Birt Hogg Dube Syndrome


Article Author:
Jonathan Crane
Veronica Rutt


Article Editor:
Amanda Oakley


Editors In Chief:
Dustin Constant
Donald Kushner


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
4/21/2019 9:35:52 PM

Introduction

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis usually manifesting in the third decade of life with multiple fibrofolliculomas, trichodiscomas, and acrochordons. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, and spontaneous pneumothorax.[1][2][3][4]

Etiology

A germline mutation of FLCN, which encodes the tumor-suppressor folliculin, is responsible and is located on chromosome 17p11.2. Multiple distinct mutations have been identified. Folliculin is thought to be a tumor suppressor, but its exact function is unknown. FLCN has been linked to the mTOR pathway.[5]

Epidemiology

Birt-Hogg-Dubé syndrome is rare. It occurs in males and females. Patients usually present for the first time during young adult life.

Pathophysiology

Mutations lead to loss of function of folliculin. Abnormal folliculin is thought to result in the production of tumors in susceptible organs such as skin and kidney.

Histopathology

In fibrofolliculomas, there is a fibrous pink orb or amphophilic fibro mucinous orb with epithelial strands (sometimes in an anastomosing pattern) radiating outward from a central follicle-like structure. The strands of epithelium are not differentiated well enough to form hair fibers. Furthermore, the hair bulb inner or outer root sheath is not present.

History and Physical

Characteristic lesions of BHDS are described as multiple, two to four millimeter, waxy, white, dome-shaped papules, that are most frequently found on the nose and cheeks. They also may be present on the ears, neck, and trunk. Expression ranges from a few localized lesions to several hundred. Histopathologically, they are benign hair follicle tumors known as trichodiscomas or fibrofolliculomas. For many years, experts have argued that fibrofolliculomas, trichodiscomas, and acrochordons in patients with BHDS may be variations of the same lesion. Trichodiscomas and fibrofolliculomas are indistinguishable on clinical examination. Some authors have shown that deeper histopathologic sections reviewed on lesions, initially called trichodiscomas, showed characteristics of fibrofolliculomas only. Furthermore, some experts argue that the proliferative epithelial components that are specific to fibrofolliculomas may only be observed in horizontal sectioning. Acrochordons, known as skin tags, are common in the general population. In BHDS, acrochordons might represent a phenotypic variant of fibrofolliculomas. Although it remains controversial, these three tumors often are considered to be part of a morphological spectrum.[6][7][8][9]

Other cutaneous manifestations of BHDS include soft papules of the lips, gingiva, and buccal mucosa, connective tissue nevi, lipomas, angiolipomas, acrochordons, and facial angiofibromas. Patients with BHDS also have been found with other systemic manifestations such as medullary thyroid cancer, thyroid adenomas, parotid oncocytomas, basal lung cysts and parathyroid adenomas. It was once thought that BHDS confers an increased development of colonic polyps and other tumors. However, studies have shown that there is no association. Given the varied expression of the syndrome, patients often may be undiagnosed. They may present with renal cancer or a spontaneous pneumothorax, both of which often occur sporadically and may not prompt physicians to look for an underlying genetic defect.

Evaluation

In 2009, Menko et al. published diagnostic criteria for BHDS. One major or two minor criteria are needed for diagnosis (Table 1). Major criteria include (1) at least five fibrofolliculomas or trichodiscomas and at least one histologically confirmed and of adult onset, and/or (2) pathogenic FLCN germline mutation. Negative FLCN gene testing does not exclude the diagnosis as up to 40% of patients with negative testing still meet diagnostic criteria. Minor criteria include (1) multiple lung cysts, which are bilateral and basally located, (2) renal cancer before the age of 50 years, or multifocal or bilateral renal cancer, or of mixed chromophobe and oncocytic histology, and (3) a first-degree relative with BHDS. Multifocal or bilateral renal cancer with hybrid chromophobe and oncocytic histology is a hallmark of BHDS. Furthermore, the mixed pattern of chromophobe cancer and oncocytoma is typical and unique to BHDS.

Chest x-ray and high-resolution chest computed tomography (CT) scans are used to assess pulmonary cysts. Abdominal CT or magnetic resonance imaging (MRI) can be used to assess the kidneys.

