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Princess Anne, United Kingdom

Ferdinandusse S.,University of Amsterdam | Barker S.,Wessex Neurological Center | Lachlan K.,Wessex Clinical Genetics Service | Duran M.,University of Amsterdam | And 3 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2010

Peroxisomal acyl-coenzyme A oxidase deficiency (formerly also called pseudoneonatal adrenoleucodystrophy) is a disorder of peroxisomal fatty acid oxidation with a severe presentation. Most patients present at birth or in early infancy, and the mean age of death was 5 years in a recently published cohort of 22 patients. Brain imaging shows a progressive leucodystrophy. The authors report here the first adult patients (two siblings, 52 and 55 years old) with peroxisomal acyl-coenzyme A oxidase deficiency with a remarkably mild clinical presentation. Magnetic resonance brain imaging revealed profound atrophy of the brainstem and cerebellum. Source

Salter C.G.,Wessex Clinical Genetics Service | Baralle D.,University of Southampton | Collinson M.N.,Wessex Regional Genetics Laboratory | Self J.E.,Southampton General Hospital | Self J.E.,University of Southampton
American Journal of Medical Genetics, Part A | Year: 2016

A variety of ocular anomalies have been described in the rare ring 14 and 14q terminal deletion syndromes, yet the character, prevalence, and extent of these anomalies are not well defined. Identification of these ocular anomalies can be central to providing diagnoses and facilitating optimal individual patient management. We report a child with a 14q32.31 terminal deletion and ring chromosome formation, presenting with severe visual impairment secondary to significant bilateral coloboma and microphthalmia. This patient is compared to previously reported patients with similar ocular findings and deletion sizes to further refine a locus for coloboma in the 14q terminal region. Those with ring formation and linear deletions are compared and the possibility of ring formation affecting the proximal 14q region is discussed. This report highlights the severity of ocular anomalies that can be associated with ring 14 and 14q terminal deletion syndromes and reveals the limited documentation of ocular examination in these two related syndromes. This suggests that many children with these genetic changes do not undergo an ophthalmology examination as part of their clinical assessment, yet it is only when this evaluation becomes routine that the true prevalence and extent of ocular involvement can be defined. This report therefore advocates for a thorough ophthalmological exam in children with ring 14 or 14q terminal deletion syndrome. © 2016 Wiley Periodicals, Inc. Source

Mavaddat N.,Center for Cancer Genetic Epidemiology | Peock S.,Center for Cancer Genetic Epidemiology | Frost D.,Center for Cancer Genetic Epidemiology | Ellis S.,Center for Cancer Genetic Epidemiology | And 31 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Methods Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. Results The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P =. 02). Conclusions Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers. © 2013 The Author. Source

Dolk H.,University of Ulster | Armstrong B.,London School of Hygiene and Tropical Medicine | Lachowycz K.,London School of Hygiene and Tropical Medicine | Vrijheid M.,London School of Hygiene and Tropical Medicine | And 5 more authors.
Occupational and Environmental Medicine | Year: 2010

Objectives To investigate whether there is an association between risk of congenital anomaly and annual ward level exposure to air pollution in England during the 1990s. Methods A geographical study was conducted across four regions of England using population-based congenital anomaly registers, 1991-1999. Exposure was measured as 1996 annual mean background sulphur dioxide (SO 2), nitrogen dioxide (NO2) and particulate matter (PM 10) concentrations at census ward level (n=1474). Poisson regression, controlling for maternal age, area socioeconomic deprivation and hospital catchment area, was used to estimate relative risk for an increase in pollution from the 10th to the 90th centile. Results For non-chromosomal anomalies combined, relative risks were 0.99 (95% CI 0.93 to 1.05) for SO2, 0.97 (95% CI 0.84 to 1.11) for NO2 and 0.89 (95% CI 0.75to 1.07) for PM10. For chromosomal anomalies, relative risks were 1.06 (95% CI 0.98 to 1.15) for SO2, 1.11 (95% CI 0.95 to 1.30) for NO2 and 1.18 (95% CI 0.97 to 1.42) for PM10. Raised risks were found for tetralogy of Fallot and SO2 (RR=1.38, 95% CI 1.07 to 1.79), NO 2 (RR=1.44, 95% CI 0.71 to 2.93) and PM10 (RR=1.48, 95% CI 0.57 to 3.84), which is of interest in light of previously reported associations between this cardiac anomaly and other air pollutants. Conclusions While air pollution in the 1990s did not lead to sustained geographical differences in the overall congenital anomaly rate in England, further research regarding specific anomalies is indicated. Source

Individuals who inherit a high penetrance cancer susceptibility gene represent a population in which cancer diagnoses occur at younger ages and much more frequently than in the general population. Screening regimens aimed at early detection of cancer may reduce cancer mortality but in order to reduce cancer incidence, surgery and medical therapies have been advocated. In high genetic risk patients, either surgical or medical intervention may provide long term protection against cancer and at young ages co-morbidities will be low. The use of genetic testing for high risk predisposition genes to refine risk estimates and inform choices about cancer prevention is now readily available in many countries and routinely used to target cancer prevention strategies. Surgical approaches to cancer prevention are currently the mainstay in many conditions where a high risk is identified but medical prevention strategies also have demonstrated some efficacy in lowering cancer risk. Using the genetic status of an individual to target cancer treatment and prevent recurrence is increasingly gaining momentum as clinical trials involving known high risk gene carriers are now being conducted using both established cytotoxic drugs and novel targeted agents. Translation of new mechanistic insights into beneficial clinical care strategies requires more research. Robust evidence supporting medical approaches to cancer prevention in particular will require well designed large international collaborative clinical trials. © 2011 Bentham Science Publishers. Source

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