RESUMEN
BACKGROUND AND PURPOSE: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia. MATERIALS AND METHODS: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities. RESULTS: Pathogenic variants in SON, causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria. CONCLUSIONS: The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.
Asunto(s)
Encefalopatías , Discapacidad Intelectual , Heterotopia Nodular Periventricular , Humanos , Encéfalo/patología , Imagen por Resonancia Magnética , Encefalopatías/patología , Discapacidad Intelectual/patologíaRESUMEN
Mutations in RAD51 have recently been linked to human Congenital Mirror Movements (CMM), a developmental disorder of the motor system. The only gene previously linked to CMM encodes the Netrin-1 receptor DCC, which is important for formation of corticospinal and callosal axon tracts. Thus, we hypothesised that Rad51 has a novel role in Netrin-1-mediated axon development. In mouse primary motor cortex neurons, Rad51 protein was redistributed distally down the axon in response to Netrin-1, further suggesting a functional link between the two. We next manipulated Rad51 expression, and assessed Netrin-1 responsiveness. Rad51 siRNA knockdown exaggerated Netrin-1-mediated neurite branching and filopodia formation. RAD51 overexpression inhibited these responses, whereas overexpression of the CMM-linked R250Q mutation, a predicted loss-of-function, had no effect. Thus, Rad51 appears to negatively regulate Netrin-1 signalling. Finally, we examined whether Rad51 might operate by modulating the expression of the Unc5 family, known negative regulators of Netrin-1-responsiveness. Unc5b and Unc5c transcripts were downregulated in response to Rad51 knockdown, and upregulated with RAD51 overexpression, but not R250Q. Thus, Rad51 negatively regulates Netrin-1 signalling, at least in part, by modulating the expression of Unc5s. Imbalance of positive and negative influences is likely to lead to aberrant motor system development resulting in CMMs.
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Corteza Motora/metabolismo , Netrina-1/metabolismo , Recombinasa Rad51/metabolismo , Animales , Axones/metabolismo , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Corteza Motora/citología , Corteza Motora/crecimiento & desarrollo , Mutación , Receptores de Netrina/genética , Receptores de Netrina/metabolismo , Netrina-1/genética , Proyección Neuronal , Recombinasa Rad51/genética , Transducción de SeñalRESUMEN
BACKGROUND: In men undergoing definitive radiation for prostate cancer, it is unclear whether early biochemical response can provide additional prognostic value beyond pre-treatment risk stratification. METHODS: Prostate cancer patients consecutively treated with definitive radiation at our institution by a single provider from 1993 to 2006 and who had an end-of-radiation (EOR) PSA (n=688, median follow-up 11.2 years). We analyzed the association of an EOR PSA level, obtained during the last week of radiation, with survival outcomes. Multivariable-adjusted cox proportional hazards models were constructed to assess associations between a detectable EOR PSA (defined as ⩾0.1 ng ml-1) and biochemical failure-free survival (BFFS), metastasis-free survival (MFS), prostate cancer-specific survival (PCSS) and overall survival (OS). Kaplan-Meier survival curves were constructed, with stratification by EOR PSA. RESULTS: At the end of radiation, the PSA level was undetectable in 30% of patients. Men with a detectable EOR PSA experienced inferior 10-year BFFS (49.7% versus 64.4%, P<0.001), 10-year MFS (84.8% versus 92.0%, P=0.003), 10-year PCSS (94.3% versus 98.2%, P=0.007) and 10-year OS (75.8% versus 82.5%, P=0.01), as compared to men with an undetectable EOR PSA. Among National Comprehensive Care Network (NCCN) intermediate- and high-risk men who were treated with definitive radiation and androgen deprivation therapy (ADT), a detectable EOR PSA was more strongly associated with PCSS than initial NCCN risk level (EOR PSA: HR 5.89, 95% CI 2.37-14.65, P<0.001; NCCN risk level: HR 2.01, 95% CI 0.74-5.42, P=0.168). Main study limitations are retrospective study design and associated biases. CONCLUSIONS: EOR PSA was significantly associated with survival endpoints in men who received treatment with definitive radiation and ADT. Whether the EOR PSA can be used to modulate treatment intensity merits further investigation.
