STUDY Birt-Hogg-Dube´ Syndrome A Novel Marker of Kidney Neoplasia Jorge R. Toro, MD; Gladys Glenn, MD, PhD; Paul Duray, MD; Thomas Darling, MD, PhD; Gregor Weirich, MD; Berton Zbar, MD; Marston Linehan, MD; Maria L. Turner, MD Background: Birt-Hogg-Dube´ syndrome (BHD) is a had a variant of papillary renal cell carcinoma. Thirteen dominantly inherited predisposition for development of patients exhibited BHD. Seven individuals, including a fibrofolliculomas, trichodiscomas, and acrochordons. set of identical twins, had renal neoplasms and BHD. An Concurrent internal tumors, such as colonic polyps and additional 4 patients (3 deceased and not examined) in renal carcinoma, have been described in patients with these families had renal neoplasms but not BHD. Birt- BHD. Hogg-Dube´ syndrome without renal neoplasms was pres- ent in 6 individuals. Thirteen patients with fibrofollicu- Objective: To evaluate kindreds with familial renal tu- lomas and trichodiscomas presented clinically with mors for cutaneous manifestations of BHD. multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral Design: One hundred fifty-two patients from 49 fami- papules were present in 9 of 28 and achrochordons in lies underwent complete oral and skin examination. Skin 11 of 28 patients. Features of BHD not previously ap- lesions were identified by their clinical appearance, and preciated included deforming lipomas in 5, collageno- the diagnosis was confirmed by results of histologic ex- mas in 4, and pulmonary cysts in 4 of 28 patients. Fami- amination. Individuals underwent screening for famil- lies with BHD did not display germline mutations in the ial renal neoplasms. von Hippel-Lindau gene or in the tyrosine kinase do- main of the MET proto-oncogene. Setting: A tertiary referral research hospital. Conclusions: Birt-Hogg-Dube´ syndrome may be asso- Patients: Individuals with familial renal tumors and their ciated with familial renal tumors. Birt-Hogg-Dube´ and asymptomatic at-risk relatives. renal tumors segregate together in an autosomal domi- nant fashion. Patients with BHD and their relatives are Main Outcome Measure: We determined whether any at risk for development of renal tumors. Therefore, pa- form of renal cancer is associated BHD. tients with BHD and their relatives should undergo ab- dominal computed tomography and renal ultrasound Results: We identified 3 extended kindreds in whom screening for renal tumors. renal neoplasms and BHD appeared to segregate to- gether. Two kindreds had renal oncocytomas and a third Arch Dermatol. 1999;135:1195-1202 N 1977, BIRT ET AL1 described a ous manifestations of BHD have been as- kindred in which 15 of 70 mem- sociated with colonic polyps2,3 and a case bers over 3 generations exhib- of renal carcinoma.4 We herein describe 3 ited multiple, small, skin- kindreds with familial renal tumors in colored, dome-shaped papules which 13 individuals also had BHD. From the Dermatology Branch Idistributed over the face, neck, and upper Renal neoplasms can be familial or (Drs Toro, Darling, and trunk inherited in an autosomal domi- sporadic. Four types of familial renal neo- Turner), the Genetic nant pattern. Histologic examination of plasms have been well described: (1) clear Epidemiology Branch these lesions revealed fibrofolliculomas cell renal carcinoma associated with he- (Dr Glenn), the Laboratory of (FFs), trichodiscomas (TDs), and acro- mangioblastomas of the brain, spine, and Pathology (Dr Duray), the chordons. This triad has become known as eye resulting from mutations in the von Laboratory of Immunology 1 13 (Drs Weirich and Zbar), and Birt-Hogg-Dube´ syndrome (BHD). Typi- Hippel-Lindau (VHL) gene ; (2) clear cell the Urologic Oncology Branch cally, cutaneous lesions of BHD have their renal carcinoma associated with constitu- (Dr Linehan), National Cancer onset during the third or fourth decade of tional, balanced translocations involving Institute, National Institutes of life. Since the initial report, several other the short arm of chromosome 314-16; (3) Health, Bethesda, Md. cases have been described.2-12 The cutane- papillary renal cell carcinoma associated ARCH DERMATOL / VOL 135, OCT 1999 WWW.ARCHDERMATOL.COM 1195 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 PATIENTS AND METHODS DERMATOLOGIC CRITERIA PATIENTS Mucocutaneous lesions were diagnosed clinically. The di- agnosis was confirmed by results of histologic examina- All patients underwent evaluation at the National Insti- tion of lesional skin biopsy specimens. We used the fol- tutes of Health Warren G. Magnuson Clinical Center, lowing clinical and histologic criteria. Fibrofolliculomas and Bethesda, Md, and were enrolled in a protocol approved TDs were multiple, 2- to 4-mm smooth-surfaced, white to by the institutional review board. Informed consent was skin-colored papules distributed over the face, neck, and obtained from all participants. Two families were in- upper trunk. Histologically, FFs were defined as multiple cluded in a previous publication of the renal findings of