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1.
Br J Radiol ; 95(1129): 20201241, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34609904

RESUMO

Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of Notch pathway, which regulates embryonic cell differentiation and angiogenesis. Clinically, ALGS is characterized by cholestasis, cardiac defects, characteristic facial features, skeletal and ophthalmologic abnormalities. The aim of this review is to illustrate neuroradiological findings in ALGS, which are less well-known and prevalent, including cerebrovascular anomalies (such as aneurysms, dolichoectasia, Moyamoya syndrome and venous peculiarities), Chiari 1 malformation, craniosynostosis, intracranial hypertension, and vertebral anomalies (namely butterfly vertebra, hemivertebra, and craniocervical junction anomalies). Rarer cerebral midline malformations and temporal bone anomalies have also been described.


Assuntos
Síndrome de Alagille/diagnóstico por imagem , Encéfalo/anormalidades , Angiografia Cerebral , Artérias Cerebrais/anormalidades , Veias Cerebrais/anormalidades , Face/anormalidades , Humanos , Imageamento por Ressonância Magnética , Neurorradiografia , Crânio/anormalidades , Coluna Vertebral/anormalidades
2.
FASEB J ; 35(11): e21955, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34613626

RESUMO

Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.


Assuntos
Anormalidades Múltiplas/metabolismo , Diferenciação Celular/genética , Proteínas de Ligação a DNA/metabolismo , Face/anormalidades , Doenças Hematológicas/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/genética , Doenças Vestibulares/metabolismo , Anormalidades Múltiplas/genética , Adolescente , Animais , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Doenças Hematológicas/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Lactente , Masculino , Camundongos , Camundongos Transgênicos , Células Musculares/patologia , Mutação , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Doenças Vestibulares/genética
3.
Iowa Orthop J ; 41(1): 55-59, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34552404

RESUMO

Coffin-Siris Syndrome (CSS) is a rare, genetic syndrome characterized by multiple anomalies, including scoliosis. However, there are only a few reports about the management of scoliosis in these patients. We present the case of an 8-year-old female with CSS presenting with a progressive, rigid thoracolumbar kyphoscoliosis. She was successfully treated with a magnetically controlled growing rod, demonstrating improved ambulatory capacity and performance of activities of daily living. In pediatric patients with Coffin-Siris syndrome, magnetic expandable rods can be considered as an option for the management of progressive early-onset scoliosis. Level of Evidence: V.


Assuntos
Anormalidades Múltiplas , Micrognatismo , Escoliose , Atividades Cotidianas , Criança , Face/anormalidades , Feminino , Deformidades Congênitas da Mão , Humanos , Deficiência Intelectual , Pescoço/anormalidades , Escoliose/cirurgia
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 861-864, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487531

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation in a child with Kabuki syndrome type 1 (KS1) caused by a mosaic frameshift variant of KMT2D gene. METHODS: Trio-based whole exome sequencing (WES) was carried for the patient and her parents. Candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 3-year-and-2-month-old Chinese girl, presented with distinctive facial features, cognitive impairment, mild developmental delay, dermatoglyphic abnormalities, minor skeletal anomalies, ventricular septal defect, and autistic behavior. Trio-based WES revealed that the proband has carried a de novo mosaic frameshit variant of the KMT2D gene, namely NM_003482.3:c.13058delG (p.Pro4353Argfs*31) (GRCh37/hg19), for which the mosaicism rate was close to 21%. The variant was unreported previously and was confirmed by Sanger sequencing. Chromosomal microarray analysis (CMA) has revealed no pathogenic or likely pathogenic copy number variations. Compared with previously reported cases, our patient has presented obvious behavior anomalies including autism, anxiety and sleep problems, which were rarely reported. CONCLUSION: This study has expanded the spectrum of KMT2D gene variants, enriched the clinical phenotypes of KS1, and facilitated genetic counseling for the family.


