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1.
Genet Med ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31723249

RESUMO

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

2.
J Child Neurol ; : 883073819881940, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31665995

RESUMO

OBJECTIVES: To report 2 additional cases of pyruvate dehydrogenase complex deficiency with reversible deep gray matter lesions following initiation of ketogenic diet and to perform a literature review of serial imaging in patients with pyruvate dehydrogenase complex. METHODS: Clinical data on 3 previously unpublished cases of patients with pyruvate dehydrogenase complex deficiency and with serial magnetic resonance imagings (MRIs) before and after institution of ketogenic diet were reported. A systematic literature review was performed to search for published cases of patients with confirmed pyruvate dehydrogenase complex deficiency who underwent serial MRIs. RESULTS: The 3 subjects in this series demonstrated clinical improvement on ketogenic diet. Two subjects showed reversal of some brain lesions on repeat MRI following initiation of ketogenic diet. Of the 21 published cases with serial MRIs, 13 patients underwent some form of treatment, and of this smaller subset 4 patients had repeat MRIs that showed definitive improvement. In both our described cases and those published in the literature, improvement occurred in lesions in the basal ganglia. CONCLUSIONS: In patients with pyruvate dehydrogenase complex deficiency, basal ganglia lesions on MRI are reversible with treatment in some cases and could serve as a biomarker for measuring response to treatment.

3.
N Engl J Med ; 381(17): 1644-1652, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31597037

RESUMO

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).


Assuntos
Proteínas de Membrana Transportadoras/genética , Mutagênese Insercional , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/genética , Oligonucleotídeos Antissenso/uso terapêutico , Medicina de Precisão , Doenças Raras/tratamento farmacológico , Biópsia , Criança , Desenvolvimento Infantil , Descoberta de Drogas , Drogas em Investigação/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Testes Neuropsicológicos , RNA Mensageiro , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Pele/patologia , Sequenciamento Completo do Genoma
4.
Am J Med Genet A ; 179(11): 2263-2271, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432588

RESUMO

Heterozygous loss of function variants in the IRF2BPL are a newly described cause of neurodevelopmental disabilities and epilepsy. As of 2019, fewer than 20 patients have been described in the published literature. This article reports an additional case of a patient with a pathogenic IRF2BPL variant and offers a comprehensive review of the published cases of individuals with IRF2BPL variants, in order to help expand the phenotype. The patient has a history of infantile spasms evolving into drug-resistant epilepsy with underlying epileptic encephalopathy consistent with Lennox-Gastaut syndrome. While at the extreme end of the spectrum, his phenotype is consistent with those previously described. Our literature review highlights the wide range of phenotypes exhibited by those with diseases related to IRF2BPL gene variants. This article also briefly discusses other comorbidities seen in the patient and those previously reported. While the molecular underpinnings of the role of IRF2BPL gene in the central nervous system are newly established, the specifics of its effects elsewhere have yet to be delineated. Furthermore, its pathogenesis in other organ systems is not yet understood and could be of importance from a management perspective.

5.
Am J Hum Genet ; 105(3): 493-508, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447100

RESUMO

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

6.
Am J Hum Genet ; 104(6): 1127-1138, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31155284

RESUMO

Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.

7.
Genet Med ; 21(7): 1652-1656, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30568308

RESUMO

PURPOSE: Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci. METHODS: We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing. RESULTS: Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype. CONCLUSION: While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.

8.
Hum Mol Genet ; 27(20): 3475-3487, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29931299

RESUMO

Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of ß3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of ß3GalT6 activity and GAG synthesis to better understand this rare condition.

9.
Skelet Muscle ; 8(1): 17, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855340

RESUMO

BACKGROUND: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation. CASE PRESENTATION: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual. CONCLUSION: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.


