Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt–Hogg–Dubé syndrome

Abstract

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic disorder characterized by fibrofolliculomas, pulmonary cysts and renal cell carcinomas (RCCs). The affected individuals inherit germline mutations in the folliculin gene (FLCN). We investigated the mutation spectrum and clinicopathologic findings of 312 patients from 120 different families (119 Japanese and 1 Taiwanese). A total of 31 different FLCN sequence variants were identified. The majority were c.1285dupC (n = 34), c.1533_1536delGATG (n = 25), and c.1347_1353dupCCACCCT (n = 19). Almost all patients presented with pulmonary cysts. The incidence of RCCs in FLCN mutation carriers over the age of 40 was 34.8% (40/115). Fifty-five RCC lesions were surgically resected; most were either chromophobe RCC (n = 24; 43.6%) or hybrid oncocytic/chromophobe tumors (19; 34.5%). Seventy-six of 156 FLCN mutation carriers (120 probands and 36 sibs, 48.7%) had skin papules; however, cutaneous manifestations were so subtle that only one patient voluntarily consulted dermatologists. Japanese Asian BHD families have three FLCN mutational hotspots. Recurrent episodes of pneumothoraces are the major symptoms suggestive of a BHD diagnosis in our cohort. Characteristic features of lung and kidney lesions may be more informative than fibrofolliculomas as diagnostic criteria for BHD in the Japanese Asian population.

Birt-Hogg-Dubé syndrome: awareness is important!

“…It is caused by a mutation in the FLCN gene, with over than 30 variants described6; FLCN is a tumourous suppressor gene located on the short arm of chromosome 17 at position 11.2 that, through interaction with its partners FNIP1 and FNIP2, has a major role in metabolic pathways like activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) 7…”

“…RCCs are normally solitary lesions6 and histologically are mainly of the chromophobe, oncocytic or hybrid oncocytoma–chromophobe subtypes, with less frequent cases of clear cell and papillary subtypes 3 5 6…”

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

“…The risk of pneumothorax is estimated to be 50-fold higher than in the general population [153]. However, the prevalence rates of spontaneous pneumothorax vary considerably depending on the cohorts analyzed [155], ranging from 23–38% in renal/dermatologic cohorts [43, 132, 153, 156, 157] to 42–76% in pulmonary cohorts [151, 158, 159]. In three large cohorts, the mean age at occurrence of the first pneumothorax was between 36 and 38 years [43, 156, 159].…”

“…Although some studies have reported the occurrence of lung adenocarcinoma, atypical adenomatous hyperplasia, or micronodular pneumocyte hyperplasia-like lesions in patients with BHD [144, 151, 163, 166], no association with pulmonary neoplasms has been formally established so far.…”

“…The prevalence of renal tumors is approximately 30% [132, 151, 153, 157, 173], with a 7-fold increased risk of developing renal cancer compared to unaffected family members [153]. The mean age at presentation is 50 years (range 31–74) [173], but it has been reported in a 20-year-old patient [167].…”