A BHD germline mutation identified in an Asian family with Birt-Hogg-Dubé syndrome.
Article: Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients.[show abstract] [hide abstract]
ABSTRACT: Birt-Hogg-Dubé (BHD) syndrome is an autosomal-dominantly inherited cancer syndrome characterized by fibrofolliculomas, lung cysts leading to pneumothorax, and chromophobic/oncocytic renal cell carcinoma. The disease is caused by heterozygous mutations in the BHD gene encoding folliculin and all mutations reported putatively lead to protein truncation. Although the function of folliculin is unknown, it is thought to be a tumor suppressor, with loss of heterozygosity (LOH) initiating tumor formation. Here, we report on four novel BHD gene mutations, including two splice-site mutations, in patients presenting with skin lesions only. We further show that LOH cannot be detected in fibrofolliculomas from three patients, suggesting that for the manifestation of cutaneous tumors in BHD syndrome haplo-insufficiency of folliculin is sufficient to initiate uncontrolled growth. Renal microscopic oncocytosis in BHD is considered as a precursor to malignant kidney tumors and may likewise be the result of haplo-insufficiency, with somatic second-hit mutations or LOH giving rise to malignancy later in life.Journal of Investigative Dermatology 04/2007; 127(3):588-93. · 6.31 Impact Factor
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ABSTRACT: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant genodermatosis predisposing to the development of multiple fibrofolliculomas (FFs), pulmonary cysts, spontaneous pneumothorax and renal neoplasms. The association of BHDS with various nonrenal neoplasms has been reported but remains controversial. To report the clinical features and germline mutations in 22 patients from 10 unrelated families with BHDS investigated during a 5-year prospective study by the Department of Dermatology at the University Hospital of Montpellier, France. Also, to define more clearly the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHDS. Twenty-two patients with clinical and histological criteria of BHDS confirmed by FLCN (previously BHD) germline mutation were evaluated. Lung cysts and pneumothorax were detected by thoracic computed tomography (CT) scanning. Abdominal magnetic resonance imaging (MRI) or CT scans and/or renal ultrasonography were performed to screen for tumours. Thyroid nodules and goitres were assessed by clinical examination, ultrasound imaging and measurement of serum thyroid-stimulating hormone and thyrocalcitonin. Eighteen of the 22 individuals affected by BHDS (82%) were diagnosed with five or more FFs. Multiple epidermal cysts, severe facial hyperseborrhoea and oral papules were noted, respectively, in three of 22 (14%), nine of 22 (41%) and nine of 21 patients (43%). Spontaneous pneumothorax was reported in seven affected patients (32%). Cystic lesions were detected in 14 of 20 patients (70%) and mainly displayed a subpleural and basal location. Renal ultrasound, CT scan and/or MRI revealed renal cysts in 10 patients (45%), without renal carcinoma diagnosed thus far. Thyroid nodules and/or cysts were disclosed by ultrasound examination in 13 of 20 cases (65%). No medullary carcinoma or other thyroid carcinomas were detected. Colonoscopy failed to detect colorectal carcinoma. We report here the largest series to date of French patients with BHDS. We noted a high prevalence of thyroid nodules and renal cysts. However, the lack of a control group does not allow assessment of whether or not such association with BHDS is fortuitous.British Journal of Dermatology 09/2009; 162(3):527-37. · 3.67 Impact Factor
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ABSTRACT: The Birt-Hogg-Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP-sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline-mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real-time quantitative PCR (RQ-PCR) was very low. Renal tumour subtype/nephron segment-specific gene expression detected by RQ-PCR demonstrated that the tumour expressed relatively high amounts of alpha-methylacyl-CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11-beta-hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub-classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron-associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD-mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification.The Journal of Pathology 05/2007; 211(5):524-31. · 6.32 Impact Factor
© 2008 Acta Dermato-Venereologica. ISSN 0001-5555
Acta Derm Venereol 88
Letters to the Editor
Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is
an autosomal dominant genodermatosis characterized
clinically by multiple occurrence of fibrofolliculoma or
trichodiscoma, and associated with an increased risk of
developing renal neoplasms and lung cysts/spontaneous
pneumothorax (1). The responsible gene has been map-
ped on chromosome 17p11.2 encoding folliculin, a cy-
toplasmic protein with unknown functions (2). Various
different BHD germline mutations have been reported;
most of which were identified in Caucasian families
(2–6). However, there have been recent reports of such
BHD mutations in Asian families, although the number
of such reports is still small (7–9). We report here an
Asian family with BHD with a BHD germline mutation,
demonstrating the importance of BHD gene analysis.
