Birt-Hogg-Dube: Autosomal Dominant Syndrome - Essay Example

?Introduction Birt-Hogg-Dube (BHD) is an autosomal dominant syndrome characterized clinically as benign tumors on the skin which are dome-shaped, andwhitish in colour (Figure 1) (Drummond Grigoris and Dutta, 2002). Clinically-associated lesions typically occur after 20 years of age and typically manifest as multiple papules on the face, especially on the cheeks and nose (Herring et al, 2009). Renal cancer is perhaps the most clinically significant complication associated with BHD; according to Coplin (2008), about 27% of patients with BHD present with renal cancer at an average age of 50 years. Both molecular and clinical diagnosis are applicable in the diagnostic procedures of BHD. Nonetheless, molecular diagnosis provides a conclusive diagnosis because it determines whether there is genetic mutation within the FLCN gene in the DNA of individuals who demonstrate clinical symptoms of BHD. Families which are affected by BHD are put under surveillance during molecular studies which aids in genetic counseling. This report will present the molecular and genetic diagnosis of BHD together with a discussion of its clinical manifestations, treatment and management, appropriate counseling and surveillance, relevant clinical studies and the future in the studies and management of the syndrome. Figure 1: Clinical manifestation of BHD in the skin of 4 patients. The skin- papules are colored and clinically compatible with trichodiscomas or fibrofolliculomas (a) papules within the neck (b) papules on the ear (c) on the forehead of patient (d) papules on the nose and the paranasal area (e) Histological picture of a biopsy of a fibrofolliculoma. Histological presentation of the syndrome illustrates dilated hair follicles with anastomosing strands in basal layer with basaloid cells which is surrounded by the fibromucinous stroma. Folliculin and Mechanisms Leading to BHD Mutations in folliculin (FLCN) are found to be causative of BHD. FLCN is mapped to chromosome 17p11.2 though it is poorly understood at the molecular level. Menko et al (2008) demonstrated its epistatic interaction with various genes involved with mammalian target of rapamycin (mTOR) signaling. The role of FLCN in BHD has prompted haplotype analyses, those which seek to determine whether individuals within a given family share alleles. Sequencing analyses of FLCN have revealed mutations along various exons of the gene, including exon 11, to be causative of BHD (figure 2). While the role of FLCN is currently poor understood, the mTOR pathway plays a central role in the regulation of cell proliferation, growth and metabolism (figure 3) (Drummond, Dutta and Grigoris, 2002). In vitro studies have demonstrated that deregulation of the mTOR pathway results from pathogenic FLCN mutations (Bessis, Giraud and Richard, 2006). It is through the deregulation of the mTOR pathway that various human diseases, especially cancer, arises (Maffe et al, 2011). Thus, the involvement of FLCN in the mTOR pathway and the associated deregulation of the same could be attributed to the renal cancer seen with BHD. Phosphorylated ribosomal protein (s6K) has also been linked to the FLCN protein. Studies have elucidated a reduction in the phosphorylation of s6K when FLCN is down regulated by endogenous short-interfering RNA (siRNA) (Coplin, 2008). Figure 3: The motor pathway illustrating the activation of AKT, P13K and the mTOR pathway itself by a tyrosine kinase receptor. mTOR leads to translation of eukaryotic initiation factor 4EBP1 and p70S6 kinase resulting in cell growth, protein sysnthesis and proliferation. Downregulation of mTOR pathway activity often leads to cell aptosis. The deregulation of the mTOR pathway, as can be caused by FLCN mutations is posited to result in BHD (Original Diagram: Information extracted (Menko et al, 2008). Molecular and clinical diagnostics of BHD In the past, BHD was diagnosed through determination of the presence of a minimum of 5-10 fibrofolliculomas, or skin-coloured papules, where at least one observed papule has been confirmed as such, histologically. Aforementioned clinical observations are followed-up by genetic analysis of FLCN for BHD status (Houweling et al, 2011). Variability in clinical presentation has been identified in BHD affected families; some individuals with confirmed FLCN mutations do not present with any skin lesions (Bessis Giraud and Richard, 2006). While the diagnosis of BHD relies of molecular testing criterion, a phenotype-genotype correlation is the most effective diagnostic criteria in reaching a conclusive diagnosis (Bowser, 2005). Patients suspected of BHD through differential diagnosis using clinical presentation should therefore be offered and accorded genetic testing so that a BHD diagnosis can be made. Using phenotype to justify genotyping, Bessis et al (2006) recommends patients with early, undefined renal cell carcinomas be considered for BHD genetic testing (Giraud and Richard, 2006). A diagnosis of BHD can also be made on the basis of unexplained pneumothorax, cystic lung disease, or both (Imada et al, 2009). Diagnosis of BHD through lesions in lung tissue is especially significant when bilateral lung cysts, located at the basal zone of the lung, are identified through histological examination. Additionally, cases of familial renal cancer or spontaneous pneumothorax, or a combination of both, define a framework for the clinical diagnosis of BHD (Drummond, Grigoris and Dutta, 2002). However, it is recommended that a referral of all BHD associated features, as they have been outlined above, be made for FLCN mutation and pedigree analyses for conclusive diagnosis of BHD. Genetic testing is highly recommended by clinicians, even when clinical diagnosis for the disorder appears unambiguous (Kluijt et al, 2009FLCN testing for BHD is the current genotyping as FLCN is the only known gene implicative of BHD. DNA testing as a basis for BHD diagnosis involves gene sequence analyses for both amplifications as well as with exon deletions (Coplin, 2008). Proper clinical diagnosis provides a basis for presymptomatic testing of relatives of affected individuals who have a genetic predisposition to BHD (Menko et al, 2008). Relatives with BHD could have a familial mutation while not presenting with clinical skin fibrofolliculomas or other, associated features. Genetic testing could serve to fill a void where clinical examination of BHD is inadequate. This is particularly important where pneumothorax (especially cases of tension pneumothorax) and renal cancer are concerned and could be monitored before their onset. This could equate to better prognostic outcomes for those presymptomatic of BHD. Molecular studies are used to investigate and analyze clinical findings of dermatological and/or neoplastic origins. Molecular analysis for BHD involves extraction of peripheral blood for DNA extraction which is analyzed through standardized methods and procedures; focused on testing for FLCN mutations (Bowser, 2005 and Pavlovich et al, (2005). The most frequently used molecular assay in the detection of FLCN mutations, is Multiplex Ligation-dependent Probe Amplification (MLPA) because it allows copy number detection in the FLCN gene mutations. A summary of genetic testing for BHD is presented on Table 1. Gene Symbol Test Method Mutations Detected Mutation Detection Frequency by Test Test Availability FLCN Sequence analysis of exon 11 Polycytosine tract deletion (c.1285delC) /duplication (c.1285dupC) 53% Clinical Testing Sequence analysis of entire coding region Sequence alterations 88% Table 1: Summary of Molecular Genetic Testing Used in Birt-Hogg-Dube Syndrome. Sequence analysis of exon 11 and the entire coding region is illustrated. Exon 11 of the FLCN gene shows polycytosine tract deletion (c.1285delC) /duplication (c.1285dupC) clinical testing illustrate sequence alterations in the entire coding region (Original Table: Mutation Detection Frequency as presented by Houweling et al, (2011). Genetic counselling and BHD In the case of BHD, genetic counseling is necessary and offered when a genetic test confirms a pathogenic mutation in FLCN (Bowser, 2005). According to Herring et al (2009), genetic testing must integrate, as part of the testing process, genetic counseling for those affected. This is posited to enable other family members at risk BHD to justify their being testing for the syndrome. Genetic counseling is usually focused on the family members who are at risk of having inherited a pathogenic mutation often follows, with consent, a cascade of genetic tests, staring from those affected or presymptomatic, leading down the pedigree toward those with a predisposition to BHD. Centres for genetic testing and counseling normally have a surveillance programme starting at age 20. Genetic counseling for BHD includes surveillance programs where high risk family members are monitored for the manifestation of clinical features. While surveillance is typically initiated at age 20, those considered capable of giving informed consent for genetic testing, typically as young as 16 years, can start the counseling process themselves. This is followed by genetic testing which is conjugated with period of counseling programs for both young and old high risk family members (Houweling et al, 2011). Discussion Future molecular and clinical studies are likely to lead to a diagnostic process which will likely qualify the nature of a mutation so as to accommodate for the variability in manifestations of pneumothorax and of renal cell carcinomas (Krunic, Medenica and Welsch, 2005). This insight could also lead to better accuracy in diagnosis