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 .
 birt - hogg - dub syndrome ( bhds ) is an autosomal dominant genodermatosis characterized by cutaneous hair follicle tumors ( fibrofolliculoma or trichodiscoma ) , pulmonary cysts , and increased risk of renal neoplasia . 
 the genetic alteration for bhds has been mapped to chromosome 17p12q11 , and the gene in this region has been cloned and believed to be responsible for the bhds . 
 mutations in the bhd gene ( also known as flcn ) have been described in the patients with bhds . 
 we present a case of a 30-yr - old korean woman with multiple mildly pruritic papules on her face and neck area . 
 the patient had several firm , flesh - colored , dome - shaped , papular lesions measuring between 2 to 5 mm . except for a history of pneumothorax 
 her medical records were not remarkable . 
 mutation analysis of the bhd gene was performed , and a novel deletion mutation ( p.f519lfsx17 [ c.1557delt ] ) causing truncation of the gene product , folliculin , was found in the exon 14 . 
 the actual incidence of bhds is unknown , but it is most likely underdiagnosed . so it is imperative that doctors recognize the skin lesions of bhds and institute proper screening to detect other manifestations of the disease . here 
 , we report a case of bhds with a novel mutation , which is the first report in korea . 
INTRODUCTION
CASE REPORT
DISCUSSION