birt - hogg - dub syndrome ( bhds ) is an inherited autosominal dominant genodermatosis that predisposes individuals to the development of fibrofolliculomas ( ff ) , trichodiscomas ( td ) , and acrochordons of the face , neck , and upper trunk ( 1 ) . there is also an increased risk for lung cysts , spontaneous pneumothorax , and renal carcinomas in affected people , and some patients may also develop colorectal polyps and cancers ( 2 - 4 ) . the disease is caused by germline mutations in the bhd ( also known as flcn ) gene located in 17p11.2 encoding folliculin , a new protein with unknown function ( 5 ) . we report a patient with bhds in which mutation analysis subsequently revealed a novel mutation . a 31-yr - old woman visited the department of dermatology for evaluation of long - standing mildly pruritic facial papules that she had had for 10 yr ( fig . previously she had been treated with co2 laser and aldara ointment with the impression of verruca or syringoma but with little effect . physical examination revealed several firm , flesh - colored , dome - shaped , papular lesions ranging from 2 to 5 mm in diameter , distributed on the face and neck area . the patient had a history of pneumothorax ; otherwise , her medical history was not notable . one sample showed concentric layers of cellular fibrous tissue around hair follicles with an aritifactual cleft separating the fibroma from adjacent connective tissue ( fig . also in another sample , a raised papule composed of connective tissue surrounded by a lateral collarette was seen ( fig . staining with alcian blue and elastin stain revealed an unencapsulated loosely woven admixture of collagen and thin elastic fibers with mucin . periodic acid - schiff ( pas ) staining showed multiple thin and thick walled blood vessels with pas - positive basement membrane within the substane of the tumor . . computed tomographic scan of the chest , abdomen , and pelvis showed multiple cysts on both lower lung zone , with sizes ranging from 1.4 - 2.4 cm and a small amount of pneumothorax noted on the left anterior basal hemithorax . there was no family history of renal tumors , colon carcinoma , or other benign or malignant neoplasm . however , the patient reported that her two aunts died of ' lung disease ' ( diagnosis unknown ) and one of her older sisters was remembered to have had multiple tumorous lesions . both of her older sisters passed away at an early age but she did not know the cause of death . molecular analysis of the bhd gene was performed after informed consent from the patient . all the coding regions of the bhd gene ( exons 4 - 14 ) were amplified using polymerase chain reaction ( pcr ) with oligonucleotide primers we designed ( table 1 ) . the amplified pcr products were sequenced using the abi 3100 genetic analyzer ( applied biosystems / hitachi , foster city , ca , u.s.a . ) . sequencing analysis revealed a novel deletion mutation ( p.f519lfsx17 [ c.1557delt ] ) in the bhd gene exon 14 of the patient ( fig . this mutation results in producing the truncated protein folliculin , which is caused by frameshift of amino acid sequence in the bhd gene product . also , this deletion mutation has not yet been found in the normal populations , indicating that this mutation is the real cause of the syndrome in this case . bhds was recently found to be caused by heterozygous loss - of - function mutations in the bhd tumor suppressor gene on chromosome 17p11.2 , which encodes the novel protein folliculin . fluorescent in situ hybridization has shown the expression of bhd mrna in many normal tissues including the skin and its appendages , the distal nephron of the kidney , stromal cells , and type 1 pneumocytes of the lung ( 6 ) . the function of the bhd gene in tumorigenesis , however , has not yet been elucidated . the defective protein in patients with bhds may affect the cell 's cytoskeleton , disrupting the extracellular matrix and affecting the regulation of cellular proliferation ( 7 ) . because patients with bhds have inactivating mutations in the bhd gene , and many bhds tumors exhibit loss of heterozygosity , the bhd gene is considered to be a tumor suppressor gene ( 7 ) . fluorescent in situ hybridization showed that bhd mrna was strongly expressed in the proliferating epithelial strands of ffs but not expressed in the renal tumors of patients with bhds . genotype - phenotype correlation remains to be evaluated for bhds , but it was recently suggested that significantly fewer renal tumors were observed in patients with the c - deletion than those with the c - insertion mutation in the exon 11 hotspot ( 9 ) . to date , several different bhd germline mutations have been identified with mutations affecting all translated exons ( 4 - 11 ) with the exception of exons 8 and 10 . 4 ) . clinical diagnosis of bhds requires a minimum of 10 skin lesions clinically compatible with ffs and at least one histologically proven ff ( 5 , 9 ) . ff and td present as asymptomatic single or multiple dome - shaped papules commonly located on the head , neck , back , and arms . however , many researchers now consider perifollicular fibroma in patients with bhds to actually represent ff ( 10 ) . thus , based on clinical and histological findings , our patient could be diagnosed as bhds . since its description in 1977 bhds patients are 9.3 times more likely to develop a renal tumor than unaffected persons , and are 32.3 times more likely to develop a spontaneous pneumothorax ( 12 ) . older age and male gender increase the risk for renal tumors , whereas the risk of spontaneous pneumothorax is inversely associated with age ( 12 ) . between 15% and 30% of bhds - affected patients , patients develop renal tumors much earlier than unaffected persons , typically developing tumors in their 20s or 30s instead of in their 70s and often presenting with multiple , bilateral renal cancers . in the absence of strictly defined guidelines , it is recommended that patients with clinical manifestations of bhds undergo abdominal computed tomography and/or renal ultrasound at the time of diagnosis . siblings should have a complete physical examination with biopsy of lesions suspicious for ff / tds beginning in their 20s . routine screening for renal pathology may begin if they have ff or at age 40 yr . tumors less than 3 cm are observed , whereas tumors larger than 3 cm are treated with nephron - sparing procedures including partial nephrectomy ( 14 ) . spontaneous pneumothorax was more likely to occur in younger patients with bhds ( 12 ) . patients with bhds should be informed of the increased risk and educated on the signs and symptoms of pneumothorax . our patient was diagnosed with pneumothorax in her 20s but other concominant abnormalities were not found . however , as the risk of renal tumors increases with age we advised the patient to have regular screening . the risk for colon polyps and colon cancer was not increased in bhds ( 12 ) , so screening for colon pathology may not be warranted . however , routine screening by colonoscopy is included in the currently recommended guideline for all patients aged > 50 yr . the decision to undergo examination at an earlier age should be discussed with the patient . the actual incidence of bhds is unknown , and the disease is most likely underdiagnosed . it is imperative that physicians recognize the skin lesions of bhds and institute proper screening to detect other manifestations of the disease , such as renal tumors and lung cysts . patients with numerous facial and truncal papules resembling ffs are candidates for biopsy . in summary , we report a case of bhds with a novel mutation , which is the first report in korea .