Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients

J Invest Dermatol. 2007 Mar;127(3):588-93. doi: 10.1038/sj.jid.5700592. Epub 2006 Nov 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Renal Cell / diagnosis
  • Carcinoma, Renal Cell / genetics*
  • Female
  • Hair Diseases / diagnosis
  • Hair Diseases / genetics*
  • Humans
  • Kidney Neoplasms / diagnosis
  • Kidney Neoplasms / genetics*
  • Loss of Heterozygosity*
  • Lung Diseases / diagnosis
  • Lung Diseases / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Neoplastic Syndromes, Hereditary / diagnosis*
  • Neoplastic Syndromes, Hereditary / genetics
  • Proteins / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Skin Neoplasms / diagnosis
  • Skin Neoplasms / genetics*
  • Tumor Suppressor Proteins / genetics*


  • FLCN protein, human
  • Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins