Birt-Hogg-Dube Syndrome

A number sign (#) is used with this entry because Birt-Hogg-Dube syndrome (BHD), also known as Hornstein-Knickenberg syndrome, is caused by heterozygous mutation in the gene encoding folliculin (FLCN; 607273) on chromosome 17p11.

See also primary spontaneous pneumothorax (173600), an allelic disorder that may represent a milder part of the spectrum of the BHD syndrome.

Description

Birt-Hogg-Dube syndrome is an autosomal dominant genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax (Nickerson et al., 2002).

BHD is similar to, but histologically and genetically distinct from, familial multiple discoid fibromas (FMDF; 190340).

Clinical Features

Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis cutis with polyps of the colon' in 2 sibs. Their father was reportedly similarly affected, indicating an inherited condition. The proband was a 47-year-old woman who developed multiple perifollicular fibromas and skin tags affecting the neck, face, back, axillae, and groin. The skin lesions were 2 to 4 mm in diameter, flat-topped, solid, and skin-colored. Most had a central pit or plug. Histologic analysis showed whorl-shaped connective tissue fibers surrounding atrophic sebaceous glands. She also was found to have several colonic polyps, one of which showed malignant degeneration. The brother had similar adult onset of the skin lesions, but refused gastrointestinal examination. The patients' father also had renal and lung cysts. The disorder was distinguished from Gardner syndrome (see 175100). Hornstein and Knickenberg (1975) suggested that patients with follicular fibromatosis be examined for intestinal polyps. Hornstein (1976) reviewed the condition in this family and considered the disorder a genodermatosis.

Birt et al. (1977) described fibrofolliculomas with trichodiscomas (see 190340) and acrochordons in a family. Onset of this dermatologic condition was invariably in adulthood. A central hair was often visible in the lesions. Hereditary medullary carcinoma of the thyroid was also segregating, apparently independently, in the kindred. In a sibship of 9, 6 had medullary carcinoma of the thyroid. Two of those with thyroid cancer and 2 without had numerous small papular skin lesions that Birt et al. (1977) labeled fibrofolliculoma. The lesion was characterized by abnormal hair follicles with epithelial strands extending from the infundibulum of the hair follicle into a hyperplastic mantle of specialized fibrous tissue. Associated skin lesions were trichodiscomas (tumor of the hair disc) and acrochordons ('wart with a thin neck;' skin tag).

Fujita et al. (1981) reported the cases of 2 brothers and the son of one of them. By history the father of the 2 brothers was considered affected. Clinically the disorder was characterized by asymptomatic dome-shaped papules primarily involving the head, neck, chest, back, and arms. Ubogy-Rainey et al. (1987) likewise reported a family with 3 affected: a mother and her daughter and son. They discussed the clinical differential diagnosis of multiple firm, skin-colored papules. They diagrammed the histogenesis of benign follicular neoplasms, indicating that trichodiscomas are derived from the mesenchymal component of the pilar complex, trichofolliculomas, trichodiscomas, and trichoepitheliomas from epithelial components, and fibrofolliculomas from both epithelial and mesenchymal proliferation. Shapiro and Kopf (1991) described a family in which a mother and son had multiple desmoplastic trichoepitheliomas. The grandmother had a single cylindroma of the scalp.

Rongioletti et al. (1989) and Le Guyadec et al. (1998) described association of Birt-Hogg-Dube syndrome with intestinal polyposis. Roth et al. (1993) observed bilateral renal cell carcinoma in association with BHD. Chung et al. (1996) described multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with BHD.

Toro et al. (1999) evaluated kindreds with familial renal tumors for cutaneous manifestations of BHD. They performed complete oral and skin examinations of 152 patients from 49 families. In this way, they identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. BHD without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and acrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene (608537) or in the tyrosine kinase domain of the MET protooncogene (164860), which are known to be associated with renal neoplasms. The pedigree pattern was entirely consistent with autosomal dominant inheritance; for example, a father and both of his twin sons had renal tumor and BHD.

