ADOPTING ORPHAN DISEASES RARE INTERSTITIAL LUNG DISEASES

adoptingorphandiseaseskapak

BIRT-HOGG-DUBÉ SYNDROME

Orkun Eray Terzi1 Elif Yelda Özgün Niksarlıoğlu2

1Bursa Yüksek İhtisas Training and Research Hospital, Department of Chest Diseases, Bursa, Türkiye
2University of Health Sciences Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, Department of Chest Diseases, İstanbul, Türkiye

Terzi OE, Ozgun Niksarlioglu EY. Birt-Hogg-Dubé Syndrome. In: Altinisik G, McCormack FX, editors. Adopting Orphan Diseases: Rare Interstitial Lung Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.75-89.

ABSTRACT

Birt-Hogg-Dubé (BHD) syndrome is an uncommon autosomal dominant condition that predominantly affects the lungs, kidneys, and skin. The underlying genetic basis involves pathogenic or likely pathogenic mutations in the FLCN gene, which encodes folliculin, a tumor suppressor protein implicated in various intracellular signaling cascades. These mutations disrupt normal folliculin function, leading to a broad clinical phenotype that can vary significantly, even among individuals harboring identical genetic alterations.

Diagnosis is commonly suspected when characteristic findings such as pulmonary cysts, recurrent pneumothorax, cutaneous fibrofolliculomas, and renal neoplasms are identified, either in isolation or in combination. Pulmonary involvement, particularly the development of multiple, bilateral, thin-walled cysts predominantly located in the lower lung zones, is the most frequent clinical manifestation. These cysts are a major contributor to spontaneous pneumothorax, which often serves as a presenting symptom. Skin findings typically include benign dome-shaped papules located on the face or upper body, consistent with fibrofolliculomas or trichodiscomas. Although renal manifestations are less prevalent, they carry greater prognostic significance due to their association with disease-specific mortality. The renal tumor spectrum most commonly comprises chromophobe renal cell carcinoma, oncocytomas, and hybrid oncocytic/chromophobe tumors, although clear cell and papillary subtypes have also been observed.

In the majority of cases, molecular confirmation is achieved through identification of pathogenic germline variants in FLCN. In scenarios where no pathogenic alteration is detected, diagnosis may still be established based on clinical features and typical radiologic findings. The 2024 ERN GENTURIS guideline outlines a multidisciplinary approach to diagnosis and surveillance, integrating clinical, imaging, and molecular assessments.

Currently, there is no curative or disease-specific therapy available for BHD syndrome. Therefore, clinical management emphasizes early recognition, regular monitoring for renal malignancies, and preventive strategies to reduce pneumothorax risk. Given its multisystem nature, lifelong follow-up and a personalized care model are essential. BHD syndrome is thus considered a hereditary cancer predisposition disorder that necessitates coordinated multidisciplinary management.

Keywords: Birt-Hogg-Dubé syndrome; Cystic lung disease; Pneumothorax; Renal cell carcinoma

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