Birt-Hogg-Dubé Syndrome: Expert Review on Pathophysiology, Imaging, and Clinical Management (FLCN Gene, Renal Cancer, and Lung Cysts Explained)

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 Keywords: Birt-Hogg-Dubé syndrome, BHD syndrome, FLCN gene, renal cell carcinoma, fibrofolliculoma, lung cysts, spontaneous pneumothorax, hereditary renal cancer, rare genetic disorder

Introduction

Birt-Hogg-Dubé Syndrome (BHD) is a rare autosomal dominant hereditary disorder characterized by benign skin tumors (fibrofolliculomas), multiple pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal neoplasms. First described by Birt, Hogg, and Dubé in 1977, BHD syndrome is caused by pathogenic variants in the FLCN (Folliculin) gene located on chromosome 17p11.2. Despite being classified as a rare disease, the true prevalence is likely underestimated due to its subtle and heterogeneous manifestations.

This article provides a comprehensive and updated review of Birt-Hogg-Dubé syndrome, based on the latest international guidelines and recent peer-reviewed literature, including its pathophysiology, epidemiology, clinical presentation, imaging features, differential diagnosis, treatment, and prognosis. All information and interpretations are structured for medical professionals and radiology board examinees seeking an expert-level understanding.

Pathophysiology

Birt-Hogg-Dubé syndrome results from germline mutations in the FLCN gene, which encodes folliculin, a tumor suppressor protein involved in regulating cell growth, metabolism, and mitochondrial function.

Molecular Mechanism

The FLCN protein interacts with FNIP1 and FNIP2 (folliculin-interacting proteins) to form a complex that modulates the AMPK–mTOR signaling pathway, a central regulator of cellular proliferation, autophagy, and energy metabolism. Loss of folliculin function disrupts this regulation, leading to abnormal cell growth and predisposition to tumor development.

  • mTOR pathway dysregulation → uncontrolled cell proliferation

  • Increased oxidative stress → cystic degeneration in lung parenchyma

  • Impaired autophagy → accumulation of abnormal cells in renal and cutaneous tissues

This loss of function predisposes to benign and malignant lesions, particularly in the skin, kidneys, and lungs.

Epidemiology

Although BHD syndrome is categorized as a rare disorder, underdiagnosis is common due to its variable and often mild clinical manifestations.

  • Inheritance: Autosomal dominant

  • Gender distribution: Equal in males and females

  • Typical onset: Third to fifth decade of life

  • Prevalence: Estimated at approximately 2 cases per 1 million globally, though higher rates are reported in Asian populations.

A nationwide study from South Korea (Lee et al., 2022) identified a prevalence of 5.67 cases per 10 million, with a median age at diagnosis of 51 years.

Because pulmonary cysts or spontaneous pneumothorax often appear earlier than renal tumors, many patients remain undiagnosed until incidental imaging findings or genetic testing reveal the condition.

Clinical Presentation

BHD syndrome exhibits pleiotropic manifestations that vary widely between individuals, even within the same family. The three primary systems involved are cutaneous, pulmonary, and renal.

1. Cutaneous Manifestations

Approximately 80% of patients develop fibrofolliculomas, benign follicular tumors appearing as small, dome-shaped papules.

  • Typical distribution: Central face, nose, and upper trunk

  • Age of onset: Third to fourth decade

  • Associated lesions: Trichodiscomas and acrochordons (skin tags)

These skin lesions are pathognomonic for BHD and serve as valuable diagnostic clues, though their absence does not exclude the disease.

2. Pulmonary Manifestations

Pulmonary cysts are one of the hallmark findings in BHD syndrome, seen in over 80% of affected individuals.

  • Location: Basal and medial lung regions (lower and mid zones predominate)

  • Shape: Irregular or lentiform (lens-shaped), often thin-walled

  • Complication: Spontaneous pneumothorax (≈ 50-fold increased risk compared to the general population)

  • Median age of pneumothorax: Around 38 years

Pneumothorax may be recurrent and bilateral. Importantly, cysts in BHD typically spare the lung apices, distinguishing them from other diffuse cystic lung diseases.

3. Renal Manifestations

Renal tumors represent the most clinically significant complication due to their potential malignancy.

