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1.
BMC Genomics ; 20(1): 349, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068123

RESUMO

BACKGROUND: Palatoschisis or cleft palate is a known anomaly in pigs resulting in their death. However, little is known about its aetiology. A detailed description of the phenotype was derived from necropsy and by computed tomography revealing that all 20 cases also exhibited hypodontia and renal cysts. Furthermore, a genetic origin was assumed due to dominant inheritance as all 20 recorded cases were confirmed offspring of a single boar. RESULTS: Single nucleotide variant (SNV) genotyping data were used to map the defect in the porcine genome and led to the detection of a chromosomal imbalance in the affected offspring. Whole genome sequencing of an affected piglet and a normal full sib was used to identify a chromosomal translocation and to fine map the breakpoints in the genome. Finally, we proved that the boar, which sired the malformed piglets, carried a balanced translocation. The detected translocation of Mb-sized segments of chromosome 8 and 14 had not been previously observed during karyotyping. All affected offspring were shown to be carriers of a partial trisomy of chromosome 14 including the FGFR2 gene, which is associated with various dominant inherited craniofacial dysostosis syndromes in man, and partial monosomy of chromosome 8 containing MSX1 known to be associated with tooth agenesis and orofacial clefts in other species. CONCLUSIONS: This study illustrates the usefulness of recently established genomic resources in pigs. In this study, the application of genome-wide genotyping and sequencing methods allowed the identification of the responsible boar and the genetic cause of the observed defect. By implementing systematic surveillance, it is possible to identify genetic defects at an early stage and avoid further distribution of congenital disorders.


Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas , Fissura Palatina/genética , Polimorfismo de Nucleotídeo Único , Suínos/genética , Anormalidades Múltiplas/patologia , Animais , Fissura Palatina/patologia , Feminino , Masculino , Síndrome , Sequenciamento Completo do Genoma
2.
BMJ Case Rep ; 12(4)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036736

RESUMO

PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course.


Assuntos
Anormalidades Múltiplas/cirurgia , Coartação Aórtica/cirurgia , Anormalidades do Olho/cirurgia , Hemangioma/tratamento farmacológico , Síndromes Neurocutâneas/cirurgia , Propranolol/administração & dosagem , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Administração Oral , Antagonistas Adrenérgicos beta , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/prevenção & controle , Coartação Aórtica/tratamento farmacológico , Coartação Aórtica/patologia , Ecocardiografia/métodos , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/patologia , Feminino , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/cirurgia , Hemangioma/diagnóstico por imagem , Humanos , Lactente , Imagem por Ressonância Magnética , Síndromes Neurocutâneas/tratamento farmacológico , Síndromes Neurocutâneas/patologia , Cuidados Pré-Operatórios/normas , Propranolol/efeitos adversos , Doenças Raras , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento
3.
Cornea ; 38(9): 1182-1184, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30950893

RESUMO

PURPOSE: Kabuki syndrome (KS) is a rare congenital disorder characterized by multiple systemic anomalies and unique facial characteristics. Here, we present the first case, to the best of our knowledge, of bilateral congenital corneal opacities as an early-onset ocular manifestation of KS associated with a KMT2D gene mutation. METHODS: The proband is a girl. At birth, bilateral corneal opacities, short fifth fingers, patent ductus arteriosus, absence of the uvula, and an ectopic kidney on the right side were noted. Ophthalmic examinations revealed vascularized, nonhomogeneous opacities in both corneas; to prevent deprivation amblyopia, bilateral corneal transplantations were performed. RESULTS: At 1 year and 10 months of age, she was referred by a general practitioner to our pediatric endocrinologist for failure to thrive. Genetic analysis at that age revealed the presence of a KMT2D gene mutation, and the patient was diagnosed with KS. CONCLUSIONS: The clinical diagnosis of KS is challenging because the most remarkable facial features are not evident until early childhood. In this case, bilateral congenital corneal opacities were identified as an early-onset ocular manifestation of KS. KS should be considered as a differential diagnosis in patients with bilateral congenital corneal opacities.


Assuntos
Anormalidades Múltiplas/patologia , Opacidade da Córnea/patologia , Face/anormalidades , Doenças Hematológicas/patologia , Doenças Vestibulares/patologia , Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/patologia , Feminino , Doenças Hematológicas/genética , Humanos , Lactente , Mutação , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética
4.
Gene ; 704: 97-102, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978478

RESUMO

In the current study, we report three cases of Asparagine Synthetase (ASNS) Deficiency from two consanguineous families. Family 1 had two early neonatal deaths due to a novel mutation in the ASNS gene c.788C > T (p.S263F) and both the children presented with microcephaly and one of them had severe intracranial haemorrhage. The proband from the second family was homozygous for c.146G > A (p.R49Q) and manifested myoclonic seizures, developmental delay, coarse hair and diffuse cortical atrophy. Molecular docking studies of both the mutations revealed alteration in the ligand binding site. Till date, 26 mutations were reported in ASNS gene in 29 affected children indicating high degree of genetic heterogeneity and high mortality. Although asparagine depletion is not of diagnostic utility, multiple linear regression model suggested that asparagine levels vary to the extent of 20.6% based on glutamine and aspartate levels and ASNS deficiency results in depletion of asparagine synthesis. ASNS deficiency should be suspected in any neonate with microcephaly and epileptic encephalopathy.