Weirich et al. (1998) described 5 families in which multiple members had multiple bilateral renal oncocytomas. On dermatologic examination, 13 members of 3 of these families were found to have cutaneous BHD lesions (Toro et al., 1999). Subsequently, through mass mailings to dermatologists, Schmidt et al. (2001) identified 33 families with BHD skin lesions and associated renal tumors, lung cysts, or pneumothorax, and/or colonic polyps, including the original Canadian family described by Birt et al. (1977). Zbar et al. (2002) showed that BHD confers an increased risk for the development of renal tumors and lung cysts or spontaneous pneumothorax but not for the development of colonic polyps.

Kidney cancer may be classified into 4 histologic types: clear cell (CCRC, 75%), papillary (PRC, 15%), oncocytoma (5%), and chromophobe (5%) (Kovacs et al., 1997). In a study of 130 renal tumors found in 30 BHD patients, the spectrum of renal histology included 34% chromophobe, 5% oncocytoma, 50% chromophobe/oncocytic hybrid, 9% clear cell, 2% papillary (Pavlovich et al., 2002).

Toro et al. (2008) reported the clinical features of 89 individuals from 51 families with BHD syndrome. Forty-six (90%) of 51 families had individuals with multiple fibrofolliculomas, and 26 (57%) of 46 BHD families had individuals with a second histologically confirmed cutaneous lesion, including angiofibroma, trichodiscoma, and perifollicular fibroma. Thirty (34%) of 89 individuals and 25 (49%) of 51 families had kidney tumours. Forty-five (88%) of 51 families and 75 (84%) of 89 individuals had lung cysts on CT imaging. Twenty-seven (53%) of 51 families and 34 (38%) of 89 individuals had a history of spontaneous pneumothorax, most often associated with lung cysts. Eighteen (58%) of 31 individuals with a family history of pneumothorax developed pneumothoraces compared to 16 (28%) of 57 individuals without family history (p = 0.011). Toro et al. (2008) noted inter- and intrafamilial phenotypic variation.

Kluijt et al. (2009) reported a large Dutch family with BHD syndrome confirmed by genetic analysis (607273.0015). The proband was a 27-year-old man with metastatic high-grade clear cell carcinoma of the kidney. His 32-year-old brother had high-grade papillary renal cell carcinoma, and a deceased sister of the maternal grandmother had a hybrid chromophobe/oncocytic renal carcinoma at age 71. She also had a history of recurrent pneumothorax. Six of 13 mutation carriers in the family who had a renal MRI scan showed unilateral or bilateral renal cysts; all were 55 years or older. Pneumothorax occurred in 8 mutation carriers at a relatively advanced age (third through sixth decades), and 5 had lung cysts and bullous lung disease. Eleven carriers had facial papules, most with onset after age 40. Kluijt et al. (2009) suggested that the relatively early age of renal cancer in some family members may be due to a modifier gene. Importantly, the clinical features of the family also illustrated that skin anomalies and/or lung disease are not mandatory for considering BHD in patients with renal cancer.

Pathologic Findings

The Hornstein-Knickenberg syndrome had been thought to be characterized by perifollicular fibromas, whereas BHD was characterized by fibrofolliculomas and trichodiscomas. Schulz and Hartschuh (1999) reported a father and daughter with a diagnosis of BHD. Extensive histologic examination of papular skin lesions indicated that histologic differences between the skin lesions are artificial and caused by interpretation of different sectioning planes; thus, fibrofolliculoma, perifollicular fibroma, and so-called trichodiscoma are in fact the same lesion. Similarly, some think that acrochordons are in fact fibrofolliculomas (Happle, 2012).

Starink et al. (2012) favored use of the term 'discoid fibroma' rather than 'trichodiscoma,' and suggested that most lesions described as 'trichodiscoma' in BHD were in fact 'fibrofolliculomas.'

