Furuya et al. (2016) present a new study describing genetic, epidemiologic and clinicopathologic features of 312 Asian individuals with BHD manifestations based on data from 120 probands from different families (119 Japanese and 1 Taiwanese), 36 siblingss with genetic testing and 156 siblings without genetic testing.
Among the 120 probands that were grouped as ‘Possible BHD’ due to their symptoms, 118 had germline FLCN mutations. In total, 31 different FLCN mutations were identified, fourteen were frameshift type and other types included nonsense, in-frame deletion, missense and splice-site mutations. There were 3 very frequent mutations: a cytosine duplication in a C8 mononucleotide stretch within exon 11 (c.1285dupC), followed by a four-base pair deletion in exon 13 (c.1533_1536delGATG) and a seven-base pair duplication in exon 12 (c.1347_1353dupCCACCCT). The 36 siblings that also received genetic testing were confirmed to have the same mutations as their relatives.Among the 156 FLCN mutation carriers (120+36), 142 had chest CTs and all but one family presented with pulmonary cysts. Among the entire cohort of 312 more than 70 % presented with pneumothorax with initial episodes ranging from 15 to 69 years old.The incidence of RCCs in the FLCN mutation carriers over the age of 40 was 34.8% and the exon 11 mutation (c.1285dupC) exhibited the highest RCC frequency. Most RCC lesions were either chromophobe RCC or hybrid oncocytic/chromophobe tumors. All patients with RCC also presented pulmonary cysts. Of the 312 individuals 19% presented with solid renal masses.Regarding cutaneous manifestations, 48% of the 156 FLCN mutation carriers had skin papules; however, cutaneous manifestations were so subtle that only one patient voluntarily consulted dermatologists.Other manifestations observed in a few patients of the overall study included colorectal cancer (6 patients), lung cancer (13 patients), oncocytic thyroid carcinoma (1 patient) and parotid gland oncocytoma (1 patient).
In summary, recurrent episodes of pneumothorax are the major symptoms suggestive of a BHD diagnosis. Lung and kidney manifestations are more informative as diagnostic criteria for BHD in the Japanese population as the cutaneous manifestations are very subtle.
Yukawa et al. (2016) report the case of a 56-year-old female presenting with a sudden onset of dyspnea. Chest X-ray was performed and confirmed bilateral pneumothorax. She had a history of right pneumothorax occurring at the ages of 37 and 45 years. A computed tomography (CT) scan revealed multiple bilateral thin-walled cysts, predominantly distributed in the basilar regions of the lower lung lobes, however, no tomographic finding was observed in the abdomen. Skin examination revealed multiple but discrete dome shaped skin-coloured papules on the nose and cheek. Family history revealed that the patient’s mother, brother, and sons had also suffered spontaneous pneumothorax. The patient underwent bilateral sequential bullectomy but the left spontaneous pneumothorax recurred twice after the surgery; she was then treated with pleurodesis and cured. The resected lung specimen showed multiple cysts. Molecular analysis revealed a novel deletion mutation (c.57_58delCT) in exon 4 of the FLCN gene and confirmed this case as BHD Syndrome. Authors are planning to perform genetic analysis of family members of the patient and suggested annual screening for renal tumour for the patient and her family.
Further studies using large cohorts are still needed to clarify possible genotype–phenotype correlations in BHD. As novel FLCN mutations are still being identified all over the world, to add to the 152 already listed in LOVD-hosted FLCN mutation database, it is possible that different populations might have different prevalence of symptoms or specific mutations.
- Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, Baba M, Matsushima J, Nomura F, & Nakatani Y (2016). Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dubé syndrome. Clinical genetics, 90 (5), 403-412 PMID: 27220747
- Yukawa T, Fukazawa T, Yoshida M, Morita I, Kato K, Monobe Y, Furuya M, & Naomoto Y (2016). A Case of Birt-Hogg-Dubé (BHD) Syndrome Harboring a Novel Folliculin (FLCN) Gene Mutation. The American journal of case reports, 17, 788-792 PMID: 27780965