of patients not presenting with fibrofolliculomas even though they have a ‘pathogenic’ mutation in FLCN. Future testing methods for BHD will involve early surveillance of the syndrome and close monitoring of those at-risk family members so that BHD-associated features, particularly those with high morbidity, may be contained earlier than before (Menko et al, 2008). Future testing methods for BHD are likely to involve chest roentgenogram, or X-ray, screening, particularly for those at-risk of lesions of the skin, lungs or kidneys (Herring et al, 2009). As far as treatments for BHD, there exist a few therapeutic approaches. Rapamycin analogues are considered to be the most viable therapeutic approach to patients of disseminated renal cancer in those with BHD. Other mTOR inhibitors such as dual PI3K have been recommended for treatment and management of renal cancer. Therapeutic measures using rapamycin in animal models illustrated diminished renal cell carcinomas and other, associated pathologies (Coplin, 2008). Herring et al (2009) points out that in the treatment of BHD, surgical methods can also be applied to remove the papules especially in extreme expression of fibrofolliculomas. Conclusion Molecular diagnosis provides a conclusive diagnosis because it determines whether there is genetic mutation within the FLCN gene which is attributed to BHD. Therefore the clinical symptoms which manifest on the skin as whitish papules require a conclusive diagnosis through genetic examination of the genotype of the affected individual. The DNA of individuals who demonstrate clinical symptoms of BHD is examined through assays such as Multiplex Ligation-dependent Probe Amplification to detect even copy mutations within the FLCN gene. Molecular studies of Birt-Hogg-Dube (BHD) Syndrome within the affected families provide the basis for genetic counseling. References Al Fares A, Millington G, and Tischkowitz M (2010). Dermatological features of inherited cancer syndromes in adults. Clinical and Experimental Dermatology 35(5): 462-467. Bessis D, Giraud S, and Richard S (2006). A novel familial germline mutation in the initiator codon of the BHD gene in a patient with Birt–Hogg–Dube syndrome. British Journal of Dermatology 155(5): 1067-1069. Bowser A (2005). Multiple facial papules? Consider Birt-Hogg-Dube. Dermatology Times 26(2): 66-67. Coplin R. E (2008) Birt Hogg Dube syndrome. Internet Journal of Pulmonary Medicine 9(2): 2. Drummond C, Grigoris I, and Dutta, B (2002). Birt–Hogg–Dube syndrome and multinodular goitre. Australasian Journal of Dermatology 43(4): 301-304. Herring K, Reed S, O'Hearn D, White C, White K, & Simpson E (2009). Spontaneous Pneumothorax and Facial Papules: Birt-Hogg-Dube? Syndrome. Internet Journal of Pulmonary Medicine 11(1): 11. Houweling A, Gijezen L, Jonker M, van Doorn M, Oldenburg R, van Spaendonck-Zwarts K, Leter E, van Os T, van Grieken N, Jaspars E et al (2011). Renal cancer and pneumothorax risk in Birt-Hogg-Dube syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. British Journal of Cancer 105(12): 1912-1919. Imada K, Dainichi T, Yokomizo A, Tsunoda T, Song Y, Nagasaki A, Sawamura D, Nishie W, Shimizu H, Fukagawa S et al (2009). Birt–Hogg–Dube syndrome with clear-cell and oncocytic renal tumour and trichoblastoma associated with a novel FLCN mutation. British Journal of Dermatology 160(6): 1350-1353. Kluger N, Giraud S, Coupier I, Avril M, Dereure O, Guillot B, Richard S, and Bessis D (2010). Birt–Hogg–Dube syndrome: clinical and genetic studies of 10 French families. British Journal of Dermatology 162(3): 527-537. Kluijt I, de Jong D, Teertstra H, Axwijk P, Gille J, Bell K, van Rens A, van der Velden A, Middelton L, and Horenblas S (2009). Early onset of renal cancer in a family with Birt–Hogg–Dube syndrome. Clinical Genetics 75(6): 537-543. Lindor N, Hand J, Burch P, & Gibson L (2001). Birt-Hogg–Dube Syndrome: an autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. International Journal of Dermatology 40(10): 653-656. Maffe AB, Toschi G, Circo D, Giachino S, Giglio A Rizzo, and Genuardi M (2011). Constitutional FLCN mutations in patients with suspected Birt-Hogg-Dube syndrome ascertained for non-cutaneous manifestations. Clinical Genetics 79(4): 345-354. Menko F, Leter E, Koopmans A, Gille J, van Os T, Vittoz G, David E, Jaspars E, Postmus P, van Moorselaar et al (2008). Birt-Hogg-Dube Syndrome: Clinical and Genetic Studies of 20 Families. Journal of Investigative Dermatology. 128(1): 45-49. Pavlovich CP, Grubb RL, Hurley K, Glenn GM, Toro J, Schmidt LS, Torres-Cabala C, Merino MJ, Zbar B, Choyke P et al (2005). Evaluation and management of renal tumors in Birt- Hogg-Dube syndrome. Journal of Urology. 173(5): 1482-1486. Welsch M, Krunic A, and Medenica M (2005). Birt–Hogg–Dube Syndrome. International Journal of Dermatology. 44(8): 668-673. Read More