In order to further understand the clinical aspects and symptoms of BHD syndrome, it is important that novel findings discovered during patient analysis are published in case reports. This assists in unravelling genotype-phenotype correlations, and also in identifying trends, for example the age of onset of certain symptoms.
Alonso-Gonzalez et al. (2011) recently reported the case of a 64 year-old woman who presented with localised fibrofolliculomas on the right side of the neck. The patient had no other evident BHD symptoms, however benign renal and hepatic cysts were found upon further investigation. There was no family history of BHD symptoms, but subsequent genetic testing identified a son with a FLCN mutation who had multiple lung cysts.
Only two previous cases have been reported with localised fibrofolliculomas (Schulz et al., 2001 and Weintraub and Pinkus, 1977). These cases also had no systemic disease symptoms and the case reported by Schulz et al. had no family history of BHD syndrome. It has been proposed that localised fibrofolliculomas may be related to a less severe form of BHD syndrome.
Alonso-Gonzalez and colleagues identified a novel FLCN mutation in the reported patient. The mutation in exon 5 substitutes a Valine for a Serine at position 124 and is predicted to introduce a premature stop codon, resulting in the production of a truncated form of FLCN. The two previously reported cases of localised fibrofolliculomas were not analysed for FLCN mutations and so no genotype-phenotype correlation can be found.
Kluger et al. (2010) have previously proposed that the localisation of fibrofolliculomas might be caused by a segmental type 2 manifestation. This is the loss of the corresponding wildtype allele in a heterozygous embryo. Other skin diseases characterised by a type 2 segmental manifestation include cutaneous leiomyomatosis (the skin symptoms associated with HLRCC) and tuberous sclerosis (Happle, 2001), both of which are related to BHD syndrome.
This report shows that mutations in FLCN can also cause localised forms of BHD. However, as these cases are infrequently documented, their severity and association with other clinical symptoms of BHD syndrome is unknown. Recently, Starink et al. (2011) characterised the distinction between FMDF skin lesions and fibrofolliculomas (discussed in a previous blog post), which will aid in the differential diagnosis of these two diseases. It is hoped that future research into fibrofolliculomas will lead to a greater understanding of their development and to the discovery of successful treatments.
- Alonso-González J, Rodríguez-Pazos L, Fernández-Redondo V, Vega-Gliemmo A, Toribio J. Birt-Hogg-Dubé syndrome in a patient with localized fibrofolliculomas and a novel mutation in the FLCN gene. Int J Dermatol. 2011 Aug;50(8):968-71. PMID:21781069
- Happle R. Segmental type 2 manifestation of autosome dominant skin diseases. Development of a new formal genetic concept. Hautarzt. 2001 Apr;52(4):283-7. PMID:11382117
- Kluger N, Giraud S, Coupier I, Avril MF, Dereure O, Guillot B, Richard S, Bessis D. Birt-Hogg-Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010 Mar;162(3):527-37. PMID:19785621
- Schulz T, Ebschner U, Hartschuh W. Localized Birt-Hogg-Dubé syndrome with prominent perivascular fibromas. Am J Dermatopathol. 2001 Apr;23(2):149-53. PMID:11285413
- Starink TM, Houweling AC, van Doorn MB, Leter EM, Jaspars EH, van Moorselaar RJ, Postmus PE, Johannesma PC, van Waesberghe JH, Ploeger MH, Kramer MT, Gille JJ, Waisfisz Q, Menko FH. Familial multiple discoid fibromas: A look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus. J Am Acad Dermatol. 2011 Jul 25. [Epub ahead of print]. PMID:21794948
- Weintraub R, Pinkus H. Multiple fibrofolliculomas (Birt-Hogg-Dubé) associated with a large connective tissue nevus. J Cutan Pathol. 1977 Dec;4(6):289-99. PMID:753849
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.