Birt-Hogg-Dubé Syndrome

Disease Overview

Summary

Birt-Hogg-Dubé (BHD) syndrome is a rare complex genetic skin disorder (genodermatosis) characterized by the development of skin papules generally located on the head, face and upper torso. These benign (noncancerous) tumors of the hair follicle are called fibrofolliculomas. BHD syndrome also predisposes individuals to the development of benign cysts in the lungs, repeated episodes of a collapsed lung (pneumothorax) and increased risk for developing kidney neoplasia. BHD syndrome is caused by changes (pathogenic variants or mutations) in the FLCN gene and is inherited in an autosomal dominant pattern.

Introduction

BHD syndrome was first described in the medical literature in 1977 by three Canadian physicians (Drs. Birt, Hogg and Dubé) for whom the disease was named.

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Synonyms

• BHD syndrome
• Hornstein-Knickenberg syndrome

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Subdivisions

• No subdivisions found

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Signs & Symptoms

The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax) and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary in affected members of a single BHD family who inherit the same FLCN gene variant, and patients may develop one, two or all three of the characteristic features in any combination.

The skin papules known as fibrofolliculomas that are associated with BHD syndrome commonly occur on the scalp, face and neck, but can also be found on the ear lobes and in the oral mucosa. They are generally 2-3mm in size, dome shaped, flesh-colored and are not associated with any pain or discomfort. The onset is usually after the age of 20. Skin lesions may increase in number as affected individuals age. The number of skin lesions can vary dramatically; some individuals may only have a few skin lesions, while others may have a hundred or more.

In the original description of BHD syndrome, two other skin lesions were noted: trichodiscomas, benign tumors of the hair disc, and acrochordons or skin tags that appear as soft small growths that hang off the skin and are common in the general population. Some researchers believe that trichodiscomas and fibrofolliculomas are the same lesion despite different surface appearances.

Individuals with BHD syndrome may also develop multiple lung (pulmonary) cysts in both lungs, which occur in greater than 80% of individuals affected with BHD. These cysts usually do not cause symptoms (asymptomatic) and lung function is generally normal, but up to one-third of affected individuals may experience repeated occurrences of a collapsed lung (spontaneous pneumothorax). A collapsed lung occurs when air or gas is trapped in the space surrounding the lungs. When the cause is not known (e.g., trauma, injury), it is referred to as spontaneous. Pneumothorax in BHD syndrome occurs more often in younger individuals and has been reported in children as young as 7 years old. Individuals in a BHD family who inherit the diseae-causing FLCN variant have a 50-fold greater risk of developing spontaneous pneumothorax than their unaffected siblings.

Approximately 15-30 % of individuals with BHD syndrome may develop multiple kidney (renal) neoplasms. These are usually slow growing and can affect both kidneys (bilateral). The mean age of diagnosis for renal neoplasia is 48-50 years old. The most common tumor types are the hybrid oncocytic tumor (a hybrid consisting of both oncocytoma and chromophobe histologic cell types), and chromophobe renal cell carcinoma, both of which are malignant (cancerous). Renal oncocytomas, which are benign tumors, can also develop but occur only rarely. Individuals affected with BHD have a 7-fold greater risk of developing renal neoplasia than siblings who do not inherit the FLCN variant.

In 1975, two researchers reported on a disorder that became known as Hornstein-Knickenberg syndrome. This disorder is now considered to be the same as BHD syndrome. Affected individuals with Hornstein-Knickenberg syndrome had polyps in the colon in addition to skin lesions. Some researchers believe that colonic polyps are a coincidental finding in individuals with BHD syndrome and not part of the disorder; more family studies are needed to determine whether colon polyps are an additional symptom of BHD.

Other findings have been reported in a few cases of BHD syndrome including oral papules in the mouth, benign tumors consisting of fatty tissue (lipomas), benign tumors consisting of fatty tissue and an abnormally large number of blood vessels (angiolipomas), a benign tumor of the parathyroid glands (parathyroid adenoma), a benign tumor of the salivary gland (parotid oncocytoma) and a lesion or birthmark consisting of thickened, abnormally firm connective tissue (connective tissue nevus). Researchers do not know whether these findings are incidental or true manifestations of BHD syndrome.

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Causes

BHD syndrome is caused by changes (pathogenic variant or mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, repairs damage to the DNA of cells and tells cells when to die, a normal process called apoptosis. Variants in a tumor suppressor gene often predispose individuals to develop cancer, but having a gene variant does not absolutely guarantee development of the disease.

The predisposition to develop Birt-Hogg-Dubé syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

In some individuals, the predisposition to the disorder is due to a spontaneous (de novo) gene change that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

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Affected populations

Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. About 600 families (kindreds) affected with BHD have been described to date in the medical literature. Some researchers believe BHD syndrome is under-diagnosed, making it difficult to determine its true frequency in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Birt-Hogg-Dubé syndrome. Comparisons may be useful for a differential diagnosis.

