A study following a large number of Swedish individuals with suspected Birt-Hogg-Dubé syndrome (BHD) was recently published. 278 individuals from 78 families were followed through genetic testing and clinical assessment for BHD between 2007 and 2019. In the study there were 125 men, 153 women and the average age was 50 (ranging from 15 to 97 years of age). Of the 278 individuals, 186 (around 2 in every 3 people) had a mutation in the folliculin (FLCN) gene associated with BHD.

Clinical Assessment

This diagram shows how many of the 186 people with a FLCN variant had each of the symptoms associated with BHD.

The authors of the study noted that the number of people with lung cysts was lower than in other studies. They explained that it may be lower because not everyone had a scan of their lungs. Additionally, not every individual in the study had a scan of their kidneys.

The authors also looked at other cancers and found that 9 in186 individuals had colon cancer and/or pre-cancerous colon tumours.

Of the 30 people that had kidney tumours, it was known what type of tumour they had in 22 cases:

• 8 were hybrid chromophobe/oncocytoma
• 5 were chromophobe
• 4 had clear cell kidney cancer
• 1 was papillary type 2
• 1 was a hybrid papillary/oncocytoma
• 1 was an angiomyolipoma
• 1 was benign (not cancerous)
• 1 could not be classified

Genetic Assessment

11 different FLCN variants were identified across the 186 individuals. One FLCN variant, c.779+1G>T, was found in 44 of the 78 families in the study. It was initially thought that these families were unrelated. Further testing showed that these families were in fact distantly related. For help on how to interpret your FLCN variant, read our previous toolkit post here.

One of the questions about BHD is whether the FLCN variant you have can predict which symptoms you get. This variant has been reported before and was associated with a range of symptoms. In this study, there was also a range of symptoms reported from the families with this variant:

• 37 out of the 44 families studied had skin symptoms
• 33 out of the 44 families studied had lung symptoms
• 17 out of 44 of the families studied had kidney tumour(s)
• 7 out of 44 families studied had colon cancer and/or colon polyps

It is estimated that 1 in 3265 people in the Swedish population carry this variant. This indicates the prevalence of BHD is at least 1 in 3265 in the Swedish population. The high frequency of this variant in the cohort studied suggested that it may in fact be a founder mutation. This is a mutation  in the DNA of people who first settled there and from which the population grew.

Summary

This study follows one of the largest cohorts of individuals with BHD. It provides detailed genetic and clinical insights. However, some individuals still had an incomplete medical history. The authors suggested this was due to the lack of clear diagnostic and management guidelines for BHD. This includes the different type of scans you should have and when. Our latest toolkit describes the different scans and when you may have them. Due to the wide variation in the symptoms of BHD seen in different individuals, BHD can prove to be a diagnostic challenge.

The last author of the study, Dr Christos Aravidis (Department of Clinical Genetics, Akademiska Hospital, Uppsala University, Sweden) kindly provided this quote about their work:

“Our long term medical follow-up in Sweden, for more than a decade, identified that a unique and specific genetic change constitutes hereditary predisposition for BHD. This implies that BHD may be underdiagnosed due to the syndrome´s diversity. Physicians should be cautious regarding BHD since an early establishment may help to identify people in cancer risk through imaging techniques.“

The authors state there is a clear need for up-to-date diagnostic and management guidelines for BHD. The BHD Foundation strongly supports this statement and are actively working towards the development of these guidelines through the BHD Syndrome International Registry (BIRT). We are thrilled that the registry will be launching next week and encourage as many of you to sign up as possible. Sign up to receive updates about the registry, BHD Foundation events and more here.