Treatment / Management

Treatment for BHDS skin lesions includes destruction by electrocautery, curettage, and laser ablation, but is often followed by recurrence. Because folliculin has been implicated in the mTOR pathway, medications such as rapamycin, a mTOR inhibitor, have theoretical application in the treatment of Birt-Hogg-Dubé lesions. In animal models using BHDS-condition knock-out mice, rapamycin decreased kidney pathology and increased overall survival. However, a double-blind, randomized facial left-right controlled trial in 2014 by Gijezen et al. using topical rapamycin revealed no significant difference in the treatment of fibrofolliculomas. The exact function of folliculin has yet to be elucidated.

Patients with BHDS are at increased risk of developing renal tumors lifelong, with an average age of onset at 50 years. Lifelong renal surveillance should begin at the age of twenty. Some experts recommend initial MRI followed by annual MRI or ultrasound, while others suggest CT scans every 3 to 5 years. There is also a risk for pneumothoraces, which occur in 25% of patients during the third to sixth decades. Ninety percent of adult patients will show radiographic evidence of lung cysts. Patients should be counseled on pneumothorax symptoms and a high baseline resolution CT of the chest should be performed with follow-up scans every 3 to 5 years. There is no data to support the idea that patients with BHDS should be advised against air travel. However, they should be counseled on smoking cessation to prevent pneumothoraces. Additionally, a full-body skin examination at routine intervals to evaluate for suspicious pigmented lesions should be implemented since there may be an association between malignant melanoma and BHDS.

Differential Diagnosis

Firm, dome-shaped papules present on the head and neck in several other syndromes. Multiple hamartoma syndromes (Cowden Syndrome) presents with multiple trichilemmomas on the face, neck, and ears. It has an autosomal dominant inheritance and also is associated with oral papillomas which create a cobblestone surface texture on the lips and mucosa. They also may have acral keratoses and cardiomegaly. Hornstein-Knickenberg syndrome (HKS) is in the differential diagnosis as well, which is also autosomal dominant and characterized by cutaneous, flesh-colored papules or perifollicular fibromas but is further differentiated by a propensity for colonic neoplasms and polyps. Some experts also argue that perifollicular fibromas are the same lesions of BHDS but cut in different section planes and that HKS and BHDS are on the spectrum of disease. Similarly, tuberous sclerosis and Brooke-Spiegler also can present with flesh-colored papules. Tuberous sclerosis, due to a defect in TSC-1 or TSC-2 gene, presents with angiofibroma, collagenomas, hypopigmented macules, and periungual fibromas. Angiofibromas also can occur in BHDS but are a less prominent feature. Additionally, they can have overlap features of fibrofolliculomas. Brooke-Spiegler syndrome results from a defect in the CYLD gene, and patients present with spiradenomas, trichoepitheliomas, and cylindromas. Trichoepitheliomas are firm, flesh-colored nodules that concentrate on the nasolabial folds, nose, upper lip, and scalp. Basaloid follicular hamartoma syndrome also presents with similar flesh-colored lesions; however, they gradually become pinker in color and plaque-like. Biopsy of the lesions and obtaining a thorough review of systems, past medical history, and family history often can provide clues to narrow the differential diagnosis of flesh-colored papules on the face.

Lung cysts and pneumothorax may also occur in lymphangioleiomyomatosis, emphysema and pulmonary Langerhans cell histiocytosis. Renal tumors are features of von Hippel-Lindau syndrome and hereditary leiomyomatosis. Most pneumothoraces and renal carcinomas are sporadic.

Pearls and Other Issues

Genetic testing and counseling should be offered to near relatives older than the age of 20 years.

Enhancing Healthcare Team Outcomes

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis usually manifesting in the third decade of life with multiple fibrofolliculomas, trichodiscomas, and acrochordons. Because of the risk of malignancies later in life these patients are best managed by a multidisciplinary team that includes a geneticist, pulmonologist, thoracic surgeon, dermatologist, urologist and an internist. The patients need to be educated by the primary care provider and nurse practitioner to avoid smoking and have regular imaging studies to detect cystic/solid lesions. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, and spontaneous pneumothorax. Caution against air travel should be exercised.[10]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Birt Hogg Dube Syndrome - Questions

Take a quiz of the questions on this article.