  • Incidence: Lifetime risk ~25–35%

  • Age of onset: Mean age ≈ 50 years

  • Common histologic types:

    • Chromophobe renal cell carcinoma (RCC)

    • Hybrid oncocytic/chromophobe tumors

    • Oncocytoma

    • Clear cell and papillary RCC (less frequent)

Tumors are often bilateral, multifocal, and slow-growing. Because of this indolent course, nephron-sparing surgery (partial nephrectomy) is preferred over radical nephrectomy to preserve renal function.

Imaging Features

Radiologic evaluation plays a critical role in identifying BHD and differentiating it from other cystic or neoplastic conditions.

1. Renal Tumors

Figure 1. Axial CT showing renal tumor (right anterior kidney, 1 cm lesion).


Figure 2. Sagittal CT (arterial phase) illustrating peritumoral vascular anatomy.


Figure 3. Coronal CT showing bilateral kidneys with focal right renal mass.

These findings are typical for BHD-related renal neoplasms—multifocal, bilateral, and small (<3 cm). Contrast-enhanced CT or MRI reveals well-defined enhancing lesions, frequently with mixed attenuation corresponding to hybrid oncocytic–chromophobe histology.

2. Pulmonary Cysts

Figure 4. Sagittal lung window CT showing cystic changes in both lungs.


Figure 5. Axial lung CT (initial study) revealing multiple thin-walled cysts.


Figure 6. Axial lung CT (5 years later) showing mild progression in cyst number and size.


Figure 7. Sagittal CT (5 years later) demonstrating lentiform cyst formation.


Figure 8. Coronal MinIP lung image showing distribution of pulmonary cysts.

Typical Imaging Features of BHD Lung Cysts:

  • Multiple, thin-walled, air-filled cysts

  • Basal and subpleural predominance

  • Lentiform or irregular shape

  • Often adjacent to interlobular fissures or vessels

  • Absence of nodules or significant ground-glass opacity

These imaging findings are distinctive from other diffuse cystic lung diseases such as LAM and PLCH, as discussed below.

Differential Diagnosis

Differentiating BHD from other causes of diffuse lung cysts or hereditary renal cancers is essential for accurate management and genetic counseling.

ConditionTypical FindingsKey Differences from BHD
LAM (Lymphangioleiomyomatosis)Diffuse, evenly distributed lung cysts, chylous effusions, angiomyolipomasOccurs almost exclusively in women; cysts involve all lung zones without sparing; associated with TSC1/TSC2 mutations
PLCH (Pulmonary Langerhans Cell Histiocytosis)Irregular cysts and nodules, upper lobe predominance, smoking historyBHD has basal predominance and lacks nodules
EmphysemaCentrilobular or paraseptal airspace destructionNo discrete thin-walled cysts; lacks renal or skin involvement
Marfan Syndrome and Ehlers-Danlos SyndromeBullae formation and spontaneous pneumothoraxAbsence of FLCN mutation or renal tumors
Tuberous Sclerosis ComplexCortical tubers, AMLs, seizuresDifferent genetic cause (TSC1/TSC2); brain involvement typical

Treatment and Management

Optimal care of BHD requires a multidisciplinary approach, including nephrology, pulmonology, dermatology, and genetics.

1. Renal Surveillance and Management

  • Nephron-sparing surgery (partial nephrectomy) is the treatment of choice for tumors ≥3 cm.

  • Active surveillance is appropriate for smaller lesions (<3 cm) due to slow growth.

  • Imaging surveillance: Begin in early adulthood (around 20 years) using MRI every 12–24 months.

  • Goal: Preserve renal function and prevent metastasis.

2. Pulmonary Management

  • Pneumothorax management: Early pleurodesis is recommended to reduce recurrence risk.

  • Avoidance of barotrauma risks: Scuba diving, unpressurized air travel, or activities with sudden pressure changes.

  • Preventive care: Vaccination (influenza, pneumococcal) and smoking cessation.

3. Dermatologic Management

  • Treatment options: CO₂ laser ablation, electrocautery, cryotherapy, or surgical excision.

  • Lesions often recur; cosmetic counseling and psychological support may be beneficial.

4. Genetic Counseling

  • Family screening: FLCN gene testing for first-degree relatives.

  • Benefits: Enables early detection, preventive imaging, and informed reproductive decisions.

Prognosis

The prognosis for most BHD patients is favorable if managed properly.

  • Renal tumors: Typically indolent, with slow progression and low metastatic potential if detected early.