Assuntos
Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA , Anormalidades Múltiplas , China , Proteínas de Ligação a DNA/genética , Face/anormalidades , Feminino , Doenças Hematológicas , Humanos , Lactente , Proteínas de Neoplasias/genética , Fenótipo , Doenças Vestibulares
6.
BMC Pediatr ; 21(1): 379, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479534

RESUMO

OBJECTIVE: A significant number of patients with KS have cleft palate (CP) or submucous cleft palate (SMCP) and show delayed speech development. However, few reports have discussed the characteristics of CP in KS and the outcomes of postoperative speech development. The purpose of this study was to investigate the characteristics and surgical outcomes of CP in patients with KS, and to discuss the importance of the diagnosis of CP or SMCP. METHODS: We conducted a retrospective study on patients with clinically diagnosed KS who underwent palatoplasty. Clinical and surgical data were collected from patients' medical records, and velopharyngeal function was evaluated using nasopharyngoscopy and speech analysis. RESULTS: In 11 cases, 5 patients had CP (45.5%) and 6 had SMCP (54.5%). Four patients who were genetically tested had a pathogenic variant of KMT2D. Seven of nine patients (77.8%) who underwent conventional palatoplasty showed velopharyngeal insufficiency and hypernasality. All patients who underwent pharyngeal flap surgery achieved velopharyngeal competency. Statistical analysis revealed a statistically significant difference in postoperative results between non-syndromic and KS patients. CONCLUSION: Patients with SMCP may be more common than previously reported. The results showed that it is difficult to produce optimal results with conventional palatoplasty; therefore, pharyngeal flap surgery should be considered as a treatment to obtain favorable results. Pharyngeal flap surgery in patients with KS should be carefully designed based on speech evaluation and nasopharyngoscopic findings.


Assuntos
Anormalidades Múltiplas , Fissura Palatina , Anormalidades Múltiplas/cirurgia , Fissura Palatina/diagnóstico , Fissura Palatina/cirurgia , Face/anormalidades , Doenças Hematológicas , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Doenças Vestibulares
7.
Elife ; 102021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34463256

RESUMO

Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations. We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki [KS] type 1 and 2 and Rubinstein-Taybi type 1 [RT1] syndromes). We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.


Assuntos
Anormalidades Múltiplas/genética , Epigênese Genética/genética , Face/anormalidades , Variação Genética/genética , Doenças Hematológicas/genética , Síndrome de Rubinstein-Taybi/genética , Transcriptoma/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/metabolismo , Animais , Cromatina/genética , Modelos Animais de Doenças , Feminino , Técnicas Genéticas , Doenças Hematológicas/metabolismo , Camundongos , Fenótipo , Síndrome de Rubinstein-Taybi/metabolismo , Doenças Vestibulares/metabolismo
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 753-756, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365617

RESUMO

OBJECTIVE: Clinical examination and molecular genetic analysis were carried out for one case with special facial features with developmental retardation, hearing impairment and cleft lip and palate. METHODS: The intelligence test, hearing test, and MRI test were performed. At the same time, the blood were collected to detect the copy number variation of the whole genome with the chromosomal karyotype analysis and the chromosomal microarray analysis (CMA). And the whole exome sequencing (WES) was used to analyze the pathogenic variant. RESULTS: The children had mild mental retardation and the IQ was 61. There was moderate hearing loss in both ears(left ear 60 dB, right ear 65 dB). And bilateral horizontal hypoplasia of semicircular canal was found by cranial MRI test. No copy number abnormality was found by chromosome karyotype analysis and chromosome microarray analysis in peripheral blood. And whole exome sequencing suggested that there was heterozygous pathogenic variants in KMT2D gene (p.Leu545Argfs*385). CONCLUSION: The patient has a peculiar face and multiple system defects, and was diagnosed as Niikawa-Kuroki syndrome type I by KMT2D gene variant. The whole exome sequencing is helpful for the diagnosis of complex genetic diseases.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Criança , Variações do Número de Cópias de DNA , Face/anormalidades , Doenças Hematológicas , Humanos , Doenças Vestibulares
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 757-760, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365618

RESUMO

OBJECTIVE: To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome. METHODS: Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis. RESULTS: The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4). CONCLUSION: The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.