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Pronóstico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/radioterapia , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/administración & dosificación , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/efectos de la radiación , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Dosificación RadioterapéuticaRESUMEN
There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective longitudinal Dunedin Study (n=1037). Analyses showed that the persistence of internalizing disorders across repeated assessments from ages 11 to 38 years predicted shorter LTL at age 38 years in a dose-response manner, specifically in men (ß=-0.137, 95% confidence interval (CI): -0.232, -0.042, P=0.005). This association was not accounted for by alternative explanatory factors, including childhood maltreatment, tobacco smoking, substance dependence, psychiatric medication use, poor physical health or low socioeconomic status. Additional analyses using DNA from blood collected at two time points (ages 26 and 38 years) showed that LTL erosion was accelerated among men who were diagnosed with internalizing disorder in the interim (ß=-0.111, 95% CI: -0.184, -0.037, P=0.003). No significant associations were found among women in any analysis, highlighting potential sex differences in internalizing-related telomere biology. These findings point to a potential mechanism linking internalizing disorders to accelerated biological aging in the first half of the life course, particularly in men. Because internalizing disorders are treatable, the findings suggest the hypothesis that treating psychiatric disorders in the first half of the life course may reduce the population burden of age-related disease and extend health expectancy.
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Trastornos de Ansiedad/fisiopatología , Trastorno Depresivo/fisiopatología , Leucocitos/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Telómero/metabolismo , Adolescente , Adulto , Envejecimiento/genética , Envejecimiento/fisiología , Trastornos de Ansiedad/genética , Niño , Trastorno Depresivo/genética , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , Caracteres Sexuales , Trastornos por Estrés Postraumático/genética , Adulto JovenRESUMEN
Nager syndrome belongs to the group of acrofacial dysostosis, which are characterized by the association of craniofacial and limb malformations. Recently, exome sequencing studies identified the SF3B4 gene as the cause of this condition in most patients. SF3B4 encodes a highly conserved protein implicated in mRNA splicing and bone morphogenic protein (BMP) signaling. We performed SF3B4 sequencing in 14 families (18 patients) whose features were suggestive of Nager syndrome and found nine mutations predicted to result in loss-of-function. SF3B4 is the major gene responsible for autosomal dominant Nager syndrome. All mutations reported predict null alleles, therefore precluding genotype-phenotype correlations. Most mutation-negative patients were phenotypically indistinguishable from patients with mutations, suggesting genetic heterogeneity.
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Predisposición Genética a la Enfermedad/genética , Haploinsuficiencia/genética , Disostosis Mandibulofacial/genética , Fenotipo , Proteínas de Unión al ARN/genética , Secuencia de Bases , Femenino , Genes Dominantes/genética , Humanos , Masculino , Disostosis Mandibulofacial/patología , Datos de Secuencia Molecular , Mutación/genética , Factores de Empalme de ARN , Análisis de Secuencia de ADNRESUMEN
Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X-linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.
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Proteínas Adaptadoras Transductoras de Señales/genética , Eliminación de Gen , Discapacidad Intelectual/genética , Osteosclerosis/genética , Proteínas Supresoras de Tumor/genética , Cromosomas Humanos X/genética , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Femenino , Genes Ligados a X/genética , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Mutación Puntual , Factores de Intercambio de Guanina Nucleótido RhoRESUMEN
Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by facial dysmorphology and radiographic abnormalities [Melnick and Needles, 1966;97:39-48]. Previously, all published cases of MNS were associated with only 4 mutations [Robertson et al., 2003;33:487-491; Santos et al., 2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are associated with MNS. One affected member of the first family with the mutation p.Y1229S presented with a stroke while this patient's daughter, previously known to be affected from a young age, developed multiple sclerosis. A second unrelated patient with a typical phenotype is shown to have the mutation c.1054G>T (p.G352W) within exon 7 of FLNA. A third individual with an atypical presentation but radiological findings very similar to those seen in classic MNS has a deletion likely to affect residues within repeat domain 14. These findings indicate that the mutational spectrum for MNS is wider than previously appreciated and has implications for genetic testing strategies employed to confirm a diagnosis of this rare disorder.
RESUMEN
Periventricular heterotopia (PH) is a brain malformation characterised by heterotopic nodules of neurons lining the walls of the cerebral ventricles. Mutations in FLNA account for 20-24% of instances but a majority have no identifiable genetic aetiology. Often the co-occurrence of PH with a chromosomal anomaly is used to infer a new locus for a Mendelian form of PH. This study reports four PH patients with three different microdeletion syndromes, each characterised by high-resolution genomic microarray. In three patients the deletions at 1p36 and 22q11 are conventional in size, whilst a fourth child had a deletion at 7q11.23 that was larger in extent than is typically seen in Williams syndrome. Although some instances of PH associated with chromosomal deletions could be attributed to the unmasking of a recessive allele or be indicative of more prevalent subclinical migrational anomalies, the rarity of PH in these three microdeletion syndromes and the description of other non-recurrent chromosomal defects do suggest that PH may be a manifestation of multiple different forms of chromosomal imbalance. In many, but possibly not all, instances the co-occurrence of PH with a chromosomal deletion is not necessarily indicative of uncharacterised underlying monogenic loci for this particular neuronal migrational anomaly.
