A 43-year-old man presented with a 15-year history of intermittent pruritic, multiple, skin-colored papules on the face and neck. The lesions developed on the face at first, and then slowly progressed to the neck, covering a 15-year period. Physical examination revealed multiple firm, skin-colored, 2~4 mm sized, papular lesions distributed on the face and neck area (). Except for the cutaneous findings, the patient was otherwise well and had no past history of kidney disease, pneumothorax, or other tumors. The result of the routine laboratory studies and chest x-ray were either normal or negative. His father died after suffering from colon cancer and his younger brother was ill with a pneumothorax. He also stated that his daughters had similar symptoms to his skin lesions.\nA biopsy of one of the facial papules was performed, and the lesion was reminiscent of a fibrofolliculoma by concentric fibrous tissue around follicular epithelium with thin and anastomosing bands separating from adjacent fibrovascular proliferation (). Meanwhile, another section of the same sample showed a relatively well-defined fibrovascular lesion with vascular proliferation and hair follicle at the margin of the lesion, suggesting trichodiscoma (). We studied the molecular genetic status of the FLCN gene after informed consent from the patient. We performed direct amplification of all exons (exon 1-14) of FLCN using previously reported primer sets and PCR conditions. Direct amplification of FLCN from EDTA-treated whole blood was performed using AnyDirectMaxTM Taq REDMix (BioQuest, Seoul, Korea). After gel purification of direct amplicon using a Gel Purification Kit (Solgent, Daejeon, Korea), direct sequencing was performed by ABI 3730XL Sequencer (Applied Biosystems, Foster, CA, USA). Sequencing analysis revealed a heterozygotic c.1285dupC mutation (accession No. NM_144997) in the FLCN gene exon 11 (). This mutation was the same as the previously described 1733insC mutation. This mutation results in producing the truncated protein folliculin, which is caused by a frameshift of the amino acid sequence in the FLCN gene product (). Based on this, we were able to diagnose this patient as BHDS, with support from his clinical and histological findings, family history, and gene mutation revealed by sequencing analysis at genomic DNA level.
A 54-year old man with asymptomtic, tiny, multiple, flesh-colored papules on both cheeks () was referred to us from the cardiothoracic surgery department, where he had been treated for recurrent pneumothorax of the left lung. He did not remember the onset of the lesions, but stated that the number was increasing. He had no special medical or family history. The papules were thought to be sebaceous hyperplasia or verruca plana and a punch biopsy was performed. The specimen showed an epithelial cord and fibrous stroma in the dermis and an anastomosing band from follicular epithelium (). A diagnosis of fibrofolliculoma was made, which is the major feature of BHDS.\nThere was no family history of the skin lesions, lung disease, and of benign or malignant tumors. Furthermore, multiple variable-sized lung cysts were found on his chest following computed tomographic scan and a right renal cyst 2 cm in diameter was found on abdominal sonography (). Molecular analysis of FLCN was performed after informed consent from the patient. Sequencing revealed a single nucleotide frameshift duplication occurring within the polycytosine tract located in exon 11, c.1285dupC (p.H429Pfs*27), resulting in a change of the 429th amino acid from histidine to proline in the FLCN gene product. Based on this, it is possible to accurately diagnose BHDS.\nHis pneumothorax was treated with thoracostomy and pleurodesis, and active treatment was not required for the skin lesions, lung cysts and renal cyst. He is on regular follow-up because renal and colorectal cancer can occur in this syndrome.