Currently, the only proven BHD symptoms are skin lesions, lung cysts, collapsed lungs and kidney cancer. As BHD is a rare disease, if only a few BHD patients develop another symptom it is very difficult to tell for certain if this symptom is caused by BHD or by coincidence. However, there are some symptoms that might be linked to BHD, so patients and their doctors should be aware of these:
- Colon polyps and colon cancer
- Parotid tumours
- Thyroid nodules and thyroid cancer
The VHL Alliance have launched MyVHL: Patient Natural History Study which aims to gather information on the natural history of BHD to help researchers and clinicians to learn more about risk factors for patients with BHD and other rare conditions.
Colon polyps and colon cancer
Some studies have suggested that colon polyps and cancer are associated with BHD, while other studies have found that they are not linked (1). Colon polyps and cancer are themselves quite common, meaning that a number of BHD patients may develop these symptoms by chance. This makes it very difficult to conclusively prove they are a symptom of BHD.
There is a region in the Folliculin gene called the polyC tract. Mutations in the polyC tract are very common and roughly half of BHD patients have a mutation in this region. There is limited evidence that mutations in the polyC tract – but not other Folliculin mutations – might cause colon polyps and cancers, although this is not conclusive.
There have been at least eight cases of BHD patients developing parotid tumours (2,3). As BHD and parotid tumours are both so rare, it seems quite unlikely that eight patients have developed both by chance alone. For this reason, some BHD experts think that parotid tumours are a rare symptom of BHD, although there is still not enough evidence at the moment to statistically prove this link.
Thyroid nodules and cancer
Two studies have found that around half of BHD patients have thyroid nodules. However, neither study accounted for the fact that thyroid nodules are quite common in the general population. This means that at the moment we do not have enough information to know if these cases were coincidence, or if BHD causes thyroid nodules.
The BHD gene, Folliculin, has been shown to be lost in two thyroid tumours – one in a BHD patient, and in one sporadic case (i.e. the patient had thyroid cancer, but didn’t have BHD.) This suggests that BHD patients may have a very small risk of developing thyroid cancer, but again, at the moment there is not enough information to conclusively prove this.
There have been a number of case studies that report BHD patients with other cancers (4–9). We are actively researching the link between BHD and cancers but currently the only cancer shown to be associated with BHD is kidney cancer.
1. van de Beek I, Glykofridis IE, Wolthuis RMF, Gille HJJP, Johannesma PC, Meijers-Heijboer HEJ, et al. No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome. Br J Cancer [Internet]. 2020 Feb 18 [cited 2021 Apr 27];122(4):590–4. Available from: https://pubmed.ncbi.nlm.nih.gov/31857718/
2. Yoshida K, Miyagawa M, Kido T, Ide K, Sano Y, Sugawara Y, et al. Parotid Oncocytoma as a Manifestation of Birt-Hogg-Dubé Syndrome. Case Rep Radiol. 2018 Jun;2018:1–7.
3. Lindor NM, Kasperbauer J, Lewis JE, Pittelkow M. Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors. Hered Cancer Clin Pract. 2012 Oct;10(1):13.
4. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management [Internet]. Vol. 10, The Lancet Oncology. Lancet Oncol; 2009 [cited 2021 May 11]. p. 1199–206. Available from: https://pubmed.ncbi.nlm.nih.gov/19959076/
5. Daccord C, Good JM, Morren MA, Bonny O, Hohl D, Lazor R. Birt–hogg–dubé syndrome. Eur Respir Rev. 2020 Sep;29(157):1–14.
6. Welsch MJ, Krunic A, Medenica MM. Birt-Hogg-Dube syndrome. Int J Dermatol. 2005 Aug;44(8):668–73.
7. Tong Y, Schneider JA, Coda AB, Hata TR, Cohen PR. Birt–Hogg–Dubé Syndrome: A Review of Dermatological Manifestations and Other Symptoms [Internet]. Vol. 19, American Journal of Clinical Dermatology. Springer International Publishing; 2018 [cited 2021 May 18]. p. 87–101. Available from: https://link.springer.com/article/10.1007/s40257-017-0307-8
8. Lee JH, Jeon MJ, Song JS, Chae EJ, Choi JH, Kim GH, et al. Birt-Hogg-Dubé syndrome in Korean: Clinicora-diologic features and long term follow-up. Korean J Intern Med. 2019;34(4):830–40.
9. Murthy NK, Potts MB, Jahromi B. A Case of Birt-Hogg-Dubé Syndrome and Multiple Intracranial Aneurysms. Cureus. 2020 Feb;12(2).
Publication date: December 2014
Review date: May 2021