The literature data base has been updated with the following papers:
Basic research
Liu et al. generated the first constitutive knock out of the Drosophila homologue of FLCN, DBHD. DBHD acts recessively in flies and loss of both alleles is lethal at the larval stage. This phenotype was partially reversed by increased dietary leucine, allowing flies to form pupae. Furthermore, Rapamycin treatment abrogated the positive effect of dietary leucine, suggesting that reduced mTOR signalling is responsible for the lethal phenotype observed in DBHD-null flies. Introduction of the human FLCN gene also partially rescued the mutant phenotype, indicating that FLCN and DBHD do have some shared function. This paper is available to download from the BHD Articles Library:Basic section.
Luijten et al. show that FLCN localises to primary and motile cilia in a number of different cell types, and that both knock down and overexpression of FLCN inhibits the onset of ciliogenesis. IMCD3 spheroids both lacking and over-expressing FLCN failed to divide in a controlled manner to generat a luminal space, indicating that planar cell polarity signalling was impaired in these cells. In FLCN-modified cells, B-catenin levels were reduced in cilia, while the amount of active phosphorylated B-catenin was increased in the cell body, which may account for the planar cell polarity defects seen. These results suggest that BHD is a novel ciliopathy.
Laviolette et al. show that FLCN expressing cells show a 2-4 hour delay in progression through S-phase of the cell cycle, which increased to a 2 – 6 hour delay in the G2/M phase, when compared with FLCN-null cells. This effect was seen in both UOK257 and MEF isogenic cell lines, indicating that FLCN delays cell cycle progression. The authors tested the effects on cell cycle progression of three constructs carrying FLCN mutations known to be associated with BHD. All three showed cell cycle profiles similar to FLCN-null UOK-257 suggesting that all three ablate FLCN function. The authors also show that S62 and S73 become phosphorylated as the cell cycle progresses, and that when FLCN is phosphorylated at these residues, it is less stable and is no longer able to slow cell cycle progression. This paper is available to download from the BHD Articles Library:Basic section.
Clinical research
Sander et al. describe the case of a 37 year old woman who presented in clinic with sudden shortness of breath and chest pain. She had a medical history of recurrent pneumothorax and also had a positive family history of pneumothorax. Further examination revealed the presence of facial skin lesions and multiple bilateral lung cysts. Genetic testing confirmed a diagnosis of Birt-Hogg-Dubé syndrome.
Raymond et al. describe the case of a 62 year old woman with histologically confirmed trichodiscomas indicative of BHD. Further screening revealed the presence of two lung cysts and an adrenal mass. Resection of the adrenal mass confirmed it to be an oncocytic adrenal tumour, which was likely to be malignant. Genetic testing confirmed a diagnosis of BHD. The authors analysed the prevalence of adrenal masses in a cohort of 14 BHD patients; one patient was found to have an adrenal nodule. Retrospective analysis of the literature yielded three additional reports of adrenal tumours in BHD patients. However, no patients in a cohort of 359 cases of sporadic adrenocortical carcinoma fulfilled the diagnostic criteria for BHD.
Zenone describes the case of a 38 year old woman who presented in clinic with spontaneous pneumothorax. 8 years later she presented with dyspnea. CT scans revealed the presence of lung cysts and further examination found she had multiple skin lesions on the neck. Her brother also presented with multiple white papules on the face and neck. Histological analysis determined these were fibrofolliculomas in both cases and genetic testing confirmed a diagnosis of BHD.
Reviews
Hes et al. review renal hybrid oncocytic/chromophobe tumors in the context of sporadic disease, renal oncocytomatosis and BHD syndrome.
Przybycin et al. review the histologic features of hereditary renal tumours, including those seen in VHL, HLRCC, TSC and BHD.
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