RESUMEN

The nonrandom co-occurrence of vertebral, anorectal, cardiac, tracheoesophageal, genitourinary, and limb malformations, recognized as the VACTERL association, has not been satisfactorily explained from either a causation or embryopathogenesis standpoint. Few familial cases have been identified and maternal diabetes is the only environmental influence implicated to date. Mutations in single genes have been found in a number of syndromes with one or more of the VACTERL malformations, but these syndromes usually have other features which distinguish them from the VACTERL association. Animal models have provided clues to molecular pathways that may be involved in the embryogenesis of the VACTERL structures. What is lacking is the systematic study of individual genes and pathways in well-composed cohorts of patients, which is now possible with high throughput molecular technologies.

Asunto(s)

Enfermedades de los Bovinos/inducido químicamente , Cobre/envenenamiento , Intoxicación/veterinaria , Animales , Femenino

RESUMEN

High winter mortality (28 per cent) in female Jersey calves (80 IU/l in healthy females aged 3-24 weeks, and correlated with serum aspartate transaminase (AST). Copper supplementation of total mixed rations during lactation was excessive (40-60 mg added Cu/kg DM) and reduced to 16-28 mg Cu/kg, but supplementation of milk replacer and creep feed (10 and 35 mg added Cu/kg DM, respectively) continued. The syndrome recurred two years later, and liver Cu remained high in casualties (13.6 ± 2.6) and culled cows (6.38 ± 2.38 mmol/kg DM) prompting withdrawal of all Cu supplements. Mortality remained low (6-9 per cent) thereafter. Three years after removal of all Cu supplements, six culled newborn were examined postmortem; five had normal liver Cu (4.5 ± 1.73), but a sixth had 11.65 mmol/kg DM. In live, healthy calves (1-6 months old) sampled at the same time, GLDH and AST increased with age to levels found five years earlier, indicating possible subclinical hepatopathy. Causative links between Cu supplementation, high calf mortality and hepatopathy are plausible, and reductions in Cu supplementation may prove beneficial in other dairy herds.

Asunto(s)

Enfermedades de los Bovinos/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/veterinaria , Cobre/efectos adversos , Suplementos Dietéticos/efectos adversos , Hígado/efectos de los fármacos , Hígado/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Animales Recién Nacidos , Bovinos , Enfermedades de los Bovinos/sangre , Enfermedades de los Bovinos/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cobre/administración & dosificación , Femenino , Glutamato Deshidrogenasa/sangre , Hígado/enzimología , Hígado/patología , Masculino , Mortalidad/tendencias , Estaciones del Año

RESUMEN

We report an 18 year old patient with mild intellectual disability who was diagnosed with a late onset teratoid/rhabdoid tumour by histological and immunohistochemical studies. Array-CGH studies, performed on a peripheral blood sample, showed a 3.4Mb deletion of chromosome 22q11.2, distal to the common DiGeorge syndrome (DGS) or Velocardiofacial syndrome (VCFs) region. This deletion is consistent with a diagnosis of distal 22q11.2 deletion syndrome. The deletion encompasses the INI1/SMARCB1 tumour suppressor gene. Biallelic inactivation of this gene is characteristic of atypical teratoid/rhabdoid tumours. Although several constitutional chromosome conditions are known to have increased susceptibility to various forms of cancer, very little is known regarding the magnitude of risk for malignancy associated with distal 22q11.2 deletion syndrome. In view of this finding we suggest that patients diagnosed with distal 22q11.2 deletion syndrome undergo careful prolonged monitoring for this type of tumour. This case demonstrates the need to carefully assess regions found to be deleted in individuals, referred for dysmorphia and/or developments delay, by array-CGH for the presence of genes known to be implicated in malignancy.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 22/genética , Tumor Rabdoide/genética , Teratoma/genética , Adolescente , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Eliminación de Gen , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Tumor Rabdoide/patología , Proteína SMARCB1 , Síndrome , Teratoma/patología , Factores de Transcripción/genética

RESUMEN

Gastroschisis is a significant birth defect that in many countries has shown an increased prevalence in recent decades, and the change has affected primarily younger mothers. Despite numerous epidemiological studies no other consistent associated risk factor has been identified. In this paper we review the five main theories related to the pathogenesis of this malformation and outline the reasons why we think none fully explains the embryogenesis of gastroschisis. We briefly present some clinical observations we have made that we consider germane to the pathogenesis and outline a hypothesis that we think can account for the origins of this malformation. Our proposal is that the determining defect in gastroschisis is failure of the yolk sac and related vitelline structures to be incorporated into the umbilical stalk. Otherwise, ventral closure of the lateral abdominal walls occurs normally, thus orphaning the vitelline duct and yolk sac outside both the main body stalk and the abdominal wall. Thus, in addition to the umbilicus, the abdominal wall has a separate perforation through which the midpoint of the gut is attached to the exteriorized vitelline structures. This connection through the ventral wall prevents normal egress of the gut into the umbilical cord during the second month of development and acts as the egress point for the gut resulting in gastroschisis.

Asunto(s)

Gastrosquisis/embriología , Saco Vitelino/patología , Desarrollo Embrionario , Femenino , Gastrosquisis/etiología , Gastrosquisis/patología , Humanos , Intestinos/anomalías , Intestinos/embriología , Intestinos/patología , Embarazo , Cordón Umbilical/embriología , Cordón Umbilical/patología , Conducto Vitelino/embriología , Conducto Vitelino/patología

RESUMEN

BACKGROUND: FG syndrome (FGS) is an X-linked disorder characterised by mental retardation, hypotonia, particular dysmorphic facial features, broad thumbs and halluces, anal anomalies, constipation, and abnormalities of the corpus callosum. A behavioural phenotype of hyperactivity, affability, and excessive talkativeness is very frequent. The spectrum of clinical findings attributed to FGS has widened considerably since the initial description of the syndrome by Opitz and Kaveggia in 1974 and has resulted in clinical variability and genetic heterogeneity. In 2007, a recurrent R961W mutation in the MED12 gene at Xq13 was found to cause FGS in six families, including the original family described by Opitz and Kaveggia. The phenotype was highly consistent in all the R961W positive patients. METHODS: In order to determine the prevalence of MED12 mutations in patients clinically diagnosed with FGS and to clarify the phenotypic spectrum of FGS, 30 individuals diagnosed previously with FGS were evaluated clinically and by MED12 sequencing. RESULTS: The R961W mutation was identified in the only patient who had the typical phenotype previously associated with this mutation. The remaining 29 patients displayed a wide variety of features and were shown to be negative for mutations in the entire MED12 gene. A definite or possible alternative diagnosis was identified in 10 of these patients. CONCLUSION: This report illustrates the difficulty in making a clinical diagnosis of FGS given the broad spectrum of signs and symptoms that have been attributed to the syndrome. Individuals with a phenotype consistent with FGS require a thorough genetic evaluation including MED12 mutation analysis. Further genetic testing should be considered in those who test negative for a MED12 mutation to search for an alternative diagnosis.

Asunto(s)

Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Discapacidad Intelectual Ligada al Cromosoma X/diagnóstico , Discapacidad Intelectual Ligada al Cromosoma X/genética , Anomalías Múltiples/patología , Adolescente , Sustitución de Aminoácidos , Niño , Preescolar , Femenino , Humanos , Masculino , Complejo Mediador , Discapacidad Intelectual Ligada al Cromosoma X/patología , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Mutación , Fenotipo , Receptores de Hormona Tiroidea/genética , Síndrome

RESUMEN

OBJECTIVES: In 2000, the Ministry of Health in Ontario, Canada, introduced a publicly funded program to provide genetic services for hereditary breast/ovarian and colorectal cancers. We surveyed physicians to determine their awareness, use and satisfaction with this program. METHODS: A self-administered questionnaire was mailed to a random sample of 25% of Ontario family physicians and all gynecologists, oncologists (radiation, surgical and medical), gastroenterologists and general surgeons. RESULTS: Response rate was 49% (n = 1,427). Awareness of genetic testing for breast/ovarian cancer was high (91%) but less for colorectal cancer (60%). Use of services was associated with physician age of 40 or greater, urban location, confidence in knowledge of referral criteria and core competencies in genetics, and awareness of the program and where to refer. Almost half were dissatisfied with notification about the program. CONCLUSIONS: Ontario physicians are aware of cancer genetics services, and use is associated with increased knowledge of services, and confidence in skills. They would like more timely services and education about hereditary cancers and susceptibility testing.