The proband, a 67-year-old Japanese woman, presented with
a 10-year history of multiple papules on her face and neck. A
clinical examination revealed numerous, smooth, dome-shaped,
white to skin-coloured papules, measuring 2–4-mm in diameter
on her face and neck (Fig. 1A). The medical histories of her
family members (Fig. 1B) and of the patient herself did not
reveal any incidences of renal and other visceral neoplasms or
of pneumothorax, and she was also not aware of other family
members who had similar papules on the face and neck. A sub-
sequent, careful examination of her 2 daughters (aged 38 and 35
years, respectively), however, revealed several, scattered, white
to skin-coloured, small papules on the face and neck in her oldest
daughter and only a few skin-coloured, small papules on the neck
in her second daughter. Neither daughter had noticed the papular
lesions. No other family members could be examined. Biopsy
specimens of 8, 2 and 1 papule were removed from the proband,
her oldest daughter, and her second daughter, respectively.
Histopathological examination revealed the 8 papules from the
proband to be 3 fibrofolliculomas (Fig. 1C) and 5 trichodiscomas.
The histopathological features of both papules from the oldest
daughter and one papule from the second daughter showed a
superficial, dilated or cystic infundibulum with a small amount of
perifollicular connective tissue and the sebaceous lobules below
the infundibulum despite examination of many serial sections;
these features were not sufficient to diagnosis fibrofolliculoma
or trichodiscoma. Based on these clinical and histopathological
findings of the papules, the proband was diagnosed with BHD,
while her daughters were suspected to have BHD. Renal ultra-
sound as well as chest and abdominal computed tomography
(CT) scans for the proband and her daughters demonstrated no
renal neoplasms, but revealed a lung cyst on the left lung in the
oldest daughter and multiple bilateral lung cysts in the second
daughter (but no lung cysts in the proband). Colonoscopy for the
proband revealed a single adenomatous polyp.
A DNA sequence analysis of the BHD gene was performed for
the proband and her 2 daughters after obtaining informed consent.
Her brother, 2 sisters, and 2 grandsons were not available for
testing. DNA was extracted from peripheral blood leukocytes, and
subjected to mutation screening. All the exons of the BHD gene
were amplified by PCR using pairs of oligonucleotide primers
synthesized according to a previous report (2). The sequencing
analyses of the PCR products revealed a deletion of guanine/
adenine/thymine/guanine in exon 13 (c.1988delGATG) in the
proband and both her daughters (Figs 1 and 2). This deletion
causes the formation of a stop codon, TGA at the deletion site
in exon 13. No further analyses were performed to determine
whether this mutation results in nonsense-mediated mRNA decay
or the production of a truncated protein. This deletion mutation
was found in one allele, while another allele had the wild-type
sequence in all the individuals. No mutation analysis has yet been
performed on the papules of the patients.
Various types of germline BHD mutations in Caucasian
patients have been reported, although a mutational
hotspot, a C insertion/deletion in exon 11, is frequently
A BHD Germline Mutation Identified in an Asian Family with Birt-Hogg-Dubé Syndrome
Noriyuki Misago1, Keiichiro Joh2, Hitomi Yatsuki2, Hidenobu Soejima2 and Yutaka Narisawa1
1Department of Internal Medicine, Division of Dermatology, and 2Department of Biomolecular Sciences, Division of Molecular Biology & Genetics,
Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga JP-849-8501, Japan. E-mail: email@example.com
Accepted December 21, 2007.
Fig. 1. (A) Multiple, smooth, dome-shaped, white to skin-coloured papules,
on the face. (B) The family pedigree. (C) Histopathology of one of the papules
in the proband, showing the features of fibrofolliculoma.
Letters to the Editor
(40–50%) observed in BHD-affected families (2–4).
The recent reports of mutations of the BHD gene in
Japanese patients demonstrated either a hot spot mu-
tation of a C insertion in exon 11 or novel mutations
in exons 6, 12, 13 and in intron 5 (7–9). These recent
reports showed that the hot spot mutation in exon 11, as
well as genetic heterogeneity, in BHD gene mutations
tends to be observed worldwide despite differing ethnic
backgrounds. The mutation (c.1988delGATG) in exon
13 described herein corresponds with a recently repor-
ted, novel BHD gene mutation in a Japanese family (9).
It is unclear whether the presented proband is a BHD
sporadic case, because neither a genetic analysis nor a
clinical examination was conducted for her deceased
parents and her siblings (one brother and 2 sisters).
The clinical phenotypic features of BHD vary among
family members; some individuals show cutaneous
lesions associated with renal neoplasms and/or lung
cysts/pneumothorax, and others harbour only one of the
3 types of lesions (cutaneous, renal and lung lesions) (1,
9). A recent investigation, however, revealed no corre-
lation between the clinical phenotypic features of BHD
and location of mutations (4). Significantly fewer renal
neoplasms are observed, however, in patients with the
C-deletion than those with the C-insertion mutations,
in patients with a mutation in the exon 11 hot spot (4).
The reported Japanese family of BHD with a mutation
in exon 13 clinically showed only lung cysts without
cutaneous and renal lesions (9). However, the Japanese
family presented herein, with the same type of mutation
in exon 13, has shown either typical cutaneous lesions
only or subtle cutaneous lesions in association with lung
cysts to date.
Cutaneous lesions generally appear in the third and
fourth decades in patients with BHD (10), and spon-
taneous pneumothorax may occur in younger patients
(11). The renal neoplasms typically develop from the
fifth decade of life onward (12). However, the renal
neoplasms may occur as early as 20 years of age (3, 11).
The proband’s 2 daughters with subtle cutaneous lesions
(aged 38 and 35 years) as well as the proband (aged
67 years) with typical cutaneous lesions will require
follow-up especially to check the future development
of renal neoplasms. The possibility of the development
of spontaneous pneumothorax should also be carefully
kept in mind regarding the 2 daughters who were shown
to have lung cysts.
It is notable that the 2 proband’s daughters with subtle
cutaneous lesions proved to have a mutation in BHD
gene as well as lung cysts. It was easy to overlook the
cutaneous lesions, i.e., only a few or several scattered
papules on the face and/or neck, and they had not no-
ticed the lesions at all. Similarly, a more recent report
described that none or less than 10 cutaneous lesions
were observed in 2 mutation carriers at the age of 67
and 29 years, respectively (6). The present study further
demonstrated that these inconspicuous cutaneous lesions
were also histopathologically subtle and insufficient for
the diagnosis of fibrofolliculoma or trichodiscoma. These
subtle clinicopathological features of the cutaneous le-
sions are considered to be caused by the incipient stage of
fibrofolliculoma or trichodiscoma. It has been suggested,
however, that there are individuals with BHD gene mu-
tations in their 30s or 40s, and sometimes in their 50s or
60s, who have no clinical evidence of BHD syndrome
(3). These findings have been explained by the late age
onset of BHD or by the possibility that BHD has reduced
penetrance in some people (3).
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Fig. 2. The sequences of the mutated and wild-type BHD gene alleles.
The proband and her 2 daughters showed a deletion of GATG in exon 13
(c.1988delGATG). The deleted sequence is underlined in the wild-type
sequence. The created stop codon, TGA, is boxed in the mutated sequence.
Acta Derm Venereol 88
Letters to the Editor
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