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by variants in the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformations that can affect any area of the body. Hamartomas are composed of mature cells and tissue normally found in the affected area. PHTS includes virtually all cases of Cowden syndrome (also known as multiple hamartoma syndrome) and a percentage of cases of Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome and Proteus-like syndrome (i.e., those associated with variants in the PTEN gene). Cowden syndrome is a difficult to recognize, under-diagnosed genetic disorder characterized by the development of multiple, benign tumor-like malformations (hamartomas) in various areas of the body. Affected individuals also have a predisposition to developing certain cancers, especially cancer of the breast, thyroid or mucous membrane lining the uterus (endometrium). The specific symptoms of Cowden syndrome vary from person to person.

Some researchers think symptoms of tuberous sclerosis complex including skin and lung hamartomas and angiomyolipomas of the kidney (and rare renal neoplasia) are similar to BHD.

Recently, germline variants in the FLCN gene have been identified in families with familial spontaneous pneumothorax, in which affected family members develop frequent lung collapse without other typical BHD skin lesions or renal neoplasia.

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Diagnosis

A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms including two or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophobe or hybrid oncocytic renal tumors.

Surgical removal and microscopic evaluation (biopsy) of affected skin tissue is performed to determine the type of skin lesion present. Detection of a pathogenic (disease-causing) FLCN variant in a DNA-based genetic test confirms the diagnosis of BHD. Since renal neoplasia has been reported in individuals with BHD as young as 14, genetic testing is recommended starting at age 21 in at-risk family members.

Clinical Testing and Work-up

If a diagnosis of BHD syndrome is made, computed tomography (CT) scans of the lungs are recommended to detect pulmonary cysts/pneumothorax. Individuals with BHD have a lifelong risk for developing renal tumors and therefore, should undergo periodic surveillance by abdominal imaging (CT or magnetic resonance imaging to reduce radiation exposure is recommended) for early detection of renal tumors.

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Standard Therapies

Treatment

The treatment of Birt-Hogg-Dubé (BHD) syndrome focuses on managing specific symptoms present in each affected person.

• Skin lesions: Treatment may include laser ablation, which is effective but often results in lesion recurrence (relapse).
• Lung collapse: Treatment of a collapsed lung is intended to remove the air surrounding the lungs, allowing the lungs to re-inflate. A tube is inserted into the chest to allow the air or gas to escape (aspiration). In cases where repeated lung collapses occur, surgery may be necessary. Repeated collapses may necessitate surgery.
• Renal tumors: People affected with BHD are at higher risk for renal tumors, which often affect both kidneys, have multiple lesions (are multifocal) and are slow growing.
  • The European Reference Network recommends lifelong MRI surveillance preferably with contrast (ultrasound can be used if MRI is not available or appropriated) every 1–2 years starting at age 20 to minimize radiation exposure.
    • The recommendations have been published in the European Journal of Human Genetics and   the full guidelines and a plain language summary are available to read.
  • The National Cancer Institute (NCI) and other U.S. institutions generally recommend MRI or CT imaging every 2–3 years for individuals without renal tumors at diagnosis, focusing on detecting early-stage, slow-growing tumors
    • Patients with a confirmed FLCN gene variant but no renal lesions are recommended to start MRI or CT scans at least once every 2–3 years age 20 until a lesion is detected.
      • Once lesions appear, the frequency of imaging depends on tumor size and growth rate.

Surgeons need to remove the kidney tumor so it does not grow larger and spread (metastasis). They may also remove part or all the kidney (nephrectomy) if the tumor burden is extensive. The main objective of surgery in individuals with renal neoplasia is to preserve as much kidney tissue as possible, thereby preserving as much of the kidney function as possible.

• • Tumors ≥3 cm: Nephron-sparing surgery (NSS) is performed to remove the largest tumor while preserving kidney function.
  • Smaller tumors (<3 cm) are monitored with periodic imaging based on growth rate.
  • Thermal Ablation: For patients unfit for surgery, thermal ablation is an alternative for tumors <3 cm, with promising outcomes reported.

Genetic counseling is recommended for individuals and families with a confirmed FLCN gene variant to guide surveillance and management.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about Birt-Hogg-Dubé syndrome:

Laura S. Schmidt, PhD
Principal Scientist, BSP, Leidos Biomedical Research, Inc. and
Urologic Oncology Branch
National Cancer Institute
10 Center Drive MSC 1107
BLDG 10 CRC Room 1-3961
Bethesda, MD 20892
Tel: 240-858-3939
Fax: 240-541-4600
E-mail: [email protected]

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References

JOURNAL ARTICLES

Kijlertsuphasri S, Petnak T, Moua T. Diagnosis of renal tumors in Birt-Hogg-Dube syndrome: Clinical presentation and risk factors in a single-center retrospective cohort. BMC Nephrol. 2024;25(1):329. Published 2024 Oct 1. doi:10.1186/s12882-024-03775-9

Singh S, Chaurasia A, Gopal N, Malayeri A, Ball MW. Treatment strategies for hereditary kidney cancer: Current recommendations and updates. Discov Med. 2022;34(173):205-220.

