lesion is less than 3 cm in diameter. They also advise removing any intraoperatively discovered lesions.[15]
References
- ↑ Birt, A. R., Hogg, G. R., and Dubé, W. J. 1977. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch. Derm. 113: 1674-1677. PMID 596896
- ↑ Lim DH. "A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene". PMID 19802896. Check
|pmid=value (help). - ↑ Nickerson, M. L. et al. 2002. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2: 157-164. PMID 12204536
- ↑ Aivaz O. "Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome". PMID 25970555. Check
|pmid=value (help). - ↑ DiCicco B. "WM. Koenen's tumor and facial angiofibromas in a case of Birt-Hogg-Dubé syndrome: A cutaneous contribution to growing evidence of a relationship with tuberous sclerosis complex". PMID 27274535. Check
|pmid=value (help). - ↑ Gunji Y. "Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax". PMID 17496196. Check
|pmid=value (help). - ↑ Toro JR. "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports". PMID 18234728. Check
|pmid=value (help). - ↑ Schmidt LS. "Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome". PMID 15852235. Check
|pmid=value (help). - ↑ Pavlovich CP. "Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome". PMID 15821464. Check
|pmid=value (help). - ↑ Pavlovich CP. "Renal tumors in the Birt-Hogg-Dubé syndrome". PMID 12459621. Check
|pmid=value (help). - ↑ Schmidt LS. "Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome". PMID 26334087. Check
|pmid=value (help). - ↑ Kahle B. "Erfolgreiche Therapie mit dem CO2-laser [Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser]". PMID 11220238. Check
|pmid=value (help). - ↑ "Treatment of Birt-Hogg-Dubé syndrome with erbium:YAG laser". PMID 11050594. Check
|pmid=value (help). Text "vauthorsGambichler T" ignored (help) - ↑ "Multiple Mantelome bei Birt-Hogg-Dubé-Syndrom. Erfolgreiche Therapie mit dem CO2-laser [Multiple mantleomas in Birt-Hogg-Dubé syndrome: successful therapy with CO2 laser]". PMID 11220238. Check
|pmid=value (help). Text "vauthors Kahle B" ignored (help) - ↑ "Diagnosis and management of BHD-associated kidney cancer. Fam Cancer". PMID 23703644. Text "vauthors Stamatakis L" ignored (help)
This article incorporates public domain text from The U.S. National Library of Medicine