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2.
Clin Epigenetics ; 11(1): 60, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961659

RESUMO

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants. RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer. CONCLUSIONS: Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.

3.
PLoS One ; 14(3): e0214257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913273

RESUMO

Due to its ease of genetic manipulation and transparency, Caenorhabditis elegans (C. elegans) has become a preferred model system to study gene function by microscopy. The use of Aequorea victoria green fluorescent protein (GFP) fused to proteins or targeting sequences of interest, further expanded upon the utility of C. elegans by labeling subcellular structures, which enables following their disposition during development or in the presence of genetic mutations. Fluorescent proteins with excitation and emission spectra different from that of GFP accelerated the use of multifluorophore imaging in real time. We have expanded the repertoire of fluorescent proteins for use in C. elegans by developing a codon-optimized version of Orange2 (CemOrange2). Proteins or targeting motifs fused to CemOrange2 were distinguishable from the more common fluorophores used in the nematode; such as GFP, YFP, and mKate2. We generated a panel of CemOrange2 fusion constructs, and confirmed they were targeted to their correct subcellular addresses by colocalization with independent markers. To demonstrate the potential usefulness of this new panel of fluorescent protein markers, we showed that CemOrange2 fusion proteins could be used to: 1) monitor biological pathways, 2) multiplex with other fluorescent proteins to determine colocalization and 3) gain phenotypic knowledge of a human ABCA3 orthologue, ABT-4, trafficking variant in the C. elegans model organism.

4.
Bone ; 124: 14-21, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30914273

RESUMO

B4GALT7 encodes beta-1,4-galactosyltransferase which links glycosaminoglycans to proteoglycans in connective tissues. Rare, biallelic variants in B4GALT7 have been associated with spondylodysplastic Ehlers-Danlos and Larsen of Reunion Island syndromes. Thirty patients with B4GALT7-related disorders have been reported to date with phenotypic variability. Using whole exome sequencing, we identified male and female siblings with biallelic, pathogenic B4GALT7 variants and phenotypic features of spondylodysplastic Ehlers-Danlos syndrome as well as previously unreported skeletal characteristics. We also provide detailed radiological characterization and describe the siblings' responses to growth hormone treatment. Our report extends the phenotypic spectrum of B4GALT7-associated spondylodysplastic Ehlers-Danlos syndrome and reports results of growth hormone treatment for patients with this rare disorder.

5.
Am J Hum Genet ; 103(6): 968-975, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30414627

RESUMO

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.


Assuntos
Retardo do Crescimento Fetal/genética , Variação Genética/genética , Perda de Heterozigosidade/genética , Progéria/genética , RNA Polimerase III/genética , Adolescente , Adulto , Alelos , Pré-Escolar , Feminino , Genótipo , Humanos , Fenótipo , Adulto Jovem
6.
Pediatr Res ; 84(3): 435-441, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29967526

RESUMO

BACKGROUND: Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants. METHODS AND RESULTS: We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant's fibroblasts to determine primary ciliary phenotype. RESULTS: We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia. CONCLUSION: Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants.


Assuntos
Encéfalo/anormalidades , Proteínas de Transporte/genética , Doenças Cerebelares/genética , Microcefalia/genética , Convulsões/genética , Alelos , Encéfalo/diagnóstico por imagem , Proteínas de Ciclo Celular , Cílios , Exoma , Evolução Fatal , Fibroblastos/metabolismo , Deleção de Genes , Variação Genética , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Insuficiência Respiratória
7.
Neonatal Netw ; 37(3): 169-177, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29789058

RESUMO

Respiratory distress syndrome (RDS) impacts a high proportion of preterm neonates, resulting in significant morbidity and mortality. Advances in pharmacotherapy, specifically antenatal corticosteroids and postnatal surfactant therapy, have significantly reduced the incidence and impact of neonatal RDS. Antenatal corticosteroids accelerate fetal lung maturation by increasing the activity of enzymes responsible for surfactant biosynthesis, resulting in improved lung compliance. Maternal antenatal corticosteroid treatment has improved survival of preterm neonates and lowered the incidence of brain injury. After birth, exogenous surfactant administration improves lung compliance and oxygenation, resulting in reductions in the incidence of pneumothorax and of death. Future research will identify the optimal surfactant product, timing of the initial dose, and mode of delivery.


Assuntos
Lesões Encefálicas , Glucocorticoides/uso terapêutico , Pneumotórax , Surfactantes Pulmonares/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido , Lesões Encefálicas/etiologia , Lesões Encefálicas/prevenção & controle , Humanos , Recém-Nascido , Recém-Nascido Prematuro/fisiologia , Terapia Intensiva Neonatal/métodos , Pulmão/patologia , Administração dos Cuidados ao Paciente/métodos , Pneumotórax/etiologia , Pneumotórax/prevenção & controle , Cuidado Pré-Natal/métodos , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Síndrome do Desconforto Respiratório do Recém-Nascido/tratamento farmacológico
8.
World J Pediatr ; 14(1): 52-56, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29411327

RESUMO

BACKGROUND: To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. METHODS: We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants. RESULTS: We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang populations (0.0045 vs. 0.0064, respectively, P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous variants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB; F341L was also not previously reported in exome sequencing project. CONCLUSIONS: The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1, CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Predisposição Genética para Doença/epidemiologia , Variação Genética , Fosfatidilcolinas/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Grupo com Ancestrais do Continente Asiático/genética , Peso ao Nascer , China , Estudos de Coortes , Feminino , Frequência do Gene , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Masculino , Mutação , Fosfatidilcolinas/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico , Estudos Retrospectivos , Análise de Sequência de DNA , Transdução de Sinais , Análise de Sobrevida
9.
J Pediatr ; 194: 158-164.e1, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29198536

RESUMO

OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.


Assuntos
Transplante de Pulmão/métodos , Síndrome da Persistência do Padrão de Circulação Fetal/diagnóstico , Alvéolos Pulmonares/anormalidades , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Lactente , Recém-Nascido , Pulmão/patologia , Masculino , Mutação , Síndrome da Persistência do Padrão de Circulação Fetal/complicações , Síndrome da Persistência do Padrão de Circulação Fetal/cirurgia , Alvéolos Pulmonares/cirurgia , Veias Pulmonares/anormalidades , Taxa de Sobrevida
10.
Am J Perinatol ; 35(5): 494-502, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29183099

RESUMO

OBJECTIVE: Preterm birth (PTB) at <37 weeks of gestation complicates 10% of pregnancies and requires accurate counseling regarding anticipated neonatal outcomes. PTB classification as spontaneous or indicated is commonly used to cluster PTB into subtypes, but whether neonatal outcomes differ by PTB subtype is unknown. We tested the hypothesis that neonatal morbidity differs based on subtype of PTB. METHODS: We performed a retrospective cohort study of live-born, non-anomalous preterm infants from 2004 to 2008. Spontaneous PTB was defined as PTB from spontaneous preterm labor or preterm rupture of membranes. Indicated PTB was defined as PTB from any maternal or fetal medical complication necessitating delivery. The primary outcome was a composite of early respiratory morbidity. Secondary outcomes included late composite respiratory morbidity and other neonatal morbidities. RESULTS: Of 1,223 preterm neonates, 60.9% were born after spontaneous PTB and 30.1% after indicated PTB. Composite early respiratory morbidity was significantly higher after indicated PTB versus spontaneous PTB (1.3, 95% confidence interval [CI] 1.2-1.4). Composite late respiratory morbidity (1.8, 95% CI 1.3-2.3) and neonatal death (2.8, 95% CI 1.5-5.1) were also significantly higher after indicated PTB versus spontaneous PTB. CONCLUSION: Neonatal respiratory outcomes and death differ according to PTB subtype. PTB subtype should be considered while counseling families and anticipating neonatal outcomes after PTB.


Assuntos
Ruptura Prematura de Membranas Fetais , Mortalidade Infantil , Doenças do Prematuro/mortalidade , Recém-Nascido Prematuro , Trabalho de Parto Prematuro , Adulto , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Missouri/epidemiologia , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
11.
Hum Mutat ; 38(11): 1477-1484, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28726266

RESUMO

Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Assuntos
Artrogripose/diagnóstico , Artrogripose/genética , Genes Letais , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fenótipo , Artrogripose/mortalidade , Biópsia , Análise Mutacional de DNA , Evolução Fatal , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Raízes Nervosas Espinhais/ultraestrutura , Sequenciamento Completo do Exoma
12.
J Pediatr ; 184: 157-164.e2, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28215425

RESUMO

OBJECTIVE: To compare outcomes of infants and children who underwent lung transplantation for genetic disorders of surfactant metabolism (SFTPB, SFTPC, ABCA3, and NKX2-1) over 2 epochs (1993-2003 and 2004-2015) at St Louis Children's Hospital. STUDY DESIGN: We retrospectively reviewed clinical characteristics, mortality, and short- and long-term morbidities of infants (transplanted at <1 year; n = 28) and children (transplanted >1 year; n = 16) and compared outcomes by age at transplantation (infants vs children) and by epoch of transplantation. RESULTS: Infants underwent transplantation more frequently for surfactant protein-B deficiency, whereas children underwent transplantation more frequently for SFTPC mutations. Both infants and children underwent transplantation for ABCA3 deficiency. Compared with children, infants experienced shorter times from listing to transplantation (P = .014), were more likely to be mechanically ventilated at the time of transplantation (P < .0001), were less likely to develop bronchiolitis obliterans post-transplantation (P = .021), and were more likely to have speech and motor delays (P ≤ .0001). Despite advances in genetic diagnosis, immunosuppressive therapies, and supportive respiratory and nutritional therapies, mortality did not differ between infants and children (P = .076) or between epochs. Kaplan-Meier analyses demonstrated that children transplanted in epoch 1 (1993-2003) were more likely to develop systemic hypertension (P = .049) and less likely to develop post-transplantation lymphoproliferative disorder compared with children transplanted in epoch 2 (2004-2015) (P = .051). CONCLUSION: Post-lung transplantation morbidities and mortality remain substantial for infants and children with genetic disorders of surfactant metabolism.


Assuntos
Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Doenças Pulmonares Intersticiais/genética , Masculino , Surfactantes Pulmonares , Estudos Retrospectivos
13.
Ann Am Thorac Soc ; 13(12): 385-393, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27925785

RESUMO

Pediatric rare lung disease (PRLD) is a term that refers to a heterogeneous group of rare disorders in children. In recent years, this field has experienced significant progress marked by scientific discoveries, multicenter and interdisciplinary collaborations, and efforts of patient advocates. Although genetic mechanisms underlie many PRLDs, pathogenesis remains uncertain for many of these disorders. Furthermore, epidemiology and natural history are insufficiently defined, and therapies are limited. To develop strategies to accelerate scientific advancement for PRLD research, the NHLBI of the National Institutes of Health convened a strategic planning workshop on September 3 and 4, 2015. The workshop brought together a group of scientific experts, intramural and extramural investigators, and advocacy groups with the following objectives: (1) to discuss the current state of PRLD research; (2) to identify scientific gaps and barriers to increasing research and improving outcomes for PRLDs; (3) to identify technologies, tools, and reagents that could be leveraged to accelerate advancement of research in this field; and (4) to develop priorities for research aimed at improving patient outcomes and quality of life. This report summarizes the workshop discussion and provides specific recommendations to guide future research in PRLD.


Assuntos
Pesquisa Biomédica/tendências , Pneumopatias/terapia , Doenças Raras/terapia , Criança , Humanos , Pneumopatias/etiologia , National Heart, Lung, and Blood Institute (U.S.) , Pediatria , Guias de Prática Clínica como Assunto , Qualidade de Vida , Doenças Raras/etiologia , Estados Unidos
14.
Am J Respir Cell Mol Biol ; 55(5): 716-721, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27374344

RESUMO

Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome and childhood interstitial lung disease. As most ABCA3 mutations are rare or private, determination of mutation pathogenicity is often based on results from in silico prediction tools, identification in unrelated diseased individuals, statistical association studies, or expert opinion. Functional biologic studies of ABCA3 mutations are needed to confirm mutation pathogenicity and inform clinical decision making. Our objective was to functionally characterize two ABCA3 mutations (p.R288K and p.R1474W) identified among term and late-preterm infants with respiratory distress syndrome with unclear pathogenicity in a genetically versatile model system. We performed transient transfection of HEK293T cells with wild-type or mutant ABCA3 alleles to assess protein processing with immunoblotting. We used transduction of A549 cells with adenoviral vectors, which concurrently silenced endogenous ABCA3 and expressed either wild-type or mutant ABCA3 alleles (p.R288K and p.R1474W) to assess immunofluorescent localization, ATPase activity, and organelle ultrastructure. Both ABCA3 mutations (p.R288K and p.R1474W) encoded proteins with reduced ATPase activity but with normal intracellular localization and protein processing. Ultrastructural phenotypes of lamellar body-like vesicles in A549 cells transduced with mutant alleles were similar to wild type. Mutant proteins encoded by ABCA3 mutations p.R288K and p.R1474W had reduced ATPase activity, a biologically plausible explanation for disruption of surfactant metabolism by impaired phospholipid transport into the lamellar body. These results also demonstrate the usefulness of a genetically versatile, human model system for functional characterization of ABCA3 mutations with unclear pathogenicity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Mutação/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Células A549 , Adenosina Trifosfatases/metabolismo , Adenoviridae/metabolismo , Imunofluorescência , Células HEK293 , Humanos , Immunoblotting , Lactente , Proteínas Mutantes/metabolismo , Organelas/metabolismo , Organelas/ultraestrutura , Frações Subcelulares/metabolismo
15.
J Pediatr ; 172: 69-74.e2, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26935785

RESUMO

OBJECTIVE: To determine the genetic contribution to risk for respiratory distress syndrome (RDS) among moderately preterm, late preterm, and term infants (estimated gestational age ≥32 weeks) of African- and European-descent. STUDY DESIGN: We reviewed clinical records for 524 consecutive twin pairs ≥32 weeks gestation. We identified pairs in which at least 1 twin had RDS (n = 225) and compared the concordance of RDS between monozygotic and dizygotic twins. Using mixed-effects logistic regression, we identified covariates that increased disease risk. We performed additive genetic, common environmental, and residual effects modeling to estimate genetic variance and used the ratio of genetic variance to total variance to estimate genetic contribution to RDS disease risk. RESULTS: Monozygotic twins were more concordant for RDS than dizygotic twins (P = .0040). Estimated gestational age, European-descent, male sex, delivery by cesarean, and 5-minute Apgar score each independently increased risk for RDS. After adjusting for these covariates, genetic effects accounted for 58% (P = .0002) of the RDS disease risk variance for all twin pairs. CONCLUSIONS: In addition to environmental factors, genetic factors may contribute to RDS risk among moderately preterm, late preterm, and term infants. Discovery of risk alleles may be important for prediction and management of RDS risk.


Assuntos
Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Nascimento a Termo , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Feminino , Predisposição Genética para Doença , Idade Gestacional , Humanos , Recém-Nascido , Modelos Logísticos , Masculino , Gravidez , Estudos Retrospectivos , Fatores de Risco
16.
Cureus ; 7(7): e289, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26244121

RESUMO

Congenital leukemia is rarely encountered in clinical practice, even in tertiary children's hospitals. Leukemia may cause significant coagulopathy, putting the patient at risk of intracranial hemorrhage. In this case, the authors present a female infant with a unique mixed phenotypic congenital acute myeloid leukemia showing mixed-lineage leukemia (MLL) rearrangement and severe coagulopathy resulting in a large subdural hematoma. Despite the fatal outcome in this case, neurosurgical treatment of patients with acute myeloid leukemia should be considered if coagulopathy and the clinical scenario allow.

17.
Am J Med Genet A ; 167A(12): 2966-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26768185

RESUMO

Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD.


Assuntos
Cardiopatias Congênitas/genética , Valva Pulmonar/anormalidades , Tetralogia de Fallot/genética , Trissomia , Cromossomos Humanos Par 9 , Feminino , Humanos , Recém-Nascido , Receptor X Retinoide alfa/genética , Tetralogia de Fallot/etiologia
18.
Expert Rev Respir Med ; 8(6): 653-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25138715

RESUMO

The American Thoracic Society (ATS) recently published a clinical practice guideline regarding the classification, evaluation, and management of childhood interstitial lung disease in infancy (chILD). As disease entities among infants with ILD are often distinct from forms seen in older children and adults, the guideline encourages an age-based classification system and focuses on the diagnostic approach to neonates and infants <2 years of age. The guideline reviews current evidence and recommendations for the evaluation, relevant genetic studies, and management of symptomatic infants. Here, we summarize the ATS guideline, highlight the major concepts, and discuss future strategies aimed at addressing current gaps in knowledge.


Assuntos
Doenças Pulmonares Intersticiais/classificação , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/terapia , Gerenciamento Clínico , Humanos , Lactente , Recém-Nascido
19.
Am J Med Genet A ; 164A(8): 2013-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24842713

RESUMO

Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.


Assuntos
Elementos Facilitadores Genéticos , Fatores de Transcrição Forkhead/genética , Síndrome da Persistência do Padrão de Circulação Fetal/genética , RNA Longo não Codificante/genética , Adulto , Biópsia , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Feminino , Expressão Gênica , Humanos , Recém-Nascido , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Interferência de RNA , RNA Mensageiro/genética , Radiografia , Deleção de Sequência
20.
Am J Respir Crit Care Med ; 189(12): 1538-43, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24871971

RESUMO

RATIONALE: Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private. OBJECTIVES: To determine genotype-phenotype correlations for recessive ABCA3 mutations. METHODS: We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other. MEASUREMENTS AND MAIN RESULTS: We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001). CONCLUSIONS: Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.


Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Estudos de Associação Genética , Doenças Pulmonares Intersticiais/genética , Mutação , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Transportadores de Cassetes de Ligação de ATP/genética , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/cirurgia , Transplante de Pulmão , Masculino , Síndrome do Desconforto Respiratório do Recém-Nascido/mortalidade , Síndrome do Desconforto Respiratório do Recém-Nascido/cirurgia , Análise de Sequência de DNA
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