Asunto(s)

Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Adulto , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Oncología Médica/organización & administración , Persona de Mediana Edad , Ontario , Pautas de la Práctica en Medicina , Encuestas y Cuestionarios

RESUMEN

Prenatal diagnosis (PND) is offered routinely as part of pregnancy care to a large number of women at increased risk of fetal anomalies. Despite an extraordinary growth in the use of PND and significant resource allocation, few studies have examined outcomes of PND counseling, and virtually no research has evaluated the relative efficacy of various approaches to genetic counseling. This study was a randomized trial that compared which counseling methods - individual, group, and use of a decision aid - are effective in PND counseling for women of advanced maternal age (>/=35 years) and their partners. Three hundred and fifty-two women and 225 partners completed pre- and post-intervention questionnaires assessing changes in knowledge, decisional conflict, state anxiety, satisfaction, use of PND, and pregnancy outcomes. All participants showed a significant increase in knowledge and a decrease in decisional conflict post intervention. Those in the group intervention showed a significantly greater increase in knowledge than those in the individual counseling intervention. While high levels of satisfaction were reported by all, those in individual counseling were significantly more satisfied than those receiving group counseling or the decision aid. This study has shown unique benefits with each type of intervention such that women and their partners preferred individual genetic counseling, while they learned best in group-counseling sessions, and experienced the least decisional conflict regarding genetic testing with a decision aid.

Asunto(s)

Asesoramiento Genético/métodos , Edad Materna , Adulto , Conflicto Psicológico , Técnicas de Apoyo para la Decisión , Femenino , Procesos de Grupo , Humanos , Masculino , Escala de Ansiedad Manifiesta , Satisfacción del Paciente , Embarazo , Diagnóstico Prenatal/métodos , Encuestas y Cuestionarios

RESUMEN

In 1977 Hunter et al. J Med Genet 1977: 14 (6): 430-437, reported a family with six affected members, connected over three generations through unaffected individuals. Subsequently, several other patients purported to have the condition were reported. The condition became known as the Hunter-McAlpine syndrome, and there was debate as to whether or not it was identical to the Ruvalcaba syndrome or a type of tricho-rhino-phalangeal syndrome. In this article we confirm that the original family and a patient reported by Ades et al. Clin Dysmorphol 1993: 2 (2): 123-130 have cryptic translocations resulting in duplication of 5q35-qter. Similarities are noted between our patients and others in the literature with duplication of this chromosome segment.

Asunto(s)

Anomalías Múltiples/genética , Cromosomas Humanos Par 5 , Duplicación de Gen , Adolescente , Adulto , Anciano , Estatura/genética , Niño , Preescolar , Aberraciones Cromosómicas , Cara/anomalías , Salud de la Familia , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Microcefalia/genética , Persona de Mediana Edad , Linaje , Síndrome , Translocación Genética

Asunto(s)

Anomalías Múltiples/genética , Empalme Alternativo/genética , Proteínas Portadoras/genética , Exones/genética , Mutación/genética , Anomalías Múltiples/fisiopatología , Adulto , Secuencia de Bases , Canadá , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Nucléolo Celular/metabolismo , Análisis Mutacional de ADN , Femenino , Células HeLa , Humanos , Masculino , Fenotipo , Polirribosomas/genética , Polirribosomas/metabolismo , Transporte de Proteínas , Proteínas Represoras , Síndrome

Asunto(s)

Genes APC , Mutación/genética , Sitios de Empalme de ARN/genética , Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Adolescente , Adulto , Edad de Inicio , Empalme Alternativo/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Estudios Retrospectivos

RESUMEN

In a recent colon cancer risk study, genetic assessment and colonoscopy were offered to virtually all of the adult Ashkenazi Jews in an urban community. The present study was designed to examine factors influencing participation and response in the initial study and to suggest strategies for improving participation in future health promotion programs. The study comprised a random sample of three groups of individuals who had been targeted for participation in the previous study: those who had (a) agreed to participate (n = 234); (b) declined participation (n = 179); and (c) failed to respond to a mailed recruitment package (n = 128). All participants completed a brief telephone survey. Key multivariate predictors of both response and participation were individuals' perceptions of the drawbacks of participating in colon cancer screening research and the degree of decisional conflict they experienced. Response was further predicted by the influence of spouses, family history of colon cancer, past knowledge of genetic testing for colon cancer, and education level. Participation was predicted by awareness that the study was supported by the Ashkenazi Jewish community, past experience with genetic testing, individuals' perceptions of the benefits of participating, and whether or not they had children. The degree to which individuals understand the purpose and nature of genetic screening research, along with their levels of decisional conflict and other psychosocial factors, may influence the likelihood of their participation in such research. Results of this study suggest a number of possible strategies for improving participation and response rates in disease prevention and detection studies.

Asunto(s)

Neoplasias del Colon/prevención & control , Tamizaje Masivo , Factores de Edad , Actitud Frente a la Salud , Neoplasias del Colon/genética , Femenino , Educación en Salud , Humanos , Judíos , Masculino , Análisis Multivariante , Participación del Paciente , Servicios Preventivos de Salud

Asunto(s)

Mapeo Cromosómico , Cromosomas Humanos Par 5/genética , Deformidades Congénitas del Pie/genética , Deformidades Congénitas de la Mano/genética , Cromosomas Humanos Par 17/genética , Femenino , Dedos/anomalías , Deformidades Congénitas del Pie/clasificación , Deformidades Congénitas de la Mano/clasificación , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Linaje , Polimorfismo Genético/genética , Programas Informáticos

RESUMEN

There is a consensus among medical geneticists that it is desirable to recontact patients as new information becomes available. Furthermore, some have suggested that there are legal arguments to support an obligation, creating a duty to recontact. Thus far much of the discussion among medical geneticists has focused on the practical concerns of implementing such a policy. However, we think that any such policy raises a number of important ethical concerns that must first be considered. Furthermore, there has not been a careful evaluation of the legal precedents that may reflect on a hypothetical duty to recontact. In this paper we first present an analysis of the scope of approaches and issues to be addressed in the development of ethical policy on this question. Secondly, we examine whether there is a legal obligation to recontact former patients about advances in genetics, as well as the legal implications if such a policy were to be adopted. Finally, we consider some of the functional and resource implications of adopting a policy of recontact. Our goal is to provide a framework for further discussion of this question and to stimulate further debate and research.

Asunto(s)

Deber de Advertencia/legislación & jurisprudencia , Ética Médica , Genética Médica/normas , Recolección de Datos , Genética Médica/educación , Humanos , Responsabilidad Legal , Educación del Paciente como Asunto , Investigación

Asunto(s)

Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Genética Médica , Maternidades , Defectos del Tubo Neural/prevención & control , Admisión del Paciente , Clase Social , Adulto , Escolaridad , Femenino , Humanos , Persona de Mediana Edad , Cooperación del Paciente , Educación del Paciente como Asunto , Relaciones Médico-Paciente , Embarazo , Estudios Retrospectivos , Encuestas y Cuestionarios

RESUMEN

BACKGROUND & AIMS: The I1307K allele of the APC gene has been shown to confer a modestly elevated risk of colorectal cancer in the Ashkenazi Jewish population (relative risk, 1.5-1.7). However, it is unclear whether the alteration predisposes to adenomas and whether the genetic information can be used in clinical practice. To further address the pathogenic significance of I1307K, we offered both a genetic test and a screening program to individuals considered to be at increased risk for colorectal cancer. We compared the prevalence of polyps and their characteristics between carriers and noncarriers. METHODS: Invitations to participate in a DNA and colonoscopy screening program were mailed, together with a family questionnaire, to 3540 households forming the Jewish Community in Ottawa. The I1307K variant was analyzed in 242 eligible respondents who were selected because they had a personal or family history of colon cancer. Nearly 80% of these respondents (n = 189; age range, 32-83 years) consented to undergo a single colonoscopic examination. RESULTS: The overall carrier frequency of I1307K in the study group was 10.3%. A higher proportion of heterozygous gene carriers was found in the subgroup of colon cancer survivors (27%) than among asymptomatic individuals (8%, P < 0.02). A total of 59 polyps were identified in 44 subjects. Histologically confirmed adenomatous polyps were diagnosed in 11.8% of carriers and 12.8% of noncarriers (P > 0.5). No significant differences in polyp size, multiplicity, location, degree of villosity, or age-dependent prevalence were found between the 2 groups of participants. CONCLUSIONS: The high frequency of I1307K colorectal cancer patients found in the Ashkenazi Jewish community of Ottawa and the equivalent proportion of carriers and noncarriers who developed adenomatous polyps suggest that in this community, I1307K is associated with a significant predisposition to carcinoma but not adenoma.

Asunto(s)

Pólipos Adenomatosos/etnología , Pólipos Adenomatosos/genética , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/genética , Genes APC/genética , Judíos/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios Transversales , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Polimorfismo Genético , Prevalencia , Factores de Riesgo

RESUMEN

The medical community and general population have become aware that genetic testing is available to look for BRCA1 and BRCA2 mutations. However, criteria for who should be referred for genetic counseling and possible subsequent testing have yet to be determined, and many genetics centers have been overwhelmed by the demand for service. We set out to develop a family history assessment tool (FHAT) that could be used by physicians to select individuals for genetic counseling. Arbitrarily, we chose individuals who would have an approximate doubling of their lifetime risk for breast or ovarian cancer. The FHAT was then applied to 184 unrelated families, with an index patient who had breast or ovarian cancer and who had accepted the offer of BRCA1 BRCA2 testing. Data were compiled to compare the number of individuals who would have been referred for genetic counseling and the number of mutation-positive individuals who would have been screened out from counseling using FHAT, the tables from Claus, and the BRCAPRO system. In this population, FHAT was effective in minimizing both the number of referrals and the likelihood of missing women who were later found to be mutation-positive.

Asunto(s)

Neoplasias de la Mama/genética , Asesoramiento Genético , Mutación , Neoplasias Ováricas/genética , Adulto , Anciano , Proteína BRCA2 , Exones , Salud de la Familia , Femenino , Genes BRCA1/genética , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Factores de Riesgo , Sensibilidad y Especificidad , Encuestas y Cuestionarios , Factores de Transcripción/genética

RESUMEN

The brachydactylies are a group of conditions in which various subtypes have been defined based upon the specific pattern of digital bones involved. Type A1 brachydactyly is principally characterised by maximal involvement of the middle phalanges. We report an extended family with a mild brachydactyly A1 which was, except for some short stature, not associated with any of the additional clinical findings reported in several published families. While all the hand bones tended to be small, the principal features of the affected members were shortened middle and distal phalanges, proximal 1st phalanges, and 5th metacarpals. The feet were similarly involved and tended to have a broad, slightly adducted forefoot. The two affected children showed multiple coned epiphyses. This paper provides a detailed description of the family including the radiographic signs and metacarpophalangeal profiles, which proved to be useful in distinguishing the mildly affected persons.

Asunto(s)

Deformidades Congénitas de la Mano/diagnóstico por imagen , Articulación Metacarpofalángica/diagnóstico por imagen , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Deformidades Congénitas de la Mano/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Radiografía

RESUMEN

Terminal limb deficiency defects affect between three and eight babies per 10000 births and are an important cause of disability. Established causes for these malformations include single gene disorders, chromosome abnormalities, teratogens, and amniotic bands. However, the etiology remains unknown in a significant proportion of cases. Several authors have hypothesized that vascular accidents, either bleeds or vessel occlusions, may underlie a substantial number of cases; but, for the most part, the origin of such events remains obscure. Over the past several years, an increasing number of genetic thrombophilias have been recognized and have been associated with increased risks of peri- and post-natal occlusive disease, and with higher rates of recurrent pregnancy loss. The hypothesis to be examined in this pilot study was whether the inherited thrombophilias might be associated with a vascular cause of some terminal limb deficiency defects. Towards that end, protein C, protein S, antithrombin III, factor V Leiden mutation, prothrombin (G20210A) variant, methylenetetrahydrofolate reductase variant, plasma homocysteine, anticardiolipin IgM and IgG antibodies, and lipoprotein (a) were measured in 24 mother-child pairs in which the child had a terminal limb defect. The results provided some evidence that there may be an excess of thrombophilias present in such families and that they may play some etiological role in a subset of these types of limb malformations.

Asunto(s)

Deformidades Congénitas de las Extremidades/genética , Trombofilia/genética , Anticuerpos Anticardiolipina/sangre , Antitrombina III/química , Factor V/genética , Femenino , Homocisteína/sangre , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2) , Madres , Mutación , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Proyectos Piloto , Polimorfismo Genético , Proteína C/química , Proteína S/química

Asunto(s)

Citas y Horarios , Asesoramiento Genético/estadística & datos numéricos , Pruebas Genéticas/estadística & datos numéricos , Encuestas de Atención de la Salud , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Actitud , Canadá , Distribución de Chi-Cuadrado , Cuidado del Niño , Preescolar , Demografía , Educación , Femenino , Asesoramiento Genético/economía , Asesoramiento Genético/psicología , Predisposición Genética a la Enfermedad , Pruebas Genéticas/economía , Pruebas Genéticas/psicología , Humanos , Masculino , Estado Civil , Edad Materna , Padres/educación , Padres/psicología , Pacientes Desistentes del Tratamiento/psicología , Embarazo , Embarazo de Alto Riesgo , Derivación y Consulta , Clase Social , Teléfono , Negativa del Paciente al Tratamiento , Tolerancia al Trabajo Programado