GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

Introduction: Brachydactyly is a bone development abnormality presenting with variable phenotypes and different transmission patterns. Mutations in GDF5 (Growth and Differentiation Factor 5, MIM *601146) account for a significant amount of cases. Here, we report on a three-generation family, where the proband and the grandfather have an isolated brachydactyly with features of both type A1 (MIM #112500) and type C (MIM #113100), while the mother shows only subtle hand phenotype signs. Materials and methods: Whole Exome Sequencing (WES) was performed on the two affected individuals. An in-depth analysis of GDF5 genotype-phenotype correlations was performed through literature reviewing and retrieving information from several databases to elucidate GDF5-related molecular pathogenic mechanisms. Results: WES analysis disclosed a pathogenic variant in GDF5 (NM_000557.5:c.157dup; NP_000548.2:p.Leu53Profs*41; rs778834209), segregating with the phenotype. The frameshift variant was previously associated with Brachydactyly type C (MIM #113100), in heterozygosity, and with the severe Grebe type chondrodysplasia (MIM #200700), in homozygosity. In-depth analysis of literature and databases allowed to retrieve GDF5 mutations and correlations to phenotypes. We disclosed the association of 49 GDF5 pathogenic mutations with eight phenotypes, with both autosomal dominant and recessive transmission patterns. Clinical presentations ranged from severe defects of limb morphogenesis to mild redundant ossification. We suggest that such clinical gradient can be linked to a continuum of GDF5-activity variation, with loss of GDF5 activity underlying bone development defects, and gain of function causing disorders with excessive bone formation. Conclusions: Our analysis of GDF5 pathogenicity mechanisms furtherly supports that mutation and zygosity backgrounds resulting in the same level of GDF5 activity may lead to similar phenotypes. This information can aid in interpreting the potential pathogenic effect of new variants and in supporting an appropriate genetic counseling

Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients

Item does not contain fulltextBACKGROUND: The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients. METHODS: Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids. RESULTS: Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy. CONCLUSION: For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin

Australia's National Bowel Cancer Screening Program: does it work for Indigenous Australians?

<p>Abstract</p> <p>Background</p> <p>Despite a lower incidence of bowel cancer overall, Indigenous Australians are more likely to be diagnosed at an advanced stage when prognosis is poor. Bowel cancer screening is an effective means of reducing incidence and mortality from bowel cancer through early identification and prompt treatment. In 2006, Australia began rolling out a population-based National Bowel Cancer Screening Program (NBCSP) using the Faecal Occult Blood Test. Initial evaluation of the program revealed substantial disparities in bowel cancer screening uptake with Indigenous Australians significantly less likely to participate in screening than the non-Indigenous population.</p> <p>This paper critically reviews characteristics of the program which may contribute to the discrepancy in screening uptake, and includes an analysis of organisational, structural, and socio-cultural barriers that play a part in the poorer participation of Indigenous and other disadvantaged and minority groups.</p> <p>Methods</p> <p>A search was undertaken of peer-reviewed journal articles, government reports, and other grey literature using electronic databases and citation snowballing. Articles were critically evaluated for relevance to themes that addressed the research questions.</p> <p>Results</p> <p>The NBCSP is not reaching many Indigenous Australians in the target group, with factors contributing to sub-optimal participation including how participants are selected, the way the screening kit is distributed, the nature of the test and comprehensiveness of its contents, cultural perceptions of cancer and prevailing low levels of knowledge and awareness of bowel cancer and the importance of screening.</p> <p>Conclusions</p> <p>Our findings suggest that the population-based approach to implementing bowel cancer screening to the Australian population unintentionally excludes vulnerable minorities, particularly Indigenous and other culturally and linguistically diverse groups. This potentially contributes to exacerbating the already widening disparities in cancer outcomes that exist among Indigenous Australians. Modifications to the program are recommended to facilitate access and participation by Indigenous and other minority populations. Further research is also needed to understand the needs and social and cultural sensitivities of these groups around cancer screening and inform alternative approaches to bowel cancer screening.</p

Uniparental disomy of chromosome 16: a case report with a new cardiac malformation Abstracts from the 53rd European Society of Human Genetics (ESHG) Conference: e-Posters

Introduction: Maternal uniparental disomy of chromosome 16 [UPD(16)mat] is the most often reported UPD other than UPD(15). In literature there is not a specific phenotype associated with upd(16)mat and few follow-up data are reported. Materials and methods: We present the case of a 1-y.o. male of a healthy non-consanguineous parents. In prenatal diagnosis IUGR, polydramnios and single umbilical artery was reported. He born late preterm, small for gestational age, and showed facial dysmorphisms and congenital malformations (esophageal atresia, cardiac defects, mild bone alterations, hypospadias). Transesophageal echocardiography detected persistency of left superior vena cava draining into the left atrium through an unroofed coronary sinus. Brain ultrasound showed dilated and asymmetric lateral ventricles. At present, cognitive and language abilities are adequate for age but he has mild gross motor delay. Genomic DNA was extracted from peripheral blood and analyzed by SNP-array (Cytoscan HD; Thermo Fisher Scientific). Results: SNP-array analysis showed a 147 Kb homozygous 16p13.3 microdeletion and a 114 kb 16q24.3 microtriplication, both segregated from the mother. Region of Homozigosity (ROH) analysis showed two ROH of 7 and 13 Mb on chromosome 16 compatible with the presence of UPD(16) of maternal origin. The possible presence of a residual mosaic trisomy 16 was excluded by karyotype analysis and FISH. Conclusions: This is an additional case of the phenotypic characterization of UPD(16)mat. To date, it is the first time that an unroofed coronary sinus is described within cardiac malformations associated with UPD(16)mat. Moreover, according to literature data, it confirms the need to extend follow-up

Student perception of quality in higher education institutions

Higher education institutions have adopted education, research and cooperation as their main missions. Students, teachers and non-teaching staff articulate for lecturing, researching and developing projects and internships, according to the institution goals and strategy. Quality evaluation is of the utmost importance in the whole process, as it allows providing a competent and rigorous service as well as maintaining high level of attractiveness for additional funding, through cooperation and research projects. This chapter describes the results of an empirical study, performed in the Technology and Management School of the Polytechnic Institute of Bragança, to assess and compare the perceptions of students about the satisfaction and quality of the institutions’ services and its importance. The universe comprised 2031 students and we concluded that globally they have a high values of satisfaction. We also differentiate between study cycles (graduation and master) and field of study (Technological and Business)