How Common are the Different Features of Birt-Hogg-Dubé Syndrome?

Birt-Hogg-Dubé syndrome (BHD) is characterised by skin bumps, lung cysts, collapsed lungs and an increased risk of kidney cancer. The condition is associated with faults (also called variants) in the folliculin (FLCN) gene. There is a lot of variation in the clinical features seen between individuals and families. There is no way of knowing which feature(s) you may get. For example, some family members will have lung collapse while others may only have skin bumps. The penetrance of the clinical signs of BHD is also not clear. Penetrance refers to the proportion of people with the genetic variant who exhibit the signs or symptoms of a genetic disorder.

A new study* has estimated the penetrance of different features of BHD syndrome. The authors of the study gathered all available data that was published between 2002 and 2016 that describes one or more features from one or more families. The authors of these papers were contacted and asked to provide additional information on families and/or additional cases. The final dataset included 552 families. However, 348 of these had to be excluded as there wasn’t enough data. . This left a total of 204 families that were included in the study. However, not every family had data on every feature of BHD. This study also included data from family members who did not have a FLCN variant. The authors calculated the cumulative risk for each feature for men and women. This is the chance that by a certain age you will have a certain feature.

Skin Features

67 families (767 individuals) were used to inform the risk of skin involvement. Of these, 560 people had a FLCN variant and 356 (64%, almost two thirds of people) had skin features of BHD. Fibrofolliculomas were the most commonly reported feature, followed by trichodiscoma. However, the type of skin bump was not reported in a quarter of individuals. The cumulate risk for skin bumps by age 70 was 87% (almost 9 in 10 people) for men and 78% (almost 8 in 10 people) for women.

Lung Features

63 families (763 individuals) were used to inform the risk of lung involvement. This included lung cysts and/or collapsed lungs. 599 people had a FLCN variant. 519 out of 599 people (87%, almost 9 in 10 people) had lung cysts or a collapsed lung. Of these:

• About 1 in 4 people had lung cysts but had not had a collapsed lung.
• Around 1 in 3 people had lung cysts and a collapsed lung.
• Around 1 in 3 people had a collapsed lung but did not have lung cysts.
• However, not everyone had a scan of their lungs, and the type of lung involvement was not reported in a small number of people.

From analysing the available data the cumulate risk for lung features by age 70 was 87% (almost 9 in 10 people) for men and 82% (just over 8 in 10 people) for women.

Kidney Cancer

88 families (1076 individuals) were used to inform the risk of kidney tumour involvement. Of these, 733 had a FLCN variant and 138 (19% or just under 1 in 5 people) had a kidney tumour. The average (median) age at diagnosis was 50 years old. Different types of kidney cancer were reported:

• 15 in 100 people had clear cell kidney cancer.
• 15 in 100 people had chromophobe kidney cancer.
• 4 in 100 people had papillary kidney cancer.
• 9 in 100 people had an oncocytoma.
• 2 in 100 people had sarcomatoid kidney cancer
• 27 in 100 people had a mixed type kidney cancer.
• The type of cancer was not reported in 28 out of 100 people.

The cumulate risk for kidney tumours by age 70 was 19% (around 1 in 5 people) for men and 21% (around 1 in 5 people) for women.

Colon Polyps

29 families (221 individuals) were used to inform the risk of colon polyp involvement. Around 1 in 5 people reported having colon polyps. The cumulate risk for colon polyps by age 70 was 21% (around 1 in 5 people) for men and 32% (just over 3 in 10 people) for women. However, it is estimated that the prevalence of colon polyps in the general population over the age of 50 is between 25 and 38%. Therefore, people with BHD syndrome do not appear to be at an increased risk of colon polyps, based on this data. The authors were unable to look at the risk of colon cancer due to the lack of data in this study.

Summary

This study shows the variation of BHD presentation in a large dataset, including information from 99 new families. Skin and lung features were very common (had a high penetrance) and it is known that they tend to occur at an earlier age than kidney cancer. There didn’t appear to be a huge difference in the penetrance of features between men and women. Altogether, there is a need to raise awareness among doctors, particularly skin and lung doctors who are in a position to spot and diagnose BHD early. This allows kidney screening to occur earlier so any kidney cancer can be identified as early as possible.

However, more information is needed to answer questions about other features such as colon (or other) cancers. The BHD Foundation launched their patient registry to help answer some these questions and give people with BHD opportunity to take part in research. Find out more about the registry.

*Unfortunately this paper is not open access. Please contact us with any additional questions.