Assuntos
Nanismo , Doenças Genéticas Ligadas ao Cromossomo X , Deformidades Congênitas da Mão , Criança , Face/anormalidades , Genitália Masculina/anormalidades , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas , Humanos , Masculino , Mutação
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 678-680, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247377

RESUMO

OBJECTIVE: To explore the genetic basis of a child with recurrent infection, multiple malformation and dysmorphism. METHODS: The child and his parents were subjected to trio whole exome sequencing. RESULTS: The child had a complaint of fever and cough, with long and thin eye fissures and long eyelashes. Genetic testing revealed that the child has carried a non-triplet deletion of the KDM6A gene, which was unreported previously. The variant resulted in frameshift and premature termination of the translation. His parents were both of the wild type for the locus. After antibiotic and immunoglobulin treatment, the severe secondary pneumonia caused by immunodeficiency has improved. CONCLUSION: With combined laboratory test, imaging examination and genetic testing, the child was ultimately diagnosed with Kabuki syndrome type 2. The characteristics of immunodeficiency of Kabuki syndrome may render conventional antibiotic treatment ineffective, which deserves clinical attention.


Assuntos
Histona Desmetilases , Pneumonia , Anormalidades Múltiplas , Criança , Proteínas de Ligação a DNA/genética , Face/anormalidades , Testes Genéticos , Doenças Hematológicas , Histona Desmetilases/genética , Humanos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fenótipo , Doenças Vestibulares
11.
Genes (Basel) ; 12(6)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205270

RESUMO

Coffin-Siris syndrome (CSS, MIM 135900) is a multi-system intellectual disability syndrome characterized by classic dysmorphic features, developmental delays, and organ system anomalies. Genes in the BRG1(BRM)-associated factors (BAF, Brahma associated factor) complex have been shown to be causative, including ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, and SOX4. In order to describe more robust genotype-phenotype correlations, we collected data from 208 individuals from the CSS/BAF complex registry with pathogenic variants in seven of these genes. Data were organized into cohorts by affected gene, comparing genotype groups across a number of binary and quantitative phenotypes. We determined that, while numerous phenotypes are seen in individuals with variants in the BAF complex, hypotonia, hypertrichosis, sparse scalp hair, and hypoplasia of the distal phalanx are still some of the most common features. It has been previously proposed that individuals with ARID-related variants are thought to have more learning and developmental struggles, and individuals with SMARC-related variants, while they also have developmental delay, tend to have more severe organ-related complications. SOX-related variants also have developmental differences and organ-related complications but are most associated with neurodevelopmental differences. While these generalizations still overall hold true, we have found that all individuals with BAF-related conditions are at risk of many aspects of the phenotype, and management and surveillance should be broad.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Genótipo , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fenótipo , Anormalidades Múltiplas/patologia , Face/patologia , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/patologia , Micrognatismo/patologia , Mutação , Pescoço/patologia , Fatores de Transcrição/genética
12.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
13.
J Pediatr Rehabil Med ; 14(3): 525-532, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34180430

RESUMO

BACKGROUND: Coffin-Siris syndrome is a rare genetic disease with heterozygous variants in the ARID1A, ARID1B, ARID2, DPF2, SMARCA4, SMARCB1, SMARCE1 or SOX11 genes. It may manifest with somatic anomalies, deafness, urogenital malformations, recurrent infections, mental retardation, speech deficit, agenesis of the corpus callosum, convulsions, hypotonia, developmental delay, and scoliosis. CASE REPORT: A 14-year-old boy with Coffin-Siris syndrome due to variants in the ARID1A gene was referred to the clinic. His rehabilitation over a 9-year period was described. The problem of assessment and the approach to rehabilitation was discussed, enabling a progressive remodelling of the cognitive-behavioural disorders that most hindered the possibility of his acquiring new skills and achieving social and family integration. CLINICAL REHABILITATION: A protracted, customised, multiprofessional rehabilitation approach, centred on realistic functional objectives, implemented with the direct involvement of the family and school, was the only way to achieve the maximum independence and social and family integration permitted by his residual disability.


Assuntos
Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Anormalidades Múltiplas , Adolescente , Proteínas Cromossômicas não Histona , Cognição , DNA Helicases , Proteínas de Ligação a DNA , Face/anormalidades , Deformidades Congênitas da Mão/genética , Humanos , Deficiência Intelectual/genética , Masculino , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares , Fatores de Transcrição
14.
Sci Rep ; 11(1): 12175, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108542

RESUMO

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.