  • Pulmonary cysts: Usually stable; however, recurrent pneumothorax can impact quality of life.

  • Life expectancy: Comparable to the general population with regular surveillance and appropriate surgical management.

Quiz

Question 1. (Disease Characteristics)

A 51-year-old woman presents with a right renal 1 cm mass and multiple thin-walled pulmonary cysts on CT. Which of the following statements about Birt-Hogg-Dubé syndrome is incorrect?

A. It is an autosomal dominant genetic disorder.
B. It results from mutations in the FLCN gene that interact with the mTOR pathway.
C. Renal tumors are commonly bilateral and multifocal with chromophobe histology.
D. Pulmonary cysts predominantly involve the upper lobes of the lungs.
E. The most typical cutaneous lesion is fibrofolliculoma on the central face.

Question 2. (Imaging Features)

Which CT finding best describes pulmonary involvement in BHD syndrome?

A. Thick-walled cysts with homogeneous internal fluid.
B. Diffuse cysts without spared regions, upper lobe predominance.
C. Thin-walled air cysts, bilateral distribution, subpleural or fissural, sometimes lentiform in shape.
D. Ground-glass opacities surrounding cysts.
E. Mediastinal lymphadenopathy accompanying cysts.

Question 3. (Management Principles)

Which is the most important long-term management principle for BHD patients?

A. Observe renal tumors only when symptomatic.
B. Excise all skin lesions due to malignant potential.
C. Perform prophylactic bilateral pleurodesis in all patients.
D. Begin lifelong renal MRI surveillance from early adulthood and consider nephron-sparing surgery for significant lesions.
E. Skip genetic testing because FLCN variants do not affect prognosis.

Answer & Explanation

1. Answer: D. Explanation: BHD pulmonary cysts predominantly affect the lower and middle lung zones, not the upper lobes.

2. Answer: C. Explanation: BHD cysts are thin-walled, bilateral, and often subpleural or lentiform, distinguishing them from LAM or PLCH.

3. Correct Answer: D. Explanation: Lifelong renal imaging (preferably MRI) is vital to detect early renal tumors and enable nephron-sparing surgery. Genetic testing is essential for family risk assessment.

Conclusion

Birt-Hogg-Dubé syndrome exemplifies a multi-organ hereditary disorder where radiologic insight plays a pivotal role in early detection and prevention of complications. Recognizing its characteristic pulmonary cysts, renal neoplasms, and cutaneous papules is essential for timely genetic diagnosis.

With recent advancements in molecular genetics and surveillance protocols, BHD patients can achieve excellent long-term outcomes when managed within a multidisciplinary framework emphasizing renal preservation and pulmonary protection.

References

[1] M. Geilswijk et al., “ERN GENTURIS clinical practice guidelines for the diagnosis, surveillance and management of people with Birt-Hogg-Dubé syndrome,” Eur. J. Hum. Genet., vol. 33, pp. 27–42, Jul. 2024.
[2] H. S. Lee et al., “Epidemiology and clinical features of Birt-Hogg-Dubé syndrome: A nationwide population-based study in South Korea,” PLOS One, vol. 17, no. 7, e0269358, Jul. 2022.
[3] National Cancer Institute, “Birt-Hogg-Dubé Syndrome (PDQ®) – Health Professional Version,” NCI, Dec. 2024. [Online]. Available: https://www.cancer.gov/publications/pdq/information-summaries/genetics/bhd-syndrome-hp-pdq
[4] D. L. Al-Jafar et al., “Birt-Hogg-Dubé Syndrome,” StatPearls, NCBI Bookshelf, Jul. 2025.
[5] M. T. N. R. F. et al., “Birt–Hogg–Dubé syndrome: Clinicopathological features of the lung,” J. Clin. Pathol., vol. 66, no. 3, pp. 178–182, Mar. 2013.
[6] Radiopaedia.org, “Birt-Hogg-Dubé Syndrome,” Radiopaedia, Aug. 2025.
[7] L. N. Lim et al., “Birt-Hogg-Dubé Syndrome,” GeneReviews®, NCBI Bookshelf, Feb. 2006.
[8] A. G. M. L. S. T. et al., “Birt–Hogg–Dubé syndrome,” Eur. Respir. Rev., vol. 29, no. 157, 200042, Dec. 2020.

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