BHD syndrome and thyroid conditions

Dong et al., (2016) have recently reported two BHD syndrome patients also affected with papillary thyroid cancer. Lesions were bilateral and multifocal and small lymph node metastases occurred. Due to the small number of patients in the study the authors are unsure whether thyroid cancer in BHD patients is susceptible to exhibiting bilaterally and lymph node metastasis. However, they suggest considering thyroidectomy and prophylactic lymph node dissection for thyroid cancer patients with BHD. They also strongly recommend neck ultrasound for BHD patients and their families and suggest a large-scale investigation be conducted to evaluate the prevalence of thyroid cancer or nodules in patients with BHD.

So far, there is no evidence associating BHD and thyroid conditions.

The original BHD patients were found in a family in which six of nine siblings had hereditary thyroid medullary carcinoma (Birt et al. 1977). However, it was subsequently shown that these six patients also displayed a mutation in the RET proto-oncogene which might have caused the thyroid carcinoma (Toro et al., 1999). Several cases of thyroid cancer have been reported in BHD patients in the literature. Gunji et al. (2007) identify thyroid carcinoma in one of five unrelated BHD cases studied where the patient also had a familial history of thyroid cancer. Fahmy et al. (2007), Toro et al. (2008), Kunogi et al. (2010) and Yamada et al. (2014) describe another five cases of thyroid cancer in BHD patients. In all cases the authors did not attribute the thyroid tumour to BHD or investigate a link between the two. Benusiglio et al., 2014 describe a BHD patient with thyroid cancer where a FLCN mutation was identified both in the patient’s blood DNA and thyroid tumour DNA, this provides a molecular basis for this association, however, alternative genetic lesions or causes of thyroid cancer were not ruled out, so no association between the patient’s BHD and thyroid cancer could be shown. In a previous study Warren et al. (2004) did not find any FLCN mRNA expression in normal thyroid.

In another report, mutation of FLCN, TSC2 and TP53 were found in a case of anaplastic thyroid cancer treated with Everolimus that had a near-complete response for 18 months, at which point the tumour acquired resistance to treatment due to mutation in the mTOR gene (Wagle et al., 2014). This suggests that somatic FLCN mutation, and other genes that activate mTOR, can cause additional types of cancer to renal cell carcinoma (RCC) and make tumours resistant to treatments with mTOR inhibitors. A population-based study in the USA shows that patients with thyroid cancer have an increase in prevalence of subsequent RCC, and in patients with RCC, there is an increase in the prevalence of subsequent thyroid cancer (Van Fossen et al., 2013). This bidirectional association could be explained by shared genetic and/or environmental risk factors or treatment effects. Thyroid cancer has also been found with a greater frequency in the Cowden syndrome, familial adenomatous polyposis, and in multiple endocrine neoplasia type 2A (Cetta et al., 2000; Liaw et al., 1997; Biscolla et al., 2004).

The only study that attempts to identify a link between BHD and thyroid conditions is a five-year prospective study of twenty-two patients from ten unrelated French families with BHD (Kluger et al. 2010).  The authors identified thyroid nodules or cysts by ultrasonography in thirteen of twenty BHD patients. None of the affected individuals had thyroid carcinomas or a familial history of thyroid cancer. Overall, nine of the ten families affected by BHD with germline FLCN mutations included individuals with thyroid nodules. The high prevalence of thyroid nodules in the BHD patients in this study is suggestive, but the lack of a control group limits assessment of the significance of the results. Benhammou et al. (2011) also identified thyroid pathology in four of eleven BHD patients studied: three had hypothyroidism and one had a thyroid nodule. Mikesell et al., (2014) report another case of a BHD patient with thyroid nodules. Hypothyroidism and Hashimoto’s thyroiditis were noted in two other cases (Nadershahi et al., 1997; Khoo et al., 2002). There are also reports of multinodular goiter in association with BHD (Drummond et al., 2002; Welsch et al., 2005; Zeibek et al,. 2013; Mikesell et al., 2014). A parathyroid adenoma was diagnosed in one BHD patient of the Kluger et al. (2010) study, and previously in another BHD patient by Chung et al. (1996).

There is currently insufficient evidence to associate thyroid cancer and other thyroid conditions with BHD. However, all the studies mentioned suggest a possible link between the two that should be considered for future research.


Dong L, Gao M, Hao WJ, Zheng XQ, Li YG, Li XL, & Yu Y (2016). Case Report of Birt-Hogg-Dubé Syndrome: Germline Mutations of FLCN Detected in Patients With Renal Cancer and Thyroid Cancer. Medicine, 95 (22) PMID: 27258496

3 thoughts on “BHD syndrome and thyroid conditions

  1. I have hypertyroidism with normal calcium and normal vita D, and Bilateral thyroid nodules oNE side biopsied was benign but was spicious for thyroiditis..

  2. I have BHD and multiple nodules over my thyroid. I have recently had a biopsy and will now need yearly monitoring of my thyroid, the specialist said the biopsy showed unusual findings

  3. I have BHD and had papillary thyroid cancer along with parathyroid disease

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