Assuntos
Anormalidades Múltiplas/patologia , Anormalidades Craniofaciais/patologia , Face/patologia , Imageamento Tridimensional/métodos , Modelos Estatísticos , Atrofia Muscular/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Estudos de Casos e Controles , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Face/anormalidades , Feminino , Seguimentos , Gráficos de Crescimento , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Fenótipo , Prognóstico , Adulto Jovem
15.
Genes Cells ; 26(6): 349-359, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33960584

RESUMO

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is characterized by frequent appearance of multiradial chromosomes, which are distinctive chromosome fusions that occur at hypomethylated pericentromeric regions comprising repetitive sequences, in activated lymphocytes. The syndrome is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. De novo DNA methylation is likely defective in patients with ICF syndrome harboring mutations in DNMT3B, whereas accumulating evidence suggests that replication-uncoupled maintenance DNA methylation of late-replicating regions is impaired in patients with ICF syndrome harboring mutations in ZBTB24, CDCA7, or HELLS. ZBTB24 is a transcriptional activator of CDCA7, and CDCA7 and HELLS compose a chromatin remodeling complex and are involved in the maintenance DNA methylation through an interaction with UHRF1 in a feed-forward manner. Furthermore, our recent studies possibly provided the missing link between DNA hypomethylation and the formation of the abnormal chromosomes; it could occur via aberrant transcription from the hypomethylated regions, followed by pathological R-loop formation. The homologous-recombination dominant condition caused by a defect in nonhomologous end joining observed in several types of ICF syndrome could facilitate the formation of multiradial chromosomes. Here, the latest knowledge regarding maintenance DNA methylation and chromosome stability provided by those studies is reviewed.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Instabilidade Cromossômica/genética , Metilação de DNA/genética , Replicação do DNA/genética , Face/anormalidades , Doenças da Imunodeficiência Primária/genética , Humanos , Modelos Biológicos
16.
PLoS Genet ; 17(5): e1009528, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983923

RESUMO

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.


Assuntos
Identificação Biométrica , Face/anatomia & histologia , Genômica , Imageamento Tridimensional , Herança Multifatorial/genética , Fenótipo , Irmãos , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/genética , Conjuntos de Dados como Assunto , Europa (Continente)/etnologia , Face/anormalidades , Face/embriologia , Feminino , Estudos de Associação Genética , Humanos , Masculino , /genética
17.
Eur J Med Genet ; 64(6): 104210, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33794347

RESUMO

Kabuki syndrome (KS) is a genetic disorder caused by pathogenic variants in KMT2D or KDM6A, and manifesting with multi-systemic involvement, including recognizable facial features, developmental delay and multiple congenital anomalies. Ophthalmological involvement has been described in varying rates in several studies. We aimed to evaluate the prevalence and nature of ophthalmological findings in a cohort of KS patients in Israel. Medical records of all patients diagnosed with KS in our tertiary center between 2004 and 2020 were retrospectively reviewed. Data collected included physical examination findings, molecular analysis as well as comprehensive ophthalmic characteristics including visual acuity, ocular alignment and motility, ocular adnexa, anterior segments and dilated fundus exams. Finally, an updated systematic review of the literature was performed. Thirteen unrelated patients were included in the study, diagnosed at an age raging from the first months of life to 20 years. Of these, three (23%) showed significant ophthalmological abnormalities, beyond the characteristic structural findings of long palpebral fissures and lower eyelid eversion. These included bilateral posterior colobomata in the first patient; bilateral ptosis, hypermetropia, esotropia, blue sclera and anisocoria in the second; and bilateral congenital cataracts in the third. To conclude, our findings underscore the importance of a comprehensive ophthalmological evaluation as part of the routine multidisciplinary assessment of children suspected/diagnosed with KS.


Assuntos
Anormalidades Múltiplas/patologia , Anormalidades do Olho/patologia , Face/anormalidades , Doenças Hematológicas/patologia , Doenças Vestibulares/patologia , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Anormalidades do Olho/genética , Face/patologia , Doenças Hematológicas/genética , Histona Desmetilases/genética , Humanos , Lactente , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Acuidade Visual
18.
BMC Pregnancy Childbirth ; 21(1): 324, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33894762