anastomosing strands of 2 to 4 epithelial cells extending familial renal oncocytoma.18 One hundred fifty-two pa- from a central vellus follicle. A well-demarcated, loose, mu- tients ranging in age from 17 to 79 years underwent evalu- cin-rich or thick connective tissue stroma encapsulated the ation from April 1, 1996, to December 31, 1998. All pa- epithelial component.1 Histologically, TDs consisted of a tients underwent complete skin and oral examinations and round to elliptical well-demarcated proliferation of a thick were photographed. Patients underwent pre– and post– fibrous and vascular stroma in the reticular dermis with a contrast-enhanced computed tomography (CT) of the ab- hair follicle at the periphery.1 Collagenomas were skin- domen followed by renal ultrasound as previously de- colored to slightly hypopigmented, well-circumscribed in- scribed.19 Briefly, CT of the abdomen was performed on 1 durated papules and plaques. Histologically, collageno- of 2 units (9800 Quick or GE Hi Speed CT unit; General mas consisted of a well-demarcated proliferation of thick Electric, Milwaukee, Wis) with the intravenous injection collagen in the dermis.20 Acrochordons, or skin tags, were of 120 to 135 mL of iopamidol (Isovue-300; Bracco Diag- soft, pedunculated papules that histologically showed nostics Inc, Princeton, NJ) after a delay of 70 seconds. Slice slightly acanthotic and occasionally mild papillomatous epi- thickness was 5 mm, and imaging was performed in a non- dermis with a loose connective tissue stroma and dilated helical mode. Available CT scans from other centers were blood vessels.20 Papules of the oral mucosa were defined also reviewed in 2 patients. In addition, each patient un- as multiple 1- to 2-mm dome-shaped papules involving the derwent renal ultrasound using 1 of 2 units (Acuson 128XT; lip and buccal and gingival mucosae. Histologically, they Acuson Corporation, Mountain View, Calif, or Diasonic were characterized by a collagenous stroma with few fi- Spectra; Diasonic, San Jose, Calif). Scanning was per- broblasts.18 The diagnosis of BHD was made in patients who formed using a 3- or 5-MHz transducer. Solid lesions seen had 5 or more facial or truncal papules, of which at least 1 on results of CT scan and ultrasound suggested the pres- papule was confirmed histologically as FF or TD. ence of renal tumors. Lesions were considered indetermi- nate if they were too small (2-5 mm) to be classified as cyst MOLECULAR METHODS or solid. Individuals without renal tumors on CT findings were classified as not affected. Chest radiographs in- The DNA was extracted from peripheral blood leukocytes cluded posterior-anterior and lateral projections. Histo- of patients. The presence of mutations in the VHL gene was logic criteria for the diagnosis of renal oncocytomas and tested using Southern blotting and sequencing, as previ- papillary renal carcinoma were as described previ- ously described.21 For screening of mutations of the MET ously.18,19 In 3 patients, the diagnosis of renal carcinoma proto-oncogene, conformational, sensitive gel electropho- was made after review of death certificates, medical re- resis was performed, followed by sequencing of exons 16 cords, and pathology and autopsy reports. through 19 of abnormally migrating bands, as described.22 with germline mutations in the tyrosine kinase domain RESULTS of the MET proto-oncogene17; and (4) renal oncocy- 18 toma. Pure renal oncocytomas are considered to be be- MOLECULAR STUDIES nign tumors. Histologically, oncocytomas are com- posed of cells with an eosinophilic cytoplasm with bland Twenty individuals from 18 families with VHL had mu- round nuclei and abundant mitochondria as seen on elec- tation in the VHL gene, and 4 individuals from 5 fami- tron microscopy.18 Papillary renal cell carcinomas have lies with hereditary papillary renal cell carcinoma dis- malignant potential, and biological aggressiveness var- played a mutation in the tyrosine kinase domain of the ies with the type. Histologically, papillary renal cell MET proto-oncogene. No VHL or tyrosine kinase do- carcinomas have fingerlike projections lined by cuboi- main MET gene mutations were found in 13 patients from dal tumor cells with a basement membrane that con- 9 families with renal oncocytomas. Families with BHD tains a well-formed fibroconnective tissue stroma.19 did not display mutations in the VHL gene or the tyro- During most of their growth, these renal neoplasms are sine kinase domain of the MET proto-oncogene or karyo- asymptomatic and are often detected incidentally or typic abnormalities. The results of mutation analysis in through screening of at-risk family members. After not- the families with BHD are summarized in the Table. ing multiple FFs in a pair of identical twins with bilat- eral renal oncocytomas, we performed complete skin and RENAL FINDINGS oral examinations to search for cutaneous manifesta- tions of BHD in another 150 patients from 49 kindreds We examined 20 affected individuals from 18 families with familial renal tumors.