Birt-Hogg-Dubé syndrome (BHD) is a rare, inherited genetic disorder. It is autosomal dominant and considered to be mono-genic (‘Molecular Biology and Genetics’): the relevant gene – folliculin (FLCN) – has been identified, mapped and sequenced.

BHD was first described in 1977 by three Canadian doctors – Birt, Hogg and Dube.[2].  To date, fewer than 300 patients from fewer than 100 families have been described.  Given the phenotype (see below) and the current level of awareness of the syndrome, it is believed to be under-diagnosed.

BHD syndrome has three known symptoms, none of which appear before the second or third decade of life.

1. Non-cancerous tumours/lesions of the hair follicles on the skin. These are particularly prevalent on the face, neck and upper torso and first appear in the second or third decade of life.
2. Lung, air-filled cysts (Toro et al., 1999, Zbar et al., 2002) and an increased risk of a collapsed lung (pneumothorax).  Schmidt et al in 2005 found that 110 out of 129 (85%) BHD syndrome patients had one or more lung cysts and 64 out of 198 (32%) had pneumothorax (Schmidt et al., 2005).
3. Kidney cancer (renal cell carcinoma) Different histological types are observed within families and also within individual patients (Pavlovich et al., 2002)

There is phenotypic variation.  Patients have been observed with just one of the symptoms, or any two, or all three, and kidney cancer is seen in between 15% and 30% of cases.

It seems plausible that individuals with a mutated copy of flcn actually display an as-yet-undescribed phenotype earlier than the ‘second or third decade of life.  It is unclear what this phenotype might be.  There have been some reports that BHD individuals have an increased risk of colo-rectal tumours (Rongioletti et al 1989) but this is controversial and might be either false or true for only a subset of patients (Zbar et al., 2002, Khoo et al., 2002).

References

1. Nickerson, M. L. et al. 2002. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2: 157-164. PMID 12204536
2. Birt, A. R., Hogg, G. R., and Dubé, W. J. 1977. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch. Derm. 113: 1674-1677. PMID 596896
3. Baba, M. et al., 2006. Folliculin encoded by the BHD gene interacts wtiha binding protein, FNIP1 and AMPk, and is involved in AMPK and mTOR signalling.
4. Schmidt, L. S. et al. 2005. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.