Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Filtros adicionais











Tipo de estudo
País/Região como assunto
Intervalo de ano
1.
Genet Med ; 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31147633

RESUMO

PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management. METHODS: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed. RESULTS: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism. CONCLUSION: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.

3.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190611

RESUMO

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

4.
Wellcome Open Res ; 3: 46, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29900417

RESUMO

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.

7.
Fetal Diagn Ther ; 41(3): 234-236, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-26982014

RESUMO

Recipients of the twin-twin transfusion syndrome (TTTS) often develop cardiac manifestations, but arterial calcification has rarely been reported. Generalized arterial calcification of infancy (GACI) is a genetic disorder with high infantile mortality. We report the case of a TTTS recipient with moderate cardiomyopathy at diagnosis who developed progressive calcification of the pulmonary arteries and aorta after successful in utero laser therapy. Postnatally, both twins were diagnosed with a heterozygous ABCC6 gene mutation associated with GACI. The recipient had progressive supravalvular pulmonary and aortic stenosis, was treated with bisphosphonate therapy, and successfully underwent cardiac surgery at 4 months of age. The donor twin with the same mutation remained phenotypically normal at 15 months of age. This case illustrates monozygotic fetuses with discordant in utero hemodynamics, with subsequent development of phenotypic differences. TTTS recipients with arterial calcifications should undergo genetic testing for GACI.


Assuntos
Transfusão Feto-Fetal/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Fenótipo , Estenose de Artéria Pulmonar/genética , Gêmeos Monozigóticos/genética , Calcificação Vascular/genética , Adulto , Feminino , Transfusão Feto-Fetal/complicações , Transfusão Feto-Fetal/diagnóstico por imagem , Hemodinâmica/fisiologia , Humanos , Mutação/genética , Gravidez , Estenose de Artéria Pulmonar/complicações , Estenose de Artéria Pulmonar/diagnóstico por imagem , Calcificação Vascular/complicações , Calcificação Vascular/diagnóstico por imagem
8.
Hematology ; 20(4): 217-22, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25116001

RESUMO

OBJECTIVE AND IMPORTANCE: Homozygous Southeast Asian alpha-thalassemia mutation (--(SEA)/--(SEA)) results in deletion of all alpha-globin genes (alpha(0)-thalassemia). Since all alpha-globin chains are absent, hemoglobin F cannot be synthesized, and hemoglobin Bart's becomes the dominant fetal hemoglobin. Hemoglobin Bart's is a γ tetramer with a very high oxygen affinity, thus oxygen delivery to the tissues is poor. Clinical manifestations include severe fetal anemia, hydrops fetalis, fetal demise, and high risk of neurodevelopmental impairment in the rare survivors. CLINICAL PRESENTATION: A 39-year-old Vietnamese woman presented to our center at 28 0/7 weeks' gestation with fetal alpha(0)-thalassemia (--(SEA)/--(SEA) type deletion) and ultrasound markers suggestive of severe fetal anemia. INTERVENTION: The fetus was treated with four intrauterine transfusions followed by post-natal chronic transfusions. Formal neurodevelopmental testing (Battelle Developmental Inventory, Second Edition) was performed at 18 months of age, and the developmental quotient was 93 (32nd percentile) with all subdomains noted within normal limits, indicating overall intact neurodevelopment. CONCLUSION: We posit that earlier diagnosis and fetal treatment, prior to clinical findings suggestive of fetal anemia, may improve long-term outcomes by enhancing oxygen delivery to the tissues of the developing fetus.


Assuntos
Transfusão de Sangue Intrauterina , Doenças Fetais/terapia , Talassemia alfa/terapia , Adulto , Transfusão de Sangue , Feminino , Doenças Fetais/sangue , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Hemoglobinas Anormais/genética , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Diagnóstico Pré-Natal , Deleção de Sequência , alfa-Globinas/genética , Talassemia alfa/sangue , Talassemia alfa/diagnóstico , Talassemia alfa/genética
9.
Eur J Hum Genet ; 23(5): 663-71, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25118026

RESUMO

Copy neutral segments with allelic homozygosity, also known as regions of homozygosity (ROHs), are frequently identified in cases interrogated by oligonucleotide single-nucleotide polymorphism (oligo-SNP) microarrays. Presence of ROHs may be because of parental relatedness, chromosomal recombination or rearrangements and provides important clues regarding ancestral homozygosity, consanguinity or uniparental disomy. In this study of 14 574 consecutive cases, 832 (6%) were found to harbor one or more ROHs over 10 Mb, of which 651 cases (78%) had multiple ROHs, likely because of identity by descent (IBD), and 181 cases (22%) with ROHs involving a single chromosome. Parental relatedness was predicted to be first degree or closer in 5%, second in 9% and third in 19%. Of the 181 cases, 19 had ROHs for a whole chromosome revealing uniparental isodisomy (isoUPD). In all, 25 cases had significant ROHs involving a single chromosome; 5 cases were molecularly confirmed to have a mixed iso- and heteroUPD15 and 1 case each with segmental UPD9pat and segmental UPD22mat; 17 cases were suspected to have a mixed iso- and heteroUPD including 2 cases with small supernumerary marker and 2 cases with mosaic trisomy. For chromosome 15, 12 (92%) of 13 molecularly studied cases had either Prader-Willi or Angelman syndrome. Autosomal recessive disorders were confirmed in seven of nine cases from eight families because of the finding of suspected gene within a ROH. This study demonstrates that ROHs are much more frequent than previously recognized and often reflect parental relatedness, ascertain autosomal recessive diseases or unravel UPD in many cases.


Assuntos
Homozigoto , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Consanguinidade , Família , Feminino , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Incidência , Doenças Inflamatórias Intestinais/genética , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto Jovem
10.
J Inherit Metab Dis ; 37(2): 277-87, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24108527

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of two dose levels of galsulfase (Naglazyme®) in infants with MPS VI. STUDY DESIGN: This was a phase 4, multicenter, multinational, open-label, two-dose level study. Subjects were randomized 1:1 to receive weekly infusions of 1.0 or 2.0 mg/kg of galsulfase for a minimum of 52 weeks. Progression of skeletal dysplasia was determined by monitoring physical appearance, radiographic changes, and growth. Urinary glycosaminoglycan (GAG) levels, gross and fine motor function, cardiac function, vision, hearing, and health resource utilization were evaluated. Safety assessments were performed. RESULTS: Four infants (aged 3.3-12.7 months) participated in the study. Galsulfase was well tolerated at 1.0 and 2.0 mg/kg/week dose levels with no drug-related serious adverse events. Two subjects experienced a total of four possible treatment-related adverse events which were all considered mild. Length and weight remained within age-expected norms. Skeletal abnormalities continued to progress in all subjects. High baseline urinary GAG levels (mean: 870 µg/mg creatinine) decreased by approximately 70%; these reduced levels were maintained (mean: 220 µg/mg creatinine at week 52) despite the development of anti-galsulfase antibodies. Hearing, cardiac function, hepatosplenomegaly, and facial dysmorphism stabilized or improved, but corneal clouding progressed. There was no clear difference in safety or efficacy between the two doses. CONCLUSIONS: Galsulfase at two dose levels was safe and well tolerated in infants. Normal growth was maintained but skeletal abnormalities continued to progress. Urinary GAG levels decreased with treatment. Early initiation of galsulfase may prevent or slow progression of some disease manifestations.


Assuntos
Terapia de Reposição de Enzimas/métodos , Mucopolissacaridose VI/tratamento farmacológico , N-Acetilgalactosamina-4-Sulfatase/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Lactente , Infusões Intravenosas , Masculino , N-Acetilgalactosamina-4-Sulfatase/efeitos adversos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos
12.
Am J Med Genet A ; 161A(4): 717-31, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23495017

RESUMO

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Deleção de Genes , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Transtorno Autístico/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Éxons , Facies , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Penetrância , Fenótipo , Esquizofrenia/genética , Adulto Jovem
13.
BMC Med Genet ; 13: 19, 2012 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-22436304

RESUMO

BACKGROUND: Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the NF2 gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient. CASE PRESENTATION: We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing NF2, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1).Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1, PITPNB and TTC28. MN1, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (TEL/MN1) in human myeloid leukemias. Interestingly, Mn1-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22, a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. CONCLUSIONS: Thus, our report describes a NF2-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Fissura Palatina/complicações , Desenvolvimento Maxilofacial/genética , Neurofibromatose 2/complicações , Síndrome de Pierre Robin/complicações , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Animais , Pareamento de Bases/genética , Criança , Pré-Escolar , Fissura Palatina/genética , Facies , Feminino , Humanos , Lactente , Recém-Nascido , Camundongos , Neurofibromatose 2/genética , Síndrome de Pierre Robin/genética , Gravidez , Crânio/anormalidades , Crânio/patologia
14.
J Ultrasound Med ; 31(4): 555-60, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22441911

RESUMO

OBJECTIVES: Compared to singleton pregnancies, monochorionic twins have increased rates of perinatal morbidity and mortality, believed due in part to both twin-twin transfusion syndrome and an increased risk of congenital anomalies. Here we describe the prevalence of noncardiac structural anomalies in monochorionic twins with twin-twin transfusion syndrome who underwent laser surgery. METHODS: In a retrospective study of 221 consecutive cases of twin-twin transfusion syndrome treated with laser surgery, noncardiac anomalies were identified by review of antepartum and neonatal medical records. RESULTS: Of 377 live-born twins, 19 (5.0%) had a noncardiac anomaly. This rate was increased for donor versus recipient twins (8.5% versus 2.0%; P < .01). The presence of an anomaly was unrelated to the Quintero stage, the presence of donor intrauterine growth restriction, or 30-day survival of the donor or recipient. CONCLUSIONS: The prevalence of noncardiac anomalies in pregnancies complicated by twin-twin transfusion syndrome who underwent laser surgery was higher in donors versus recipients.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/epidemiologia , Transfusão Feto-Fetal/diagnóstico por imagem , Transfusão Feto-Fetal/epidemiologia , Comorbidade , Feminino , Humanos , Recém-Nascido , Los Angeles/epidemiologia , Masculino , Prevalência , Medição de Risco , Fatores de Risco , Ultrassonografia
15.
Mol Genet Metab ; 102(2): 149-52, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21093335

RESUMO

Mitochondrial DNA (mtDNA) depletion syndromes are autosomal recessive conditions in which the mtDNA copy number is greatly decreased in affected tissues. The encephalomyopathic group of these syndromes comprise mutations in SUCLA2 and SUCLG1 subunits [1]. In this report, we describe a patient with fatal infantile lactic acidosis associated with mutations in the SUCLG1 gene and mtDNA depletion. Histological and enzymatic abnormalities in skeletal muscle support the diagnosis of this recently described mitochondrial disorder. This case is unique in that prenatal imaging suggested the diagnosis and that the confirmatory molecular diagnosis was established at 2 weeks of age. We describe prenatal MRI and neonatal laboratory disturbances that can point the clinician toward consideration of this diagnosis when treating infantile lactic acidosis.


Assuntos
Acidose Láctica/genética , DNA Mitocondrial/genética , Doenças Mitocondriais/genética , Mutação , Succinato-CoA Ligases/genética , Acidose Láctica/diagnóstico , Adulto , Evolução Fatal , Feminino , Homozigoto , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Doenças Mitocondriais/diagnóstico , Músculo Esquelético/patologia , Gravidez , Sítios de Splice de RNA/genética
16.
Obstet Gynecol ; 116 Suppl 2: 483-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20664426

RESUMO

BACKGROUND: Twin-twin transfusion syndrome occurs in 10% of monozygotic monochorionic twin gestations and results from an unbalanced exchange of blood from the donor to the recipient fetus through placental anastomoses. CASE: We present a case of twin-twin transfusion syndrome with differing fetal sex treated with in utero laser surgery. Genetic analyses showed 46,XX/46,XY hematologic chimerism in both twins at birth and at 6 months, with the recipient twin being significantly more chimeric than the donor. Placental pathologic examination confirmed monochorionicity and laser ablation of all anastomoses. CONCLUSION: Despite in utero separation of the fetal circulations remote from delivery, hematologic chimerism persisted after birth. We speculate that the greater degree of blood chimerism in the recipient compared with the donor was related to the pathophysiology of twin-twin transfusion syndrome before laser surgery.


Assuntos
Antígenos de Grupos Sanguíneos , Quimerismo , Transfusão Feto-Fetal/cirurgia , Adulto , Feminino , Transfusão Feto-Fetal/fisiopatologia , Humanos , Terapia a Laser , Gravidez , Gêmeos
17.
Pediatr Cardiol ; 31(1): 138-41, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19967352

RESUMO

The association of cardiac defects with Kabuki syndrome has been well described. The majority of these defects are isolated shunt lesions, conotruncal abnormalities, or various forms of arch obstruction. This report describes a series of three patients with hypoplastic left heart syndrome and Kabuki syndrome. The series illustrates the full spectrum of left-sided obstructive lesions and expands the phenotype of cardiac defects associated with Kabuki syndrome.


Assuntos
Anormalidades Múltiplas , Facies , Síndrome do Coração Esquerdo Hipoplásico , Deficiências do Desenvolvimento , Feminino , Humanos , Recém-Nascido , Masculino , Síndrome
18.
Pediatr Surg Int ; 25(9): 823-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19641926

RESUMO

X-linked hydrocephalus (XLH) is characterized by increased intracranial ventricle size and head circumference secondary to aqueduct of Sylvius congenital stenosis. Exceedingly rare is the concurrence of XLH and Hirschsprung's disease (HSCR) with a theoretical incidence of 1 in 125-250 million cases. Herein, we are describing a case of a patient with concurrent XLH and HSCR. The patient was delivered via cesarean section at 37 weeks gestation and underwent uneventful ventriculoperitoneal shunt placement. As a part of a workup for constipation, we performed a rectal biopsy, which was consistent with HSCR. Genetics testing showed hemizygous for R558X hemizygous mutation in the L1CAM gene. A C --> T nucleotide substitution in exon 13 resulted in replacement of an arginine codon with a stop codon, a nonsense mutation. Although it is widely accepted that HSCR represents the failure of early embryonic neural crest cells to migrate properly, the exact mechanism is not known. The association of HSCR with XLH in the presence of L1CAM mutations remains quite interesting because cell adhesion molecules are involved in the proper migration of neural components throughout the body. Additional studies are necessary to fully elucidate the relationship between XLH and HSCR in the presence of L1CAM mutations.


Assuntos
Códon sem Sentido , Doenças Genéticas Ligadas ao Cromossomo X , Doença de Hirschsprung/genética , Hidrocefalia/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Humanos , Lactente , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA