Makiko Kunogi

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

Background Birt–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. Objectives BHDS 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. Conclusions BHDS 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.

Characteristics of pulmonary cysts in Birt–Hogg–Dubé syndrome: Thin-section CT findings of the chest in 12 patients

PURPOSE To describe in detail the characteristic chest computed tomography (CT) findings of Birt-Hogg-Dubé (BHD) syndrome. MATERIALS AND METHODS Thin-section chest CT scans of consecutive 12 patients with genetically diagnosed BHD syndrome were retrospectively evaluated by two observers, especially about the characteristics (distribution, number, size, shape and relation to pleura) of pulmonary cysts. Interobserver agreement in the identification of abnormalities on the CT images was achieved using the κ statistic, and the degree of interobserver correlation for the characterization of pulmonary cysts was assessed using the Spearman rank correlation coefficient. RESULTS Multiple pulmonary cysts were seen in all patients. The number of cysts in each patient was various (range, 29-407), and cysts of various sizes (from a few mm to 2 cm or more) were seen in all patient. 76.6% (mean) of cysts were irregular-shaped, and 40.5% (mean) of cysts were located along the pleura. The mean extent score of cysts was 13% of the whole lung, and the distribution of cysts was predominantly in the lower medial zone. Finally, cysts abutting or including the proximal portions of lower pulmonary arteries or veins were also seen in all patients. CONCLUSION Multiple, irregular-shaped cysts of various sizes with lower medial lung zone predominance are characteristic CT findings of BHD syndrome. Cysts abutting or including the proximal portions of lower pulmonary arteries or veins may also exist in this syndrome in a high probability.

Characterization of pulmonary cysts in Birt–Hogg–Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients

To characterize the pathological features of pulmonary cysts, and to elucidate the possible mechanism of cyst formation in the lungs of patients with Birt–Hogg–Dubé syndrome (BHDS), a tumour suppressor gene syndrome, using histological and morphometric analyses.

Bronchial involvement in advanced stage lymphangioleiomyomatosis: histopathologic and molecular analyses.

Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells.