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Hampshire D.J.,Haemostasis Research Group | Goodeve A.C.,Haemostasis Research Group | Goodeve A.C.,Sheffield Childrens NHS Foundation Trust
Seminars in Thrombosis and Hemostasis | Year: 2011

The online locus-specific database for von Willebrand disease (VWFdb) acts as a repository for sequence variant data and associated resources for those with an interest in the disorder. It currently holds details of 561 mutations and 217 polymorphisms in the von Willebrand factor (VWF) gene. Lists can be queried and displayed by VWF region or disease type. A total of 42% of the mutations are located in the large exon 28, the most heavily studied VWF region, and mutations have been reported in all but 4 of the 51 protein-coding exons. Polymorphisms are reported in the 5 and 3 untranslated regions and in 33 exons and 35 introns. Additional resources include references linked to sequence variation entries, descriptors of each VWD type, genomic and cDNA sequences, nomenclature for VWF and its attributes, Human Genome Variation Society sequence variant nomenclature recommendations, multimer images, and related densitometry traces for type 2 VWD. Analysis of recessively inherited VWD indicates that whereas the majority (69%) of type 3 VWD patients are homozygous for their mutations, the majority (62%) of 2N patients are compound heterozygous. Comparison of missense substitutions reported as mutations with those reported as polymorphisms suggests that loss or gain of cysteine, tryptophan, methionine, or glutamate residues are more likely to result in a pathogenic effect than loss/gain of other VWF residues. © 2011 by Thieme Medical Publishers, Inc.

James P.D.,Queen's University | Goodeve A.C.,University of Sheffield | Goodeve A.C.,Sheffield Childrens NHS Foundation Trust
Genetics in Medicine | Year: 2011

Von Willebrand disease is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery, and/or childbirth, and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: (1) type 2A-characterized by defective von Willebrand factor-dependent platelet adhesion because of decreased high-molecular-weight von Willebrand factor multimers, (2) type 2B-caused by pathologically increased von Willebrand factor-platelet interactions, (3) type 2M-caused by decreased von Willebrand factor-platelet interactions not based on the loss of high-molecular-weight multimers, and (4) type 2N-characterized by reduced binding of von Willebrand factor to factor VIII. The diagnosis of von Willebrand disease requires specialized assays of von Willebrand factor and/or molecular genetic testing of von Willebrand factor. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally inactivated plasma-derived clotting factor concentrates containing both von Willebrand factor and factor VIII. Depending on the von Willebrand disease type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia. © 2011 Lippincott Williams & Wilkins.

Goodeve A.C.,University of Sheffield | Goodeve A.C.,Sheffield Childrens NHS Foundation Trust
Blood Reviews | Year: 2010

The common autosomally inherited mucocutaneous bleeding disorder, von Willebrand disease (VWD) results from quantitative or qualitative defects in plasma von Willebrand factor (VWF). Mutation can affect VWF quantity or its functions mediating platelet adhesion and aggregation at sites of vascular damage and carrying pro-coagulant factor VIII (FVIII). Phenotype and genotype analysis in patients with the three VWD types has aided understanding of VWF structure and function. Investigation of patients with specific disease types has identified mutations in up to 70% of type 1 and 100% of type 3 VWD cases. Missense mutations predominate in type 1 VWD and act through mechanisms including rapid clearance and intracellular retention. Many mutations are incompletely penetrant and attributing pathogenicity is challenging. Other factors including blood group O contribute to low VWF level. Missense mutations affecting platelet- or FVIII-binding through a number of mechanisms are responsible for the four type 2 subtypes; 2A, 2B, 2M and 2N. In contrast, mutations resulting in a lack of VWF expression predominate in recessive type 3 VWD. This review explores the genetic basis of each VWD type, relating mutations identified to disease mechanism. Additionally, utility of genetic analysis within the different disease types is explored. © 2010 Elsevier Ltd.

Sobey G.,Sheffield Childrens NHS Foundation Trust
Archives of Disease in Childhood | Year: 2015

The term Ehlers-Danlos syndrome (EDS) encompasses a group of inherited connective tissue disorders. The manifestations of EDS can be seen in skin, joints, blood vessels and internal organs and vary from mild to severe and life threatening. Each subtype is a separate and different condition. The genetic basis of many subtypes has now been elucidated, confirming heterogeneity. An awareness of the different conditions within this group is the starting point towards accurate diagnosis. Accurate elicitation of history and clinical signs is vital in selecting the correct confirmatory investigation. Skin biopsy with electron microscopy can be helpful in the decision process of whether and when to perform genetic testing. Correct diagnosis within the EDSs allows targeted management, family screening and prenatal diagnosis.

Bonham J.R.,Sheffield Childrens NHS Foundation Trust
Journal of Inherited Metabolic Disease | Year: 2013

The early detection offered by newborn screening for phenylketonuria clearly demonstrates the benefits for patients with inherited metabolic disorders of well organised screening programmes. It is therefore perhaps surprising that 20 years after the introduction of electrospray MS/MS methods to support expanded newborn screening that considerable international variation in practice, not linked to economic factors, exists. It is likely that the commonly used criteria to assess the suitability of a disorder for screening need to be re-appraised as they apply to rare disorders. In addition, national differences in the pattern of policy making may influence the strategy adopted and these different approaches need to be scrutinised more closely. Despite this contextual variation a number of real issues do need to be addressed as the range of conditions included in screening programmes continues to increase. These include the need for well organised outcome studies based upon agreed case definitions and comparable treatment regimens; the need for appropriate information for parents to support them before and during the screening odyssey; an improved understanding of the impact of false positive results and in particular a clearer understanding of the way in which some of the problems resulting from false positive results can be avoided or ameliorated; the challenge offered by mild or atypical screen positive cases and the consequent design of proportionate treatment options. A thorough understanding of the genetic, biochemical and clinical features of screen positive cases supported by effective international outcome studies is required to optimise both screening and treatment strategies. © 2013 SSIEM and Springer Science+Business Media Dordrecht.

