Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident

Renal cancer associated with recurrent spontaneous pneumothorax in Birt-Hogg-Dubé syndrome: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Birt-Hogg-Dubé syndrome is a rare genodermatosis characterized by hair follicle hamartomas, renal tumors and spontaneous pneumothorax. We present the case of a patient with pulmonary cysts and recurrent spontaneous pneumothorax. She had typical skin lesions, and was found to have a hybrid oncocytoma which was surgically excised.</p> <p>Case presentation</p> <p>A 60-year-old Caucasian woman had a 10-year history of cystic lung disease and recurrent spontaneous pneumothoraces. She was noted to have papular lesions over her face and forehead. The result of a biopsy showed these lesions to be fibrofolliculomas. A diagnosis of Birt-Hogg-Dubé syndrome was made and she was screened for renal tumors since these are a recognized association. A hybrid oncocytoma was detected which was surgically excised by partial nephrectomy.</p> <p>Conclusion</p> <p>It is important to consider a possible diagnosis of Birt-Hogg-Dubé syndrome in cases of recurrent pneumothorax. Affected individuals must be screened for renal tumors, a potentially lethal consequence of this syndrome.</p

Interphase cytogenetics of multicentric renal cell tumours confirm associations of specific aberrations with defined cytomorphologies

To demonstrate associations of certain chromosomal aberrations with defined renal cell tumour (RCT) subtypes, we analysed 239 tumour nephrectomy cases for specimens with multicentric tumours. Chromosomal in situ hybridization was then performed on 15 cases with 34 foci (16 conventional renal cell carcinomas (RCCs), and 18 papillary RCTs (11 carcinomas and seven adenomas) for specific chromosomal aberrations, using α-satellite probes for chromosomes 3, 7 or 17. Particular preference was given to cases which had separate foci with different cytomorphologies. Furthermore, we compared aberrations in relation to tumour size, stage, grade and between different foci in a specimen. Thirty-four cases had multiple tumours. Forty-seven per cent of the multicentric tumours were conventional RCCs and 53% papillary RCTs (against 83% solitary conventional RCCs and 5% solitary papillary RCTs). Three conventional RCCs sized 8 mm (G3), 13 cm (pT2, G2) and 15 cm (pT3b, G3), respectively, revealed monosomy 3, and 13 were disomic. Seventeen papillary RCTs (11 carcinomas and six adenomas) displayed trisomy 17, irrespective of size or grade. Four papillary carcinomas and six papillary adenomas had trisomy 7, and the rest (seven papillary carcinomas and one papillary adenoma) revealed disomy 7. In conclusion, papillary RCTs were tendentially multicentric. Although specific for conventional RCCs heedless of size, monosomy 3 was only observed in high-grade and/or advanced tumours. Trisomy 17 was only detectable in papillary RCTs irrespective of tumour state, showing increased copies with tumour growth. Papillary RCTs also appeared to lose some copies of chromosome 7 with tumour progress, possibly reflecting malignancy. © 2000 Cancer Research Campaig

VHL Type 2B Mutations Retain VBC Complex Form and Function

Background: von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1a and HIF-2a), resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease. Methodology/Principal Findings: This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1a. Conclusions: Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition fo

Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

<p>Abstract</p> <p>Background</p> <p>von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the <it>VHL </it>gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children.</p> <p>Methods</p> <p>We tested 17 families (n = 109 individuals) for <it>VHL </it>mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the <it>VHL </it>gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations.</p> <p>Results</p> <p>Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02). Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01).</p> <p>Conclusions</p> <p>The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening procedures in non mutation-carriers. However, mutation-carriers showed poor adherence to long-term tumor surveillance. Therefore, many of them did not obtain the full benefit of early detection and treatment, which is central to the reduction of morbidity and mortality in VHL disease. Studies designed to improve adherence to vigilance protocols will be necessary to improve treatment and quality of life in patients with hereditary cancer syndromes.</p

Folliculin mutations are not associated with severe COPD

<p>Abstract</p> <p>Background</p> <p>Rare loss-of-function folliculin (<it>FLCN</it>) mutations are the genetic cause of Birt-Hogg-Dubé syndrome, a monogenic disorder characterized by spontaneous pneumothorax, fibrofolliculomas, and kidney tumors. Loss-of-function folliculin mutations have also been described in pedigrees with familial spontaneous pneumothorax. Because the majority of patients with folliculin mutations have radiographic evidence of pulmonary cysts, folliculin has been hypothesized to contribute to the development of emphysema.</p> <p>To determine whether folliculin sequence variants are risk factors for severe COPD, we genotyped seven previously reported Birt-Hogg-Dubé or familial spontaneous pneumothorax associated folliculin mutations in 152 severe COPD probands participating in the Boston Early-Onset COPD Study. We performed bidirectional resequencing of all 14 folliculin exons in a subset of 41 probands and subsequently genotyped four identified variants in an independent sample of345 COPD subjects from the National Emphysema Treatment Trial (cases) and 420 male smokers with normal lung function from the Normative Aging Study (controls).</p> <p>Results</p> <p>None of the seven previously reported Birt-Hogg-Dubé or familial spontaneous pneumothorax mutations were observed in the 152 severe, early-onset COPD probands. Exon resequencing identified 31 variants, including two non-synonymous polymorphisms and two common non-coding polymorphisms. No significant association was observed for any of these four variants with presence of COPD or emphysema-related phenotypes.</p> <p>Conclusion</p> <p>Genetic variation in folliculin does not appear to be a major risk factor for severe COPD. These data suggest that familial spontaneous pneumothorax and COPD have distinct genetic causes, despite some overlap in radiographic characteristics.</p