Strabismus and Poor Stereoacuity Associated with Kabuki Syndrome

Kabuki syndrome is characterized by long palpebral fissures, large ears, a depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. There have been few prior detailed descriptions of strabismus or stereopsis in these patients. We report a patient with Kabuki syndrome who showed small-angle strabismus and poor stereopsis. This case illustrates the need for patients with a diagnosis of Kabuki syndrome to have an ophthalmologic evaluation. Strabismus associated with Kabuki syndrome may have a small angle that can be easily overlooked

Colorectal Cancer in the Family: Psychosocial Distress and Social Issues in the Years Following Genetic Counselling

<p>Abstract</p> <p>Background</p> <p>This study examined: (1) levels of cancer-specific distress more than one year after genetic counselling for hereditary nonpolyposis colorectal cancer (HNPCC); (2) associations between sociodemographic, clinical and psychosocial factors and levels of distress; (3) the impact of genetic counselling on family relationships, and (4) social consequences of genetic counselling.</p> <p>Methods</p> <p>In this cross-sectional study, individuals who had received genetic counselling for HNPCC during 1986–1998 completed a self-report questionnaire by mail.</p> <p>Results</p> <p>116 individuals (81% response rate) completed the questionnaire, on average 4 years after the last counselling session. Of all respondents, 6% had clinically significant levels of cancer-specific distress (Impact of Event Scale, IES). Having had contact with a professional psychosocial worker for cancer risk in the past 10 years was significantly associated with higher levels of current cancer specific distress. Only a minority of the counselees reported any adverse effects of genetic counselling on: communication about genetic counselling with their children (9%), family relationships (5%), obtaining life insurance (8%), choice or change of jobs (2%), and obtaining a mortgage (2%).</p> <p>Conclusion</p> <p>On average, four years after genetic counselling for HNPCC, only a small minority of counselled individuals reports clinically significant levels of distress, or significant family or social problems.</p

Blood test ordering for unexplained complaints in general practice: the VAMPIRE randomised clinical trial protocol. [ISRCTN55755886]

BACKGROUND: General practitioners (GPs) frequently order blood tests when they see patients presenting with unexplained complaints. Due to the low prevalence of serious pathology in general practice, the risk of false-positive test results is relatively high. This may result in unnecessary further testing, leading to unfavourable effects such as patient anxiety, high costs, somatisation and morbidity. A policy of watchful waiting is expected to lower both the number of patients to be tested and the risk of false-positive test results, without missing serious pathology. However, many general practitioners experience barriers when trying to postpone blood testing by watchful waiting. The objectives of this study are (1) to determine the accuracy of blood tests in patients presenting with unexplained complaints in terms of detecting pathology, (2) to determine the accuracy of a watchful waiting strategy and (3) to determine the effects of a quality improvement strategy to promote the postponement of blood test ordering by GPs for patients with unexplained complaints. DESIGN: General practices are randomised over three groups. Group 1 is instructed to order blood tests immediately, group 2 to apply a watchful waiting policy and group 3 also to postpone testing, but supported by our quality improvement strategy. The trial consists of two sub-studies: a diagnostic study at patient level (group 1 versus groups 2 and 3) and a quality improvement study at GP level (group 2 versus group 3). The diagnostic strategy to be used involves of both customary and innovative tests. The quality improvement strategy consists of two small-group meetings and a practice outreach visit. Patient follow-up ends at 12 months after the initial consultation. Primary outcome measures are the accuracy and added value of blood tests for detecting pathology, the effect of a 4-week postponement of test ordering on the blood test characteristics and the quantity of tests ordered. Secondary outcome measures are the course of complaints, quality of life, satisfaction with care, anxiety of patients and practitioners, determinants of physicians' behaviour, health care utilisation and costs. DISCUSSION: The innovative aspect of this trial is that it combines a clinical-epidemiological study and a quality of care study

High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome

<p>Abstract</p> <p>Background</p> <p>An unclassified variant (UV) in exon 1 of the <it>MLH1 </it>gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this <it>MLH1 </it>variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.</p> <p>Methods</p> <p>We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.</p> <p>Results</p> <p>The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.</p> <p>Conclusions</p> <p>We conclude that the <it>MLH1 </it>variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.</p

E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo

International cancer of the pancreas screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer

Background Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. Objective To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. Methods A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed. Results There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screeni