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.
The second patient was a 35-year-old male who presented with an asymptomatic right renal tumor. The presence of the tumor was revealed by ultrasound and CT examinations (fig. ). A laparoscopic right partial nephrectomy was performed, and the tumor was diagnosed as a chromophobe renal cell carcinoma (RC; fig. ). The carcinoma was negative for CD10, vimentin, and c-kit, and was partially positive for CK-7 (fig. ) and colloidal iron (fig. ). When the patient was 40 years of age, a CT examination revealed the presence of asymptomatic bilateral multiple PCs (fig. ). His mother, aunt, uncle, and grandfather all had histories of recurrent pneumothorax (fig. ). A few firm papules were also present on the patient's face (fig. ). The results of the skin biopsies revealed that the papules were FFs (fig. ) positive for factor 13a (fig. ) and c-kit (fig. ), and negative for CD34, α-SMA, S100, and CD68. Because the findings for this patient met 1 major criterion and 2 minor criteria [], he was diagnosed with BHD.