Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature

Abstract

BackgroundBirt–Hogg–Dubé syndrome (BHDS) is an inherited autosomal genodermatosis characterised by fibrofolliculomas of the skin, renal tumours and multiple lung cysts. Genetic studies have disclosed that the clinical picture as well as responsible germline FLCN mutations are diverse.ObjectivesBHDS may be caused by a germline deletion which cannot be detected by a conventional genetic approach. Real-time quantitative polymerase chain reaction (qPCR) may be able to identify such a mutation and thus provide us with a more accurate clinical picture of BHDS.Methods This study analysed 36 patients with multiple lung cysts of undetermined causes. Denaturing high performance liquid chromatography (DHPLC) was applied for mutation screening. If no abnormality was detected by DHPLC, the amount of each FLCN exon in genome was quantified by qPCR.Results An FLCN germline mutation was found in 23 (63.9%) of the 36 patients by DHPLC and direct sequencing (13 unique small nucleotide alterations which included 11 novel mutations). A large genomic deletion was identified in two of the remaining 13 patients by qPCR (one patient with exon 14 deletion and one patient with a deletion encompassing exons 9 to 14). Mutations including genomic deletions were most frequently identified in the 3′-end of the FLCN gene including exons 12 and 13 (13/25=52.0%). The BHDS patients whose multiple cysts prompted the diagnosis in this study showed a very low incidence of skin and renal involvement.ConclusionsBHDS is due to large deletions as well as small nucleotide alterations. Racial differences may occur between Japanese and patients of European decent in terms of FLCN mutations and clinical manifestations.

Clinical and genetic study of a large Chinese family presented with familial spontaneous pneumothorax

“…However, further prospective trials are warranted to guide the choice of treatment. Renal cancer is the most life-threatening complication in BHD syndrome, with a reported range of prevalence from 6.5% to 34% (9,26,29). Hence, we recommend annual screening for early detection of renal neoplasm in such patients.…”

Autosomal Recessively Inherited Familial Primary Spontaneous Pneumothorax: A Large Family with Frequent Consanguineous Marriages

“…5,7,8,11 One of the major restrictions of our study is that the molecular genetic analysis of this gene was not performed on our cases with FPSP. Investigating the hereditary mutations in FLCN gene in these cases and their families in prospective studies may contribute to understanding the cause of FPSP that develops within this large family circle that has frequent consanguineous marriages.…”

“…[6][7][8][9][10][11]13 This can be explained as follows: It was reported by the individuals in this family while their family tree (genealogical research) was being formed that the women in this family circle had suffered from a number of miscarriages. However, no precise information could be received about genders of the infants that were lost through the spontaneous abortions.…”

“…5 There is not only genetic but also clinical heterogeneity in FPSP. [6][7][8] The clinical picture of the disease may come to light through the combinations of different organ and system involvements. 8 Although Koivisto and Mustonen reported that the autosomal recessive inheritance was responsible for the 2 cases with FPSP, most researchers hold the idea that the autosomal dominant inheritance responsible for FPSP.…”

Pneumothorax Developing for the First Time in a 73-year-old Woman Diagnosed with Birt-Hogg-Dubé Syndrome

“…Growing evidence indicates that BHDS exhibits diverse clinical heterogeneity and is not always associated with three characteristic phenotypes (involvement of the skin, kidneys and lungs) (1,5). A study by Toro et al found that 89% (177/198) of patients with BHDS had lung cysts on chest CT images, while 24% (48/198) had a history of pneumothorax, with a median age at first occurrence of 38 years (range: 22-71) (6).…”