Identification of a New BHD Syndrome-Like Condition

Birt-Hogg-Dubé syndrome (BHD) is a rare inherited condition associated with changes in the gene folliculin (FLCN). Most people are diagnosed through a genetic test to check for changes in the FLCN gene. However, a small proportion of people do not have a detectable change (or variant) in FLCN. This group of people can still be diagnosed with BHD based on the presence of clinical criteria. Features of BHD include skin lesions called fibrofolliculomas, lung cysts and collapsed lungs and an increased risk of kidney cancer.

A recent study described an individual who was initially diagnosed with BHD. They came to the clinic aged 33 with multiple skin lesions. These included fibrofolliculomas on the face and chest, skin tags, lesions in their mouth and multiple lipomas. They had no lung cysts but had one small kidney cyst. They were diagnosed with BHD based on the presence of fibrofolliculomas, but genetic testing did not find a FLCN variant. There was a family history of lipomas, other skin lesions and kidney cancer. By the age of 48, they had more than 50 lipomas surgically removed and many more still present. The patient then consented to whole exome sequencing to search for changes in other genes that might be responsible for these features. A variant in a gene called PRDM10 was found. The same change was also found in affected family members.

The authors of the study then looked at the function of PRDM10 in cells. They made cell lines (cells grown in a laboratory) that contained the PRDM10 variant. PRDM10 is proposed to function as a transcription factor. Transcription factors function to turn genes on and off to control which proteins are produced. The particular mutation in PRDM10 that this family was found to have is in a part of the protein important for turning on target genes. In a previous study in mice, it was shown that PRDM10 can turn on the FLCN gene. In this study, the authors found the same effect in human cells. This was confirmed in cells with the PRDM10 variant where the levels of FLCN were almost undetectable. They compared the cells with the PRDM10 variant to cells that were lacking FLCN and found many of the same changes. This included an increase in a protein called GPNMB which has been found in high levels in kidney tumours from people with BHD.

Linking their work in the lab back to the features found in the patient and their family, the authors suggested that the fibrofolliculomas and kidney cancer could be due to the reduction in FLCN. However, there were no lung cysts present which is a common feature of BHD. It was suggested that perhaps the levels of PRDM10 are lower in the lung than the skin and kidney. The levels of FLCN in cells may be under control of multiple different transcription factors. Lipomas were a very common feature in this patient and their family. It is yet to be discovered how the PRDM10 variant drives the formation of these. PRDM10 is likely to control other genes aside from FLCN. Although lipomas have been found in people with BHD, the authors thought that a loss of FLCN was unlikely to be responsible for this.

In summary, the authors of this study have identified a new syndrome with overlapping features of BHD. However, more work is needed to fully understand the role of PRDM10 in the development of this new condition. Identification of other families with the same variant in PRDM10 would also strengthen the data provided in this study. At the BHD Foundation, we found this study interesting as it increases our knowledge of BHD and similar conditions. We look forward to seeing future work on this, and potentially the identification of new BHD-like conditions.