Birt-Hogg-Dube Syndrome: an autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis

The proband was evaluated for abdominal pain at age 61 years and found to h ave bilateral solid renal masses. He underwent a partial left nephrectomy, Two benign renal cysts were present, and two renal cell adenocarcinomas mea suring 5.3 cm and 0.7 cm in greatest diameters were found. Histologically, both tumors contained both clear and granular cell types, He had a total ri ght nephrectomy 2 months later. Fourteen or 15 lesions were scattered over the surface of this kidney, so an adrenal-sparing radical right nephrectomy was performed. On sectioning, the diameter of the largest tumor was 4 cm, and histologically this was described as renal cell carcinoma, clear cell t ype, Fuhrman grade II. One year later, the patient shows no evidence of rec urrent disease. The proband's past medical history was notable for gastroesophageal reflux, degenerative disk disease, hyperlipidemia, and mild hyperglycemia. A genet ics consultation was requested because of a family history of renal cancers in three maternal relatives (Fig. 1). On examination, the proband was a no ndysmorphic man of normal stature with no unusual findings, except for wide spread skin findings (Fig. 2). On his face were innumerable, small, slightl y yellowish or flesh-colored papules on the forehead and especially over th e cheeks. No intraoral lesions were seen. Around the neck were innumerable, dome-shaped, firm, ivory-colored papules ranging in size from 1 to 10 mm. Very tiny, similar papules were present over the trunk and in the antecubit al area. Numerous acrochordons and some cherry angiomas were present. Sever al biopsies from the neck and upper back were obtained and were thought sug gestive of papular mucinosis. The patient's mother had had a skin biopsy of a similar lesion from her face in 1947, interpreted as an adenoma sebaceum . No angiofibromas were evident on our patient's slides nor on physical exa mination. At this point, diagnoses under consideration included von Hippel-Lindau dis ease (VHL), a familial chromosome no. 3 translocation, hereditary renal cel l cancer (gene unknown), tuberous sclerosis (TS), or Birt-Hogg-Dube syndrom e (BHDS). The patient underwent a variety of tests to evaluate these possib ilities. He had no evidence of hemangioblastomas of the central nervous sys tem, no liver or pancreatic cysts, no ocular findings for VHL or TS, and no hypomelanotic macules on skin exam. Chromosome analysis from peripheral bl ood showed a normal 46,XY karyotype. Direct DNA mutational analysis of the VHL gene detected no mutations. Additional biopsies from the patient's skin lesions were obtained, and tissue blocks from 1947 from his mother were re sectioned (Figs 3 and 4). Upon further review, multiple fibrofolliculomas w ere found in both mother and son in skin biopsies. In aggregate, these data established a diagnosis of BHDS. In addition to the renal cancers, the patient's and/or cousin's medical rec ord reported that others in the family had the same skin manifestations, in cluding his mother, maternal grandmother, maternal uncle, and two maternal first cousins by report. Cousin III.6's medical record showed a clinical di agnosis initially of "sebaceous hyperplasia" and upon skin biopsy was said to have "innumerable trichoepitheliomas over his face". He was treated with liquid nitrogen with good results. Unfortunately, we were not able to obta in tissue for review an the other renal cancers in relatives. Additional fi ndings of note are a spontaneous pneumothorax in our patient's daughter and melanoma in our patient's brother and son. This family has been invited to participate in genetic studies underway at the National Cancer Institute.