Birt-Hogg-Dubé syndrome in Korean: clinicoradiologic features and long term follow-up

Abstract

Background/aims: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder that is characterized by skin fibrofolliculomas, pulmonary cysts, and renal tumors. The objective of this study was to describe the features of Korean patients with BHD syndrome.

Methods: Clinical data were retrospectively reviewed in 12 patients (10 confirmed by direct sequencing of the folliculin (FLCN) gene and two confirmed by clinical diagnosis) diagnosed from 2004 to 2016 at Asan Medical Center, Seoul, South Korea. Criteria proposed by the European BHD consortium were used for diagnosis.

Results: The median follow-up was 52 months. The mean age was 41.3 years and 66.7% were female. Eight patients (66.7%) had a history of pneumothorax, which was recurrent in 75%. Skin lesions were detected in 25.0% and renal cancer in 25.0%. Among mutations of the FLCN gene, the duplication of cytosine in the C8 tract of exon 11 (c.1285dupC) was the most common (40%); however, a novel heterozygous sequence variant of c.31T>C (p.C11R) in exon 4 was detected in one patient. All patients had multiple and bilateral pulmonary cysts, distributed in predominantly lower, peripheral and subpleural regions of the lungs. Most patients showed preserved lung function that remained unchanged during follow-up, and two (16.7%) developed cancers (renal cancer in one and breast cancer in one).

Conclusion: Our data suggest that Korean patients with BHD syndrome may have a higher risk of pneumothorax, less frequent skin lesions, and a novel FLCN mutation compared to previous reports. Multiple bilateral and basal-predominant cysts were the most common radiologic features.

Keywords: Birt-Hogg-Dube syndrome; Carcinoma, renal cell; FLCN gene; Fibrofolliculoma; Pneumothorax.

Figure 1.

Flow diagram of patient recruitment. Twenty-four suspected patients with clinico-pathologic-radiologic features of Birt-Hogg-Dubé (BHD) syndrome were screened. According to the BHD diagnostic criteria, a total of 12 patients were diagnosed with BHD syndrome; 10 patients were confirmed by folliculin (FLCN) gene mutation analysis and the others by clinical diagnosis.

Figure 2.

Examples of chest computed tomography and histologic findings of the study patients. The pulmonary cysts in Birt-Hogg-Dubé (BHD) are distributed in predominantly lower, peripheral and subpleural regions of the lungs (A: upper lobes; B: lower lobes). Lung specimens present multiple small intraparenchymal cysts rimmed by thin fibrous walls or normal pulmonary parenchyma. (C: ×40; D: ×400).

Figure 3.

Changes in forced vital capacity (FVC) during follow-up. Nine of 12 patients underwent regular pulmonary function test follow-up. Lung function remained almost unchanged during follow-up.