Asunto(s)
Encefalopatías/genética , Coristoma/genética , Proteínas Contráctiles/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Espasmos Infantiles/genética , Encefalopatías/epidemiología , Encefalopatías/patología , Ventrículos Cerebrales/patología , Coristoma/epidemiología , Coristoma/patología , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Electroencefalografía/estadística & datos numéricos , Exones/genética , Femenino , Filaminas , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Lactante , Masculino , Metionina/genética , Mutación Missense/genética , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de Proteína , Espasmos Infantiles/epidemiología , Treonina/genéticaRESUMEN
Sixteen years of archived tufted apple bud moth, Platynota idaeusalis (Walker), trap capture data were compared with archived fruit injury data collected at the Penn State University Fruit Research and Extension Center to define the relationship of trap capture to fruit injury. Pheromone trap capture until 15 June was the best predictor of fruit injury at harvest. Using the regression equation of fruit injury on early season trap capture, and other assumptions about insecticide cost and fruit yield, a management model was developed for apple growers in the Mid-Atlantic region. When the model was tested on archived trap capture and fruit injury data, the results indicated that a grower would lose money on average by always treating and save money on average by never treating. By using the model, a grower could expect to save more money than by never treating. The model showed sensitivity to fruit price, insecticide price, and fruit yield.
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Frutas/parasitología , Control de Insectos/métodos , Malus/parasitología , Mariposas Nocturnas/fisiología , Animales , Toma de Decisiones , Insecticidas , Modelos Biológicos , Feromonas , Análisis de Regresión , Estaciones del Año , Sensibilidad y EspecificidadRESUMEN
Scientific and technological advances are lending pressure to expand the scope of newborn screening. Whereas this has great potential for improving child health, it also challenges our current perception of such programmes. Standard newborn screening programmes are clearly justified by the fact that early detection and treatment of affected individuals avoids significant morbidity and mortality. However, proposals to expand the scope and complexity of such testing are not all supported by a similar level of evidence for unequivocal benefit. We argue that screening for genetic susceptibility to complex disorders is inherently different from standard screening and, while of potential value, must be considered separately from conventional testing.
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Enfermedades del Recién Nacido/diagnóstico , Tamizaje Neonatal/ética , Diabetes Mellitus/genética , Diabetes Mellitus/prevención & control , Predisposición Genética a la Enfermedad , Pruebas Genéticas/ética , Pruebas Genéticas/métodos , Humanos , Recién Nacido , Consentimiento Informado , Padres/psicología , Autonomía Personal , Fenilcetonurias/diagnóstico , Justicia Social/éticaRESUMEN
Boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome that we have recently shown to be associated with mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. We report the identification of mutations in FLNB in two unrelated individuals with boomerang dysplasia. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans.
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Proteínas Contráctiles/genética , Proteínas de Microfilamentos/genética , Mutación , Osteocondrodisplasias/genética , Anomalías Múltiples/genética , Feto Abortado/diagnóstico por imagen , Sustitución de Aminoácidos , Animales , Sitios de Unión/genética , Secuencia Conservada/genética , Análisis Mutacional de ADN , Femenino , Filaminas , Heterocigoto , Humanos , Fenotipo , Embarazo , Segundo Trimestre del Embarazo , Radiografía , Homología de Secuencia de AminoácidoRESUMEN
The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.
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Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 19/genética , Genes Dominantes/genética , Mapeo Cromosómico , Femenino , Frecuencia de los Genes/genética , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Linaje , Recombinación Genética/genéticaRESUMEN
Otopalatodigital syndrome type 1 (OPD1) is an X-linked semidominant condition characterized by malformations of the skeleton, auditory apparatus, and palate. Previous studies have established linkage to a 16-cM region of Xq27-q28. A proposed allelic variant of OPD1, termed "OPD2," is associated with a more severe, frequently lethal phenotype with visceral and brain anomalies in addition to skeletal, auditory, and palatal defects. We report linkage of the OPD2 phenotype to a 2-cM region of distal Xq28 in a Maori kindred, with a maximum multipoint LOD score of 3.31 between the markers DXS1073 and DXS1108. This provides support for allelism between OPD1 and OPD2 and reduces the size of the disease interval to 1.8-2.1 Mb. We also demonstrate that female carriers of this disorder exhibit skewed inactivation that segregates with the high-risk haplotype and may be inversely related to the severity with which they manifest features of the disorder.
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Anomalías Múltiples/genética , Alelos , Anomalías Craneofaciales/genética , Ligamiento Genético/genética , Hueso Paladar/anomalías , Cromosoma X/genética , Anomalías Múltiples/mortalidad , Encéfalo/anomalías , Mapeo Cromosómico , Segregación Cromosómica/genética , Anomalías Craneofaciales/mortalidad , Compensación de Dosificación (Genética) , Femenino , Predisposición Genética a la Enfermedad/genética , Haplotipos/genética , Heterocigoto , Humanos , Escala de Lod , Masculino , Mutación/genética , Linaje , Fenotipo , Recombinación Genética/genética , SíndromeRESUMEN
The combination of spondyloepiphyseal dysplasia, humoral immune deficiency, growth retardation, intellectual deficit and characteristic facial dysmorphism has recently been delineated as a discrete disorder thus far only reported in males. This report describes a fifth individual with co-existent hypogonadotrophic hypogonadism, thereby expanding the phenotype and possibly offering insight into the genetic aetiology of this condition.
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Hipogonadismo/genética , Adulto , Facies , Ligamiento Genético , Trastornos del Crecimiento/genética , Humanos , Sistema Inmunológico/anomalías , Discapacidad Intelectual/genética , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/genética , Pelvis/diagnóstico por imagen , Radiografía , Enfermedades de la Retina/genética , Columna Vertebral/patología , Síndrome , Cromosoma XRESUMEN
Cutis marmorata telangiectatica congenita (CMTC) is a cutaneous disorder often accompanied by additional anomalies, most commonly segmental overgrowth. Recently a clinically discrete condition has been described comprising CMTC and congenital macrocephaly together with pre- and post-natal macrosomia, segmental overgrowth, central nervous system malformations, connective tissue abnormalities and intellectual handicap. We describe the natural history of macrocephaly-CMTC (M-CMTC) syndrome in a further five patients including the oldest reported patient, a 22 year old. The addition of our five patients brings the total number of reported patients to 28 and now makes it possible to more accurately delineate the phenotype and the frequency of clinical manifestations. We add some further clinical associations to those previously described, including anomalies of the growth of hair and teeth, neuronal migration defects, dislocated hips and stridor. We discuss potential genetic mechanisms that might account for the pleiotropic manifestations of this apparently rare segmental overgrowth disorder.
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Anomalías Múltiples/patología , Cráneo/anomalías , Telangiectasia/congénito , Anomalías Múltiples/diagnóstico por imagen , Femenino , Humanos , Lactante , Recién Nacido , Masculino , RadiografíaRESUMEN
Cantú syndrome (hypertrichosis, osteochondrodysplasia, cardiomegaly) is a rare condition, previously reported in 13 patients. We report on two additional patients with this disorder. One of the patients had pulmonary hypertension of unknown cause which was responsive to steroid therapy. She also had unusual, deep plantar creases, not reported previously in Cantú syndrome. Autosomal recessive inheritance has been suggested previously on the basis of sib recurrence in one family and consanguinity in another. We have performed a segregation analysis based on all reported families to date; the data indicate autosomal recessive inheritance is unlikely. A new dominant mutation or microdeletion syndrome are more likely possibilities, sib recurrence possibly representing gonadal mosaicism.
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Cardiomegalia/congénito , Hipertricosis/congénito , Osteocondrodisplasias/congénito , Cardiomegalia/patología , Preescolar , Cara/patología , Femenino , Humanos , Hipertricosis/patología , Osteocondrodisplasias/diagnóstico por imagen , Radiografía Torácica , SíndromeRESUMEN
A disorder affecting bone and cartilage growth is described in a mother and her 3-year-old son. A dysplastic process involving the vertebral bodies, most pronounced in the cervical region and leading to cervical dislocation in the first of these two patients, is the most significant complication of this disorder. This entity appears unrelated to other previously described skeletal dysplasias with cervical kyphosis as a major manifestation. This disorder is most likely autosomal dominant.