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1.
Pediatr Rev ; 42(Suppl 1): S103-S105, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33386376
2.
Pediatrics ; 146(Suppl 1): S13-S17, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32737227

RESUMO

Although parents are typically the most appropriate decision-makers for their children, there are limits to this authority. Medical providers may be ethically obligated to seek state intervention against a parental decision if the parent places a child at significant and imminent risk of serious harm. When parents make medical decisions for their children, they assess both the projected benefits and risks of their choices for their family. These assessments are impacted by uncertainty, which is a common feature of neonatal intensive care. The relative presence or absence of uncertainty may impact perceptions of parental decisions and a medical provider's decision to seek state intervention to overrule parents. In this article, we propose a model integrating prognostic uncertainty into pediatric decision-making that may aid providers in such assessments. We will demonstrate how to apply this model to 3 neonatal cases and propose that the presence of greater uncertainty ought to permit parents greater latitude to incorporate family values into their decision-making even if these decisions are contradictory to the recommendations of the medical team.


Assuntos
Temas Bioéticos , Tomada de Decisão Clínica/ética , Pais , Incerteza , Família , Feminino , Idade Gestacional , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Masculino , Cuidados Paliativos , Consentimento dos Pais/ética , Prognóstico , Estenose da Valva Pulmonar/cirurgia , Valores Sociais , Suspensão de Tratamento/ética
3.
Am J Med Genet A ; 182(1): 195-200, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697451

RESUMO

RASopathies are a group of phenotypically overlapping disorders that arise from dysregulation of the RAS/MAPK pathway. These disorders include Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, and neurofibromatosis-Type 1. While somatic mutations in the three human Ras genes (KRAS, HRAS, and NRAS) are a common finding in a variety of cancers, germline mutations in each of the these genes cause developmental RASopathy phenotypes with mutations in specific genes typically correlating with specific phenotypes. We present the case of a germline heterozygous NRAS mutation producing a severe phenotype involving embryonal rhabdomyosarcoma, severe intellectual disability, and numerous melanocytic nevi in addition to more typical manifestations of Noonan syndrome. Additionally, the specific p.G12R NRAS mutation in this case is a common somatic mutation in cancer cells, and analysis of previously reported NRAS-RASopathy cases suggests that mutations at traditionally oncogenic codons are associated with elevated cancer risk not present with mutations at other sites.

4.
Am J Med Genet A ; 176(11): 2243-2249, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30276953

RESUMO

Congenital lumbar hernia is a rare anomaly consisting of protrusion of abdominal organs or extraperitoneal tissue through a defect in the lateral abdominal wall. The majority of affected patients have additional anomalies in a pattern described as the lumbocostovertebral syndrome. We report four patients born to mothers with poorly controlled diabetes with congenital lumbar hernia. All patients exhibited features of lumbocostovertebral syndrome with lumbar hernia, multiple vertebral segmentation anomalies in the lower thoracic and/or upper lumbar spine, rib anomalies, and unilateral renal agenesis. Additional anomalies present in the patients included preaxial hallucal polydactyly, abnormal situs, and sacral dysgenesis, anomalies known to be associated with diabetic embryopathy. At least 11 other patients have been previously reported with the lumbocostovertebral syndrome in the setting of maternal diabetes. We suggest that congenital lumbar hernia and the lumbocostovertebral syndrome are related to diabetic embryopathy.


Assuntos
Diabetes Gestacional/patologia , Doenças Fetais/patologia , Hérnia/congênito , Hérnia/complicações , Vértebras Lombares/anormalidades , Adulto , Pré-Escolar , Feminino , Doenças Fetais/diagnóstico por imagem , Hérnia/diagnóstico por imagem , Humanos , Recém-Nascido , Vértebras Lombares/diagnóstico por imagem , Masculino , Gravidez
5.
Am J Med Genet A ; 167A(2): 271-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25394726

RESUMO

Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Éxons , Meningocele/diagnóstico , Meningocele/genética , Mutação , Receptores Notch/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Exoma , Facies , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo , Receptor Notch3 , Adulto Jovem
6.
Hum Genet ; 134(1): 97-109, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25326669

RESUMO

Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.


Assuntos
Deficiência Intelectual/genética , Microcefalia/genética , Mutação/genética , beta Catenina/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Fenótipo , Síndrome
8.
Hum Mutat ; 35(7): 779-90, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24692096

RESUMO

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.


Assuntos
Estudos de Associação Genética , Doenças Musculares/congênito , Doenças Musculares/genética , Mutação , Tropomiosina/genética , Actinas/metabolismo , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Bases de Dados Genéticas , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Fenótipo , Fosforilação , Ligação Proteica , Alinhamento de Sequência , Tropomiosina/química , Tropomiosina/metabolismo , Adulto Jovem
10.
Gene ; 537(2): 279-84, 2014 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-24378232

RESUMO

Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592_593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. This study expands the spectrum of RAD21 mutations and emphasizes the clinical utility of performing RAD21 mutation analysis in patients presenting with atypical forms of CdLS. Moreover, the variability of clinical presentation within families and low penetrance of mutations as well as the significance of performing molecular genetic testing in mildly affected patients are discussed.


Assuntos
Síndrome de Cornélia de Lange/etiologia , Mutação , Proteínas Nucleares/genética , Fosfoproteínas/genética , Adulto , Proteínas de Ciclo Celular , Pré-Escolar , Proteínas de Ligação a DNA , Síndrome de Cornélia de Lange/genética , Deficiências do Desenvolvimento/genética , Éxons , Feminino , Mutação da Fase de Leitura , Hirsutismo/genética , Humanos , Masculino , Linhagem
11.
J Clin Microbiol ; 48(7): 2599-600, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20421433

RESUMO

We investigated the proportion of methicillin-resistant Staphylococcus aureus (MRSA) isolates from pediatric patients demonstrating mupirocin resistance related to mupirocin use at our institution. No mupirocin resistance was found in 98% of isolates, whereas mupirocin prescriptions increased by 110%. Resistance rates remained low despite the increasing use of mupirocin.


Assuntos
Farmacorresistência Bacteriana , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Mupirocina , Infecções Estafilocócicas , Adolescente , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mupirocina/farmacologia , Mupirocina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
12.
Mil Med ; 173(6): 604-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18595427

RESUMO

Mupirocin is an antibiotic used for eradication and infection control of methicillin-resistant Staphylococcus aureus (MRSA). Mupirocin binds to the bacterial isoleucyl tRNA synthetase, thus disrupting bacterial protein synthesis. Four hundred nine MRSA clinical isolates collected in 2006 and 2007 at Madigan Army Medical Center were screened for mupirocin resistance by E test and polymerase chain reaction; 7 MRSA isolates (1.7%) were found to be fully resistant to mupirocin (minimum inhibitory concentration [MIC] by E test: > 1,024 microg/mL), 10 isolates (2.4%) had MIC values of 1 to 32 microg/mL, while 392 MRSA isolates (95.9%) had MIC values of < 1 microg/mL. No trend of increased mupirocin resistance was found when compared with subsequent years. These results show that mupirocin remains a valid infection control measure due to its unique mechanism of action and the high susceptibility rate of MRSA isolates. In addition, rapid screening by polymerase chain reaction of MRSA shows promise in assessing the fully resistant mupirocin phenotype.


Assuntos
Antibacterianos/farmacologia , Mupirocina/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , District of Columbia , Farmacorresistência Bacteriana , Hospitais Militares , Humanos , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase , Fatores de Tempo
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