Take Quiz
A 50-year-old male presented to the office complaining of skin tags in the groin. He stated that they would catch on his clothing. They had begun in the third decade of his life. He had been told that the tags are genetic and are associated with an autosomal dominant genodermatosis. He has a history of hypertension, diabetes, and spontaneous pneumothorax. Upon examination, there were numerous flesh-colored pedunculated lesions, axilla, and groin. Which of the following cancers is associated with the patient's underlying disorder?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 42-year-old male presented complaining of difficulty urinating at times. He stated that his urine looked dark. He has a history of lung cysts, spontaneous pneumothorax, multiple fibrofolliculomas, trichodiscomas, and acrochordons. Upon exam, there was blood in his urine. Which of the following carcinoma is most likely seen with patient's underlying diagnosis?

(Move Mouse on Image to Enlarge)
  • Image 5872 Not availableImage 5872 Not available
    Contributed by DermNetNZ
Attributed To: Contributed by DermNetNZ



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 41-year-old male presented complaining of sudden shortness of breath. He had a history of lung cysts, multiple fibrofolliculomas, trichodiscomas, acrochordons, and a thyroid adenoma. His respiratory rate was 40/min. Which of the following is the most likely cause of the patient's dyspnea?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 37-year-old white male presented to the clinic complaining of skin tags under the arms and fatty tumors along the arms. He has a history of lung cysts and diabetes. He was told that he has a rare genetic disorder that is inherited in an autosomal dominant fashion. Which of the following is commonly seen in association with a germline mutation which encodes the tumor-suppressor folliculin?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 16-year-old female presents to the dermatology office with the concerns of multiple, firm, white papules clustered on her low back that she first noticed several months ago. They are asymptomatic and not changing. She has no other medical conditions but does report that her father has similar lesions on his nose and neck as well as a family history of renal cell carcinoma. Which of the following genes may possibly be responsible for her condition?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Birt Hogg Dube Syndrome - References

References

Xu WS,Tian XL,Yang YL,Xu KF, [Birt-Hogg-Dubé syndrome: a hereditary pulmonary cystic disease]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases. 2019 Apr 12;     [PubMed]
Sakuraba M,Yamasaki H,Kusudo S,Tanaka A, [Birt-Hogg-Dubé Syndrome Incidentally Found at Surgery for Idiopathic Hemopneumothorax;Report of a Case]. Kyobu geka. The Japanese journal of thoracic surgery. 2019 Mar;     [PubMed]
Escalon JG,Richards JC,Koelsch T,Downey GP,Lynch DA, Isolated Cystic Lung Disease: An Algorithmic Approach to Distinguishing Birt-Hogg-Dubé Syndrome, Lymphangioleiomyomatosis, and Lymphocytic Interstitial Pneumonia. AJR. American journal of roentgenology. 2019 Mar 19;     [PubMed]
Inoue M,Miyazaki S,Kuno Y,Ishida J,Ikeda T, Birt-Hogg-Dubé syndrome in the elderly. Journal of general and family medicine. 2019 Mar;     [PubMed]
Kobayashi K, Incidental detection of asymptomatic pneumothorax resulting in a diagnosis of Birt-Hogg-Dubé syndrome. BMJ case reports. 2019 Jan 28;     [PubMed]
Park HJ,Chae EJ,Do KH,Lee SM,Song JW, Differentiation Between Lymphangioleiomyomatosis and Birt-Hogg-Dubé Syndrome: Analysis of Pulmonary Cysts on CT Images. AJR. American journal of roentgenology. 2019 Apr;     [PubMed]
Johannesma PC,van de Beek I,van der Wel TJWT,Reinhard R,Rozendaal L,Starink TM,van Waesberghe JHTM,Horenblas S,Gille HJJP,Jonker MA,Meijers-Heijboer HEJ,Postmus PE,Houweling AC,van Moorselaar JRA, Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome. PloS one. 2019;     [PubMed]
Furuya M,Nakatani Y, Pathology of Birt-Hogg-Dubé syndrome: A special reference of pulmonary manifestations in a Japanese population with a comprehensive analysis and review. Pathology international. 2019 Jan;     [PubMed]
Peng YC,Chen YB, Recognizing Hereditary Renal Cancers Through the Microscope: A Pathology Update. Surgical pathology clinics. 2018 Dec;     [PubMed]
Wajda N,Gupta N, Air Travel-Related Spontaneous Pneumothorax in Diffuse Cystic Lung Diseases. Current pulmonology reports. 2018 Jun;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Surgery-Podiatry Cert Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Surgery-Podiatry Cert Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Surgery-Podiatry Cert Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Surgery-Podiatry Cert Medicine. When it is time for the Surgery-Podiatry Cert Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Surgery-Podiatry Cert Medicine.