Assuntos
Distroglicanas/metabolismo , Distrofias Musculares/genética , Mutação , Proteínas Qb-SNARE/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Glicosilação , Humanos , Lactente , Músculo Esquelético/metabolismo , Distrofias Musculares/congênito , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/metabolismo
10.
J Inherit Metab Dis ; 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29736632
11.
Pediatr Nephrol ; 33(7): 1257-1261, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29637272

RESUMO

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

12.
Am J Hum Genet ; 102(4): 557-573, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576218

RESUMO

Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins. Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. Introduction of the identified PMPCB variants into the homologous S. cerevisiae Mas1 protein resulted in a severe growth and MPP processing defect leading to the accumulation of mitochondrial precursor proteins and early impairment of the biogenesis of iron-sulfur clusters, which are indispensable for a broad range of crucial cellular functions. Analysis of biopsy materials of an affected individual revealed changes and decreased activity in iron-sulfur cluster-containing respiratory chain complexes and dysfunction of mitochondrial and cytosolic Fe-S cluster-dependent enzymes. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.

13.
Mitochondrion ; 2018 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-29307858

RESUMO

Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

14.
Mol Genet Metab ; 122(4): 172-181, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29126765

RESUMO

Mutations in FARS2 are known to cause dysfunction of mitochondrial translation due to deficient aminoacylation of the mitochondrial phenylalanine tRNA. Here, we report three novel mutations in FARS2 found in two patients in a compound heterozygous state. The missense mutation c.1082C>T (p.Pro361Leu) was detected in both patients. The mutations c.461C>T (p.Ala154Val) and c.521_523delTGG (p.Val174del) were each detected in one patient. We report abnormal in vitro aminoacylation assays as a functional validation of the molecular genetic findings. Based on the phenotypic data of previously reported subjects and the two subjects reported here, we conclude that FARS2 deficiency can be associated with two phenotypes: (i) an epileptic phenotype, and (ii) a spastic paraplegia phenotype.


Assuntos
Epilepsia/genética , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Fenótipo , Fenilalanina-tRNA Ligase/deficiência , Fenilalanina-tRNA Ligase/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Aminoacil-tRNA Sintetases/metabolismo , Aminoacilação , Encéfalo/diagnóstico por imagem , Células Cultivadas , Exoma , Feminino , Fibroblastos/metabolismo , Heterozigoto , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/enzimologia , Mitocôndrias/metabolismo , Músculo Esquelético/patologia , Mutação de Sentido Incorreto/genética , Consumo de Oxigênio , RNA de Transferência/metabolismo , Análise de Sequência de DNA
15.
JIMD Rep ; 35: 1-5, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27858369

RESUMO

Cerebrotendinous xanthomatosis (CTX) is an inborn error of metabolism leading to progressive multisystem disease. Symptoms often begin in the first decade of life with chronic diarrhea, cataracts, developmental delay, intellectual disability, and cerebellar or pyramidal dysfunction. Later manifestations include tendon xanthomas, polyneuropathy, and abnormal neuroimaging. Pathogenic biallelic variants in CYP27A1 leading to compromised function of sterol 27-hydroxylase result in accumulation of detectable toxic intermediates of bile acid synthesis rendering both genetic and biochemical testing effective diagnostic tools. Effective treatment with chenodeoxycholic acid is available, making early diagnosis critical for patient care. Here we report a new patient with CTX and describe the early signs of disease in this patient. Initial symptoms included infantile spasms, which have not previously been reported in CTX. Developmental delay, mild intellectual disability with measured cognitive decline in childhood, was also observed. These clinical signs do not traditionally compel testing for CTX, and we highlight the need to consider this rare but treatable disorder among the differential diagnosis of children with similar clinical presentation. Increased awareness of early signs of CTX is important for improving time to diagnosis for this patient population.

16.
Discov Med ; 19(104): 175-83, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25828521

RESUMO

In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes known to cause isolated and combined pituitary hormone deficiencies in humans. This review will address genetic causes of adrenocorticotropic hormone deficiency, thyroid stimulating hormone deficiency, growth hormone deficiency, hypogonadotropic hypogonadism, and diabetes insipidus. Additionally, we will discuss genetic causes of combined pituitary hormone deficiency, septo-optic dysplasia, holoprosencephaly, and multisystemic syndromes in which hypopituitarism is a significant component. With the widespread clinical availability of next generation sequencing and ongoing identification of new disease causing genes, genetic diagnoses are determined for increasing numbers of patients. With new insights into mechanisms of disease resulting from multiple gene interactions, an increasingly nuanced understanding of the underlying genetic etiology of pituitary hormone deficiencies is possible.


Assuntos
Hipopituitarismo/genética , Insuficiência Adrenal/genética , Diabetes Insípido/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Holoprosencefalia/genética , Hormônio do Crescimento Humano/deficiência , Humanos , Hipogonadismo/genética , Masculino , Mutação , Fenótipo , Tireotropina/deficiência
17.
PLoS Genet ; 10(3): e1004258, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24676022

RESUMO

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is a rare disorder of enteric smooth muscle function affecting the intestine and bladder. Patients with this severe phenotype are dependent on total parenteral nutrition and urinary catheterization. The cause of this syndrome has remained a mystery since Berdon's initial description in 1976. No genes have been clearly linked to MMIHS. We used whole-exome sequencing for gene discovery followed by targeted Sanger sequencing in a cohort of patients with MMIHS and intestinal pseudo-obstruction. We identified heterozygous ACTG2 missense variants in 15 unrelated subjects, ten being apparent de novo mutations. Ten unique variants were detected, of which six affected CpG dinucleotides and resulted in missense mutations at arginine residues, perhaps related to biased usage of CpG containing codons within actin genes. We also found some of the same heterozygous mutations that we observed as apparent de novo mutations in MMIHS segregating in families with intestinal pseudo-obstruction, suggesting that ACTG2 is responsible for a spectrum of smooth muscle disease. ACTG2 encodes γ2 enteric actin and is the first gene to be clearly associated with MMIHS, suggesting an important role for contractile proteins in enteric smooth muscle disease.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Colo/anormalidades , Heterozigoto , Pseudo-Obstrução Intestinal/genética , Mutação/genética , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Colo/patologia , Exoma , Feminino , Humanos , Pseudo-Obstrução Intestinal/patologia , Masculino , Músculo Liso/metabolismo , Bexiga Urinária/patologia
18.
Pediatr Emerg Care ; 29(3): 377-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23462397

RESUMO

Topical anesthetics are commonly used in many health care settings and for many clinical conditions. However, there are a number of potential adverse effects associated with their use. Their widespread administration can convey a false sense of security and failure to appreciate possible complications. We present the case of an infant with extensive vascular malformations treated with EMLA cream who developed seizures and methemoglobinemia from lidocaine and prilocaine toxicity. We describe the pathophysiology of these morbidities, the use of pulse oximetry in this setting, and the clinical presentation and treatment of methemoglobinemia.


Assuntos
Anestésicos Locais/efeitos adversos , Lidocaína/efeitos adversos , Metemoglobinemia/induzido quimicamente , Prilocaína/efeitos adversos , Convulsões/induzido quimicamente , Administração Tópica , Anestésicos Locais/administração & dosagem , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Lidocaína/administração & dosagem , Combinação Lidocaína e Prilocaína , Metemoglobinemia/terapia , Mancha Vinho do Porto/terapia , Prilocaína/administração & dosagem
19.
Matern Child Health J ; 17(3): 501-4, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22492227

RESUMO

To determine whether asymmetric macrosomia (disproportionately large body size in comparison to head circumference) could be demonstrated in a population of infants suffering shoulder dystocia during delivery relative to those that did not suffer from shoulder dystocia. A case-control study was conducted as a retrospective chart review over 3 years at a large maternity hospital in an urban setting. Among infants over 4,000 g, those that suffered from shoulder dystocia during delivery had a smaller mean head circumference than infants of a similar size that did not suffer from shoulder dystocia. A statistically significant difference was also present when cases of documented gestational diabetes were excluded. Asymmetric macrosomia is more likely to be present in a population of infants who suffered shoulder dystocia during delivery. This knowledge could be used in designing tools to predict which pregnancies are at highest risk for shoulder dystocia during delivery.


Assuntos
Cefalometria , Distocia/epidemiologia , Macrossomia Fetal/epidemiologia , Ombro , Plexo Braquial/lesões , Estudos de Casos e Controles , Desproporção Cefalopélvica , Diabetes Gestacional/epidemiologia , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos Retrospectivos , Rhode Island/epidemiologia , Fatores de Risco , População Urbana , Vácuo-Extração/estatística & dados numéricos
20.
Discov Med ; 14(78): 301-9, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23200061

RESUMO

After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development.


Assuntos
Desenvolvimento Sexual/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Masculino , Fatores de Processamento de RNA , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Desenvolvimento Sexual/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas WT1/genética , Proteínas WT1/metabolismo
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