Clinical Variability

Maffe et al. (2011) found FLCN mutations in 9 (47%) of 19 probands who presented initially with extracutaneous tumors suggestive of BHD syndrome, either a renal tumor or pneumothorax/lung cysts. Five (56%) of the 9 probands were found to have cutaneous hamartomas. Family history showed that 8 of the patients had affected relatives; however, 7 (44%) of 16 heterozygous relatives over the age of 20 years were asymptomatic. One patient had bilateral parotid oncocytomas, and tumor tissue showed loss of heterozygosity (LOH) for the wildtype FLCN allele. Maffe et al. (2011) noted that although most patients with BHD are ascertained on the basis of skin lesions, the diagnosis should be suspected in those who present with extracutaneous manifestations.

Inheritance

Birt et al. (1977) observed this disorder in 15 persons in 3 generations, with male-to-male transmission, consistent with autosomal dominant inheritance.

Mapping

Khoo et al. (2001) mapped the BHD locus by a genomewide linkage analysis using polymorphic microsatellite markers in a large Swedish family. They found evidence of linkage to chromosome 17p12-q11.2, with a maximum lod score of 3.58 for marker D17S1852. Further haplotype analysis defined a candidate interval of approximately 35 cM between the 2 flanking markers, D17S1791 and D17S798.

Schmidt et al. (2001) performed a genomewide scan in a large kindred with BHD and, by linkage analysis, localized the BHD locus to the pericentromeric region of 17p, with a lod score of 4.98 at D17S740 (recombination fraction = 0.0). Two-point linkage analysis of 8 additional families with BHD produced a maximum lod score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within an interval of less than 4-cM between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to 17p, suggesting genetic heterogeneity. The BHD locus lies within the chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy number repeat elements, is unstable and is associated with a number of diseases.

Nickerson et al. (2002) narrowed the critical region for the BHD locus to a 700-kb segment on chromosome 17p11.2.

Molecular Genetics

By positional cloning, Nickerson et al. (2002) identified a novel gene (FLCN) in this region encoding a protein called folliculin. In several BHD families, they identified protein-truncating mutations in the FLCN gene (607273.0001-607273.0005). Nickerson et al. (2002) stated that their identification of this novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer could contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.

Khoo et al. (2002) studied 4 sporadic BHD cases and 4 families with a total of 23 affected subjects. Haplotype analysis of these families using BHD-linked markers showed that they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified 2 germline mutations on exon 11 in 3 of 4 families as well as 2 of 4 sporadic cases. A novel somatic mutation was detected in a BHD-related chromophobe renal carcinoma.

Schmidt et al. (2005) performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (Nickerson et al., 2002), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD. Each family's mutation cosegregated with disease and was not found in at least 160 unaffected individuals. Of the 51 families with a germline BHD mutation, 27 (53%) had a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (1285insC, 607273.0001; 1285delC, 607273.0002, respectively), which appears to represent a mutation hotspot. Two large families with BHD, one of them the original family reported by Birt et al. (1977), showed linkage to 17p11.2 but had no mutation in the BHD gene by direct sequencing. Schmidt et al. (2005) noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene.

In affected individuals from 51 (88%) of 58 families with BHD, Toro et al. (2008) identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., 607273.0014). The 1285insC or 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except one were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations.

Kunogi et al. (2010) screened the FLCN gene by DHPLC in 36 Japanese patients with multiple lung cysts of undetermined causes, all but 1 of whom had suffered at least 1 pneumothorax, and identified 13 different germline mutations in 23 of the patients, respectively. The remaining 13 patients were further analyzed by quantitative PCR, and large genomic deletions (see, e.g., 607273.0017) were found in 2; thus 25 (69.4%) of the 36 patients had germline FLCN mutations. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors, 1 of which was an angiomyolipoma and the other a renal cancer (histopathologic information unavailable). Kunogi et al. (2010) noted that 13 (52%) of the 25 mutations were located in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutations had a very low incidence of skin and renal involvement.

Nomenclature

Happle (2012) noted that Hornstein and Knickenberg (1975) first described this disorder as 'perifollicular fibromatosis with polyps of the colon--a cutaneo-intestinal syndrome.' Since the designation 'Birt-Hogg-Dube syndrome' is entrenched in the medical literature, it is retained here as the preferred title; 'Hornstein-Knickenberg syndrome' is used here as an alternative title to give credit to the original authors.

Animal Model

Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. Lingaas et al. (2003) narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype.