Birt-Hogg-Dubé Syndrome (BHD) has a wide range of clinical presentations and a large degree of heterogeneity between patients, even within the same family. Currently, the only clinical manifestations formally associated with BHD are skin lesions (e.g. fibrofolliculomas), lung cysts and pneumothorax, and renal tumours (1). However, there have been several reports of other findings in the literature including colon cancer, parotid tumours and thyroid pathology, but there is not yet sufficient evidence to link BHD with these other clinical presentations (2).

BHD patients can present with multiple manifestations and there is no way of predicting which signs and symptoms a person may have. However, it is estimated that:

If you suspect BHD based on the clinical presentations described below you should always take a detailed family history and if appropriate refer for genetic testing for BHD.

Skin Manifestations

Cutaneous manifestations of BHD include fibrofolliculomas, trichodiscomas and acrochordons, of which fibrofolliculomas are the most common (3). Fibrofolliculomas and trichodiscomas are hamartomas of the hair follicle or benign hair follicle tumours. It is thought that trichodiscomas and fibrofolliculomas are part of the same morphological spectrum, or even the same lesion (4). Although not specific to the general population, acrochordons are more common in BHD patients and there is some evidence that in BHD patients they may be a phenotypic variant of fibrofolliculomas (3). Rarely, angiofibromas, lipomas, oral papules, and skin cancer (basal cell carcinoma and malignant melanoma) have been identified in BHD patients.

Fibrofolliculomas are 2-4 mm pale or flesh-coloured, smooth, dome-shaped papules that are mainly found on the face, neck and trunk; the age of onset is usually from 20 years (3). Patients may have very few skin lesions or hundreds, and due to the genetic aspect of this condition, they may increase in number over time (1). It should be noted that although fibrofolliculomas are the most common manifestation in Caucasian populations, it is thought to be far less common (or possibly underdiagnosed) in East Asian BHD patients (2). If you are suspicious that a patient may have fibrofolliculomas refer to a dermatologist for a biopsy.

Examples of Fibrofolliculomas

Lung Manifestations

The most common presentations of BHD in the lung are cysts and pneumothoraces. There is currently no association between BHD and lung cancers, although lung adenocarcinoma, bronchoalveolar carcinoma and histiocytoma have been reported in BHD patients (1,2). The age of onset of lung cysts is unknown, but have been described in patients from 20 years of age and above (5). Spontaneous pneumothorax is often the first symptom reported in a BHD patient, with the average age of the first occurrence of pneumothorax is between 30 and 40, depending on the cohort analysed. However, pneumothoraces have also been reported in children with BHD, suggesting that lung cysts may form in childhood (1).   

Lung cysts have no sex predilection or association with smoking and appear to be generally asymptomatic and do not affect lung function. However, there is the propensity for these lung cysts to rupture and cause a pneumothorax. The signs and symptoms of a pneumothorax in BHD patients is identical to other spontaneous pneumothoraces: pleuritic chest pain and breathlessness. The treatment and management of this may be different due to the high recurrence rate of pneumothoraces (see Management and Treatment Guidelines page for more information).

Unless a BHD patient has a spontaneous pneumothorax, lung cysts are often an incidental finding on an xray or CT scan. It is therefore important to recognise the features of lung cysts that are specific to BHD. The most distinguishing feature of BHD-associated lung cysts is the basal predominance of the lesions (6).The size, shape and number of cysts can vary greatly between patients. The majority of cysts are less than 1 cm in diameter, but can vary from a few millimetres to over 2 cm. Cysts are mostly irregular in shape but usually have visible, thin, uniform walls. The number of cysts found in BHD patients ranges from just a few to more than 400, however the majority of patients present with fewer than 20 cysts and less than 30% lung involvement (2).

Kidney Manifestations

The most life-threatening complication of BHD is renal cell carcinoma with a typical age of onset around 50 years (2). Renal tumours in BHD are most commonly bilateral and multifocal and can reoccur. Histologically, they are typically chromophobe, oncocytoma or a hybrid of the two however clear cell carcinoma and papillary carcinoma have been reported (7). Metastatic renal cancer is uncommon in BHD as these tumours are normally slow growing, but may also be in part due to routine monitoring of the kidneys for tumours (see Management and Treatment Guidelines page for more information) (4).

The most common symptoms of renal cancer include: blood in the urine, flank pain and a lump or swelling in the side. Other symptoms include unexplained weight loss, loss of appetite, extreme tiredness, high blood pressure, night sweats and a high temperature.

Information on the treatment of BHD-associated renal cancer can be found here.

References

1.        Sattler EC, Steinlein OK. Birt-Hogg-Dubé Syndrome. GeneReviews® [Internet]. 2020 Jan 30 [cited 2021 Jul 20]; Available from: https://www.ncbi.nlm.nih.gov/books/NBK1522/

2.        Daccord C, Good JM, Morren MA, Bonny O, Hohl D, Lazor R. Birt–hogg–dubé syndrome. Eur Respir Rev [Internet]. 2020 Sep 30 [cited 2021 May 20];29(157):1–14. Available from: https://doi.org/10.1183/16000617.0042-2020].

3.        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 20]. p. 87–101. Available from: https://link.springer.com/article/10.1007/s40257-017-0307-8

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 20]. p. 1199–206. Available from: https://pubmed.ncbi.nlm.nih.gov/19959076/

5.        N G, K S, FX M. Pulmonary manifestations of Birt-Hogg-Dubé syndrome. Fam Cancer [Internet]. 2013 Sep [cited 2021 Jul 20];12(3):387–96. Available from: https://pubmed.ncbi.nlm.nih.gov/23715758/

6.        K T, Y G, M K, M K, K K, N T, et al. Characteristics of pulmonary cysts in Birt-Hogg-Dubé syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol [Internet]. 2011 Mar [cited 2021 Jul 30];77(3):403–9. Available from: https://pubmed.ncbi.nlm.nih.gov/19782489/

7.        Stamatakis L, Metwalli AR, Middelton LA, Linehan WM. Diagnosis and Management of BHD-Associated Kidney Cancer. Fam Cancer [Internet]. 2013 Sep [cited 2021 Jul 21];12(3):397. Available from: /pmc/articles/PMC4175415/