RESUMO

BACKGROUND: To establish reference ranges of fetal facial profile markers and study their correlations with crown-rump length (CRL) during the first trimester (11 ~ 13+ 6 weeks' gestation) in a Chinese population. METHODS: Ultrasonographic images of measuring fetal nuchal translucency (NT) were retrospectively selected randomly in normal fetuses whose parents were both Chinese. The facial markers included inferior facial angle (IFA), maxilla-nasion-mandible (MNM) angle, facial maxillary angle (FMA) and profile line (PL) distance. These markers were measured through ViewPoint 6 software by two experienced sonographers. RESULTS: Three hundred and eighty fetuses were selected. The ICCs (95 % CI) of intra-operator 1 reproducibility of IFA, MNM angle, FMA, PL distance were 0.944 (0.886 ~ 0.973), 0.804 (0.629 ~ 0.902), 0.834 (0.68 ~ 0.918) and 0.935 (0.868 ~ 0.969), respectively. The ICCs (95 % CI) of intra-operator 2 reproducibility of IFA, MNM angle, FMA, PL distance were 0.931 (0.857 ~ 0.967), 0.809 (0.637 ~ 0.904), 0.786 (0.600 ~ 0.892) and 0.906 (0.813 ~ 0.954), respectively. The ICCs (95 % CI) of inter-operator reproducibility of IFA, MNM angle, FMA, PL distance were 0.885 (0.663 ~ 0.953), 0.829 (0.672 ~ 0.915), 0.77 (0.511 ~ 0.891) and 0.844 (0.68 ~ 0.925), respectively. The average ± SD of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively. IFA and PL distance significantly decreased with CRL, while MNM angle and FMA significantly increased with CRL. CONCLUSIONS: It was feasible to measure fetal facial markers during the first trimester. In Chinese population, the reference ranges of IFA, MNM angle, FMA and PL distance were 80.2°±7.25°, 4.17°±1.19°, 75.36°±5.31°, 2.78 ± 0.54 mm, respectively, and the measurements were found to correlate with CRL.


Assuntos
Estatura Cabeça-Cóccix , Face , Feto/diagnóstico por imagem , Medição da Translucência Nucal/métodos , Ultrassonografia Pré-Natal/métodos , Adulto , China/epidemiologia , Precisão da Medição Dimensional , Face/anormalidades , Face/diagnóstico por imagem , Estudos de Viabilidade , Feminino , Idade Gestacional , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Reprodutibilidade dos Testes
19.
Genes (Basel) ; 12(4)2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805950

RESUMO

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.


Assuntos
Anormalidades Múltiplas/patologia , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/patologia , Histona Desmetilases/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Doenças Vestibulares/patologia , Anormalidades Múltiplas/genética , Face/patologia , Doenças Hematológicas/genética , Humanos , Doenças Vestibulares/genética
20.
Sci Rep ; 11(1): 7949, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846366

RESUMO

To determine the association between cephalometric measurements and polysomnographic parameters in Brazilian patients with midface deficiency. This was a primary, clinical, observational, longitudinal, retrospective, analytical, and single-center study. Forty-eight patients with midface deficiency were divided into two groups as follows: those who underwent surgically assisted rapid palatal expansion (SARME) and those who received maxillary advancement (MA). Pre- and post-operative cephalometric and polysomnography measurements were obtained. Pearson's correlation was used to verify the presence of any significant associations between PSG scores and cephalometric measurements. Associations between BMI (Body Mass Index) and AHI (Apnea Hypopnea Index) as well as arousals were observed. In the SARME group, associations between AHI and SNA, UAS and MP-H, arousals and SNA, and Co-A and MP-H were noted. Associations between AHI and Co-A, PoOr-A and MP-H, arousals and UAS, and between minimum saturation of O2 and SNA, SNB, and Co-A were observed in the MA group. This study demonstrates the alterations in the middle third of the face that were related to sleep disturbance. In addition, it shows the associations between the polysomnographic parameters and the cephalometric representations corresponding to the analyzed deformities and transverse or anteroposterior maxillary deficiencies.


Assuntos
Cefalometria , Face/anormalidades , Face/diagnóstico por imagem , Polissonografia , Adolescente , Adulto , Nível de Alerta , Índice de Massa Corporal , Humanos , Modelos Lineares , Maxila/cirurgia , Pessoa de Meia-Idade , Oxigênio/metabolismo , Técnica de Expansão Palatina , Adulto Jovem
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