Sequeiros J.,University of Porto | Seneca S.,Center for Medical Genetics | Martindale J.,Sheffield Childrens NHS Foundation Trust
European Journal of Human Genetics | Year: 2010

Many laboratories worldwide are offering molecular genetic testing for spinocerebellar ataxias (SCAs). This is essential for differential diagnosis and adequate genetic counselling. The European Molecular Genetics Quality Network (EMQN) started an SCA external quality assessment scheme in 2004. There was a clear need for updated laboratory guidelines. EMQN and EuroGentest organized a Best Practice (BP) meeting to discuss current practices and achieve consensus. A pre-meeting survey showed that 36 laboratories (20 countries) conducted nearly 18 000 SCA tests the year before, and identified issues to discuss. Draft guidelines were produced immediately after the meeting and discussed online for several months. The final version was endorsed by EMQN, and harmonized with guidelines from other oligonucleotide repeat disorders. We present the procedures taken to organize the survey, BP meeting, as well as drafting and approval of BP guidelines. We emphasize the most important recommendations on (1) pre-test requirements, (2) appropriate methodologies and (3) interpretation and reporting, and focus on the discussion of controversial issues not included in the final document. In addition, after an extensive review of scientific literature, and responding to recommendations made, we now produce information that we hope will facilitate the activities of diagnostic laboratories and foster quality SCA testing. For the main loci, this includes (1) a list of repeat sequences, as originally published; (2) primers in use; and (3) an evidence-based description of the normal and pathogenic repeat-size ranges, including those of reduced penetrance and those in which there is still some uncertainty. This information will be maintained and updated in © 2010 Macmillan Publishers Limited All rights reserved.

Roberts J.,Sheffield Childrens NHS Foundation Trust
Current Opinion in Urology | Year: 2010

Purpose of review: Hypospadias surgery has been in continuous evolution for many years with steadily improving reported results. Despite this many unanswered questions on its cause, management and outcomes remain. Recent research has done little to clarify most matters. Recent findings: There is increasing evidence of a balance of genetic and developmental factors in the development of hypospadias, but there is doubt whether the incidence of hypospadias is increasing or not. Many technical aspects of hypospadias repair and variations of perioperative management seem to have little effect on outcome, whereas the age at which surgery is performed may. Although efforts are being made to relate anatomical findings to outcome, a lack of objective assessment and standardization is a handicap. Severe hypospadias, particularly that associated with significant chordee, remains challenging although strategies for management are being developed. The future may lie in development of autologous tissue culture for these severe cases. Summary: Further development of hypospadias surgery would benefit from objective, standardized methods of describing anatomy and outcome measures to facilitate effective comparison of techniques and procedures. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Sobey G.,Sheffield Childrens NHS Foundation Trust
Clinical Medicine, Journal of the Royal College of Physicians of London | Year: 2014

All clinicians need to be aware of EDS and its variable presentations that, in some types, can be life threatening. Recognition of EDS can allow accurate diagnosis by genetic testing, genetic counselling and specific, appropriate management and follow-up. © Royal College of Physicians 2014. All rights reserved.

Goodeve A.C.,University of Sheffield | Goodeve A.C.,Sheffield Childrens NHS Foundation Trust
Blood | Year: 2013

In this issue of Blood, Johnsen et al have analyzed the frequency of coding sequence variants in the von Willebrand factor gene (VWF) and have identified 7 missense variants independently associated with levels of von Willebrand factor (VWF) or factor VIII (FVIII).1 Several rare missense variants have been previously identified, predominantly in European patients with von Willebrand disease (VWD),2,3 and some have now been reported to be common African American sequence variations. Copyright © 2011 by The American Society of Hematology; all rights reserved.

Hill C.L.,Sheffield Childrens NHS Foundation Trust | Baird W.O.,University of Sheffield | Walters S.J.,University of Sheffield
Health and Quality of Life Outcomes | Year: 2014

Background: Osteogenesis Imperfecta (OI) is a disease with varying severity affecting physical, social and emotional well-being of the child and their family. There is no existing evidence on how the OI population regard their quality of life (QoL). The main aim of this study was to determine how OI impacts on the quality of life and well-being of children and their family. It is the first stage of a larger project to develop a disease specific quality of life measure for children with OI.Methods: Purposive sampling was used to cover the diversity of the OI population. Twenty-five qualitative interviews were undertaken with children (n = 10), parents (n = 10) and health professionals (n = 5). Interviews were digitally recorded and transcribed verbatim. Significant themes were identified, extracted and organised, undergoing framework analysis.Results: Six main themes were identified; being safe and careful, reduced function, pain, fear, isolation, independence. There was a large amount of agreement between the three groups of interviewees, although discrepancies did occur between parents and children, with regard to the themes independence and fear.Conclusions: This data presents the first step in developing items for a disease specific QoL measure for children with OI. Several of the themes uncovered showed similarity to other QoL measures, but the addition of being safe and careful, particularly in relation to fractures, demonstrated the need for a disease specific measure for children with OI. © 2014 Hill et al.; licensee BioMed Central Ltd.

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