Birt-Hogg-Dube syndrome

Autosomal dominant disease characterized by skin lesions, pulmonary cysts, spontaneous pneumothorax and increased predisposition to renal cancer.

Birt-Hogg-Dub syndrome (BHD) is characterized by cutaneous lesions, renal tumors and pulmonary cysts that may be associated with pneumothorax. It is a rare clinicopathologic condition with an estimated prevalence of 1 in 200,000 people, but the exact incidence is unknown. BHD syndrome is transmitted in an autosomal dominant mode and is caused by the presence of pathogenic variants of the FLCN tumor suppressor gene.

Symptoms

The main clinical manifestations occur from adulthood onwards and include benign skin tumors, lung cysts and different types of renal tumors.

Dermatologic changes occur, usually developing during the third and fourth days of life and persisting indefinitely. Fibrofolliculomas are benign tumors that appear in the hair follicles and look like small, raised, whitish lumps located on the skin of the face, ears, neck and chest. Other characteristic cutaneous anomalies are trichodiscomas and acrochordons (cutaneous papillomas). Multiple pápulas and lipomas (benign tissue formed by fatty tissue) may also form.

Disease management

There is no specific treatment for the clinical symptoms of the syndrome. Regarding the dermatologic manifestations, surgical and laser treatment may result in temporary improvement of the folliculomas, but the lesions frequently recur. If possible, nephron-sparing surgery is the treatment of choice for renal tumors, depending on their location and size.

Patients with BHD should avoid exposure to large environmental pressure differences, as this situation could trigger a pneumothorax. Patients who are engaged, for example, in piloting or deep-sea diving should seek advice from a pulmonary physician. In addition, avoidance of smoking is recommended because it may be a risk factor for pneumothorax and renal cancer, although this association still requires further scientific evidence.

Genes analyzed

FLCN

Bibliography

Jensen, D. K., Villumsen, A., Skytte, A. B., et al. Birt-Hogg-Dubé syndrome: a case report and a review of the literature. European clinical respiratory journal. 2017 Feb 20;4(1):1292378.

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Nahorski, M. S., Lim, D. H., Martin, L., et al. Investigation of the Birt-Hogg-Dube tumor suppressor gene (FLCN) in familial and sporadic colorectal cancer. Journal of medical genetics. 2010 Jun;47(6):385-90.

Sattler, E. C., Reithmair, M., Steinlein, O. K. Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dubé syndrome. PloS one. 2018; 13(12): e0209504.

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Sattler, E. C., Steinlein, O. K. Birt-Hogg-Dubé Syndrome. GeneReviews®. University of Washington, Seattle.

Sattler, E. C., Syunyaeva, Z., Mansmann, U., et al. Genetic Risk Factors for Spontaneous Pneumothorax in Birt-Hogg-Dubé Syndrome. Chest. 2020 May;157(5):1199-1206.

Schmidt, L. S., Linehan, W. M. Clinical Features, Genetics and Potential Therapeutic Approaches for Birt-Hogg-Dubé Syndrome. Expert opinion on orphan drugs. 2015;3(1):15-29.

Toro, J. R., Wei, M. H., Glenn, G. M., et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. Journal of medical genetics. 2008 Jun;45(6):321-31.

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