Novel folliculin gene mutations in Polish patients with Birt–Hogg–Dubé syndrome

Abstract

Background Birt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS. Materials and methods The first case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 families have been identified. Thirteen patients were confirmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations. Results BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of first pneumothorax and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respectively. Five patients (33%) were ex-smokers (2.1 ± 1.37 packyears), and 10 (67%) had never smoked cigarettes. Twelve patients (83%) had a history of recurrent symptomatic pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Different mutations of the FLCN gene were identified (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41). Conclusions All analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identified.

Epidemiology and clinical features of Birt-Hogg-Dubé syndrome: A nationwide population-based study in South Korea

“…This study has some limitations. Considering that it used a nationwide medical claims database, BHD syndrome without FLCN gene mutation is not included in our dataset, thereby possibly omitting approximately 10% of patients with BHD syndrome [ 30 ]. Our study also did not include those with a family history of BHD syndrome and FLCN gene mutation, thereby reducing the representation of genetic features.…”

High-Resolution Computed Tomography of Cystic Lung Disease

“…99 The use of CT has been reported to diagnose small asymptomatic pneumothoraces in 20% (3/15) of BHD patients. 92 Pulmonary cysts in BHD syndrome may develop prior to skin or renal manifestations.…”

“…1,91 BHD is caused by a variety of FLCN gene mutations resulting in abnormal folliculin protein (FLCN). 92,93 Lung involvement is commonly the earliest manifestation of BHD syndrome, although it is often initially asymptomatic. 94 In 30% of patients, pulmonary cysts may be the only abnormality at presentation.…”

Birt-Hogg-Dube syndrome coexisting with bullous pemphigoid and basal cell carcinoma

“…Frequency of the syndrome in the general population is estimated at about 2 cases per million [13]. According to the available literature data, the Polish population of patients diagnosed with BHDS consists of 15 patients from 10 families [14].…”