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 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 (). 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. Skin biopsies of the facial papules were performed. One sample showed concentric layers of cellular fibrous tissue around hair follicles with an aritifactual cleft separating the fibroma from adjacent connective tissue (). Also in another sample, a raised papule composed of connective tissue surrounded by a lateral collarette was seen (). 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. The biopsy findings were consistent with perifollicular fibroma and trichodiscoma, respectively.\nComputed 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. The scan did not show any abnormalities in the kidney or colon. 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.\nMolecular analysis of the BHD gene was performed after informed consent from the patient. Genomic DNA was extracted from peripheral blood leukocytes, and subjected to mutation analysis. All the coding regions of the BHD gene (exons 4-14) were amplified using polymerase chain reaction (PCR) with oligonucleotide primers we designed (). 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 (). 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.