1. ¹Department of Dermatology, University Hospital Maastricht, Maastricht, The Netherlands
2. ²Department of Clinical Genetics, University Hospital Maastricht, Maastricht, The Netherlands

Correspondence: Dr Maurice A.M. van Steensel, Department of Dermatology, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: mvst@sder.azm.nl

Received 7 April 2006; Revised 4 August 2006; Accepted 24 August 2006; Published online 23 November 2006.

Abstract

Birt-Hogg-Dubé (BHD) syndrome is an autosomal-dominantly inherited cancer syndrome characterized by fibrofolliculomas, lung cysts leading to pneumothorax, and chromophobic/oncocytic renal cell carcinoma. The disease is caused by heterozygous mutations in the BHD gene encoding folliculin and all mutations reported putatively lead to protein truncation. Although the function of folliculin is unknown, it is thought to be a tumor suppressor, with loss of heterozygosity (LOH) initiating tumor formation. Here, we report on four novel BHD gene mutations, including two splice-site mutations, in patients presenting with skin lesions only. We further show that LOH cannot be detected in fibrofolliculomas from three patients, suggesting that for the manifestation of cutaneous tumors in BHD syndrome haplo-insufficiency of folliculin is sufficient to initiate uncontrolled growth. Renal microscopic oncocytosis in BHD is considered as a precursor to malignant kidney tumors and may likewise be the result of haplo-insufficiency, with somatic second-hit mutations or LOH giving rise to malignancy later in life.