Geilswijk M, Bendstrup E, Madsen MG, Sommerlund M, Skytte AB. Childhood pneumothorax in Birt-Hogg-Dubé syndrome: A cohort study and review of the literature. Mol Genet Genomic Med. 2018;6(3):332-338.

Schmidt LS, Linehan WM. FLCN: The causative gene for Birt-Hogg-Dubé syndrome.Gene. 2018;640:28-42.

Schneider M, Dinkelborg K, Xiao X, Chan-Smutko G, Hruska K, Huang D, Sagar P, Harisinghani M, Iliopoulos O. Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. Fam Cancer. 2018;17(1):135-139.

Gupta N, Kopras EJ, Henske EP, James LE, El-Chemaly S, Veeraraghavan S, Drake MG, McCormack FX. Spontaneous pneumothoraces in patients with Birt-Hogg-Dubé syndrome. Ann Am Thorac Soc. 2017;14(5):706-713.

Tong Y, Schneider JA, Coda AB, Hata TR, Cohen PR. Birt-Hogg-Dubé syndrome: a review of dermatological manifestations and other symptoms. Am J Clin Dermatol. 2017;Jul 10.

Johannesma PC, van de Beek I, van der Wel JW, Paul MA, Houweling AC, Jonker MA, van Waesberghe JH, Reinhard R, Starink TM, van Moorselaar RJ, Menko FH, Postmus PE. Risk of spontaneous pneumothorax due to air travel and diving in patients with Birt-Hogg-Dubé syndrome. Springerplus. 2016;Sep 7;5(1):1506.

Gupta N, Sunwoo BY, Kotloff RM. Birt-Hogg-Dubé syndrome. Clin Chest Med. 2016;37(3):475-86.

Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2015;12(10):558-69.

Vernooij M, Claessens T, Luijten M, van Steensel MA, Coull BJ. Birt-Hogg-Dubé syndrome and the skin. Fam Cancer. 2013;12(3):381-5.

Stamatakis L, Metwalli AR, Middelton LA, Linehan WM. Diagnosis and management of BHD-associate kidney cancer. Fam Cancer. 2013;12(3):397-402.

Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199-206.

Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, Turner M, Choyke P, Merino MJ, Pinto PA, Steinberg SM, Schmidt LS, Linehan WM. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45(6):321-31.

Gunji Y, Akiyoshi T, Sato T, et al. Mutations of the Birt-Hogg-Dubé gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet. 2007;44(9):588-93.

Murakami T, Sano F, Huang Y, et al., Identification and characteristic of Birt-Hogg-Dubé associated with renal carcinoma. J Pathol. 2007;211(5):524-31.

Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dubé syndrome. Clinicopathologic findings and genetic alterations. Arch Pathol Lab Med. 2006;130(12):1865-70.

Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005;76(6):1023-33.

Schaffer JV, Gohara MA, McNiff JM, et al. Multiple facial angiofibromas: a cutaneous manifestation of Birt-Hogg-Dubé syndrome. J Am Acad Dermatol. 2005;53(2 Suppl 1):S108-11.

Vincent A, Farley M, Chan, E, James WD. Birt-Hogg-Dubé syndrome: a review of the literature and the differential diagnoses of firm facial papules. J Am Acad Dermatol. 2003;49(4):698-705.

Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, Walther M, Choyke P, Weirich G, Hewitt SM, Duray P, Gabril F, Greenberg C, Merino MJ, Toro J, Linehan WM. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393-400.

Nickerson ML, Warren MB, Toro JR, et al. 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-Dubé syndrome. Cancer Cell. 2002;2(2):157-64.

Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113(12):1674-7.

INTERNET

Birt-Hogg-Dubé Syndrome (PDQ®)–Health Professional Version. National Cancer Institute. October 30, 2023. https://www.cancer.gov/publications/pdq/information-summaries/genetics/bhd-syndrome-hp-pdq#_341 Accessed Dec 19, 2024.

Sattler EC, Steinlein OK. Birt-Hogg-Dubé Syndrome. 2006 Feb 27 [Updated 2024 Dec 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1522/ Accessed Dec 19, 2024.

Buckley KK, Bongiorno M. Birt-Hogg-Dubé Syndrome. Medscape. July 22, 2021. https://emedicine.medscape.com/article/1060579-overview Accessed Dec 19, 2024.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Birt-Hogg-Dube Syndrome; BHD. Entry No: 135150. Last Edited: 02/29/2024. Available at: https://omim.org/entry/135150 Accessed Dec 19, 2024.

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