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Clin Genet. 2016 Nov;90(5):403-412. doi: 10.1111/cge.12807. Epub 2016 Jun 30.

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

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Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Medical Mycology Research Center, Chiba University, Chiba, Japan.
Department of Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.
Department of Diagnostic Pathology, Kochi Red Cross Hospital, Kochi, Japan.
International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
Department of Diagnostic Pathology, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba, Japan.


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; FLCN; Japanese Asian cohort; epidemiology; germline mutation

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