Assuntos
Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/genética , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Grupo com Ancestrais do Continente Asiático , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/deficiência , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Família , Feminino , Humanos , Índia , Lactente , Recém-Nascido , Hemorragias Intracranianas/congênito , Hemorragias Intracranianas/genética , Masculino , Microcefalia/patologia , Técnicas de Diagnóstico Molecular , Morte Perinatal , Convulsões/complicações , Convulsões/genética
5.
Medicina (Kaunas) ; 55(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934652

RESUMO

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.


Assuntos
Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Síndrome de Chediak-Higashi/patologia , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Diagnóstico Diferencial , Feminino , Cabelo/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Humanos , Hipertricose/induzido quimicamente , Iris/anormalidades , Masculino , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/imunologia , Síndromes Neurocutâneas/patologia , Piebaldismo/diagnóstico , Piebaldismo/genética , Piebaldismo/imunologia , Piebaldismo/patologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/patologia , Qualidade de Vida , Doenças Raras/imunologia , Doenças Raras/patologia , Anormalidades da Pele , Proteínas rab27 de Ligação ao GTP/genética
6.
Mol Genet Genomic Med ; 7(5): e639, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924321

RESUMO

BACKGROUND: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. METHODS: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. RESULTS: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three-dimensional modeling, as well as expression analysis. CONCLUSION: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Manchas Café com Leite/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Perda Auditiva Neurossensorial/genética , Fenótipo , Anormalidades Múltiplas/patologia , Manchas Café com Leite/patologia , Linhagem Celular , Células Cultivadas , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/patologia , Humanos , Mutação , Síndrome
7.
Cell Mol Gastroenterol Hepatol ; 7(2): 411-431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739867

RESUMO

BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. METHODS: To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-ß (TGF-ß) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. RESULTS: Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-ß pathway in CAID pathogenesis. Canonical TGF-ß signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. CONCLUSIONS: Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-ß signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/metabolismo , Epigenômica , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adulto , Metilação de DNA/genética , Derme/patologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Canais de Potássio/metabolismo , Proteoma/metabolismo , Reprodutibilidade dos Testes , Síndrome
8.
Nat Rev Genet ; 20(5): 299-309, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30760854

RESUMO

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.


Assuntos
Envelhecimento/genética , Genômica/história , Neoplasias/genética , Telomerase/genética , Telômero/química , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Envelhecimento/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica , Genômica/métodos , História do Século XX , História do Século XXI , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Progéria/genética , Progéria/metabolismo , Progéria/patologia , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
9.
J Hum Genet ; 64(5): 487-492, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30765867

RESUMO

We herein report two individuals with novel nonsense mutations in STAG2 on Xq25, encoding stromal antigen 2, a component of the cohesion complex. A male fetus (Case 1) clinically presented with holoprosencephaly, cleft palate and lip, blepharophimosis, nasal bone absence, and hypolastic left heart by ultrasonography at 15 gestational weeks. Another female patient (Case 2) showed a distinct phenotype with white matter hypoplasia, cleft palate, developmental delay (DD), and intellectual disability (ID) at 7 years. Whole-exome sequencing identified de novo nonsense mutations in STAG2: c.3097C>T, p.(Arg1033*) in Case 1 and c.2229G>A, p.(Trp743*) in Case 2. X-inactivation was highly skewed in Case 2. To date, only 10 STAG2 pathogenic variants (four nonsense, four missense, and two frameshift) have been reported in patients with multiple congenital anomalies, ID, and DD. Although Case 2 showed similar clinical features to the reported female patients with STAG2 abnormalities, Case 1 showed an extremely severe phenotype, which could be explained by the first detected truncating variant in males.


Assuntos
Anormalidades Múltiplas/genética , Antígenos Nucleares/genética , Códon sem Sentido , Mutação de Sentido Incorreto , Anormalidades Múltiplas/patologia , Criança , Feminino , Humanos , Masculino , Fatores Sexuais
10.
J Hum Genet ; 64(5): 467-471, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796325

RESUMO

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.


Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Mutação da Fase de Leitura , Homozigoto , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Biomarcadores Tumorais/metabolismo , Humanos , Lactente , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Escoliose/genética , Escoliose/metabolismo , Escoliose/patologia , Sinostose/metabolismo , Sinostose/patologia , Vértebras Torácicas/metabolismo , Vértebras Torácicas/patologia
11.
Mol Genet Genomic Med ; 7(2): e00507, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30614210

RESUMO

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Síndrome
12.
Growth Horm IGF Res ; 44: 17-19, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30583238

RESUMO

OBJECTIVE: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. PATIENTS AND METHODS: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. RESULTS: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). CONCLUSION: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.


Assuntos
Anormalidades Múltiplas/genética , Fissura Palatina/genética , Mutação da Fase de Leitura , Hipopituitarismo/congênito , Hipopituitarismo/genética , Proteínas Nucleares/genética , Proteína Gli2 com Dedos de Zinco/genética , Anormalidades Múltiplas/patologia , Fissura Palatina/patologia , Humanos , Hipopituitarismo/patologia , Recém-Nascido , Masculino , Fenótipo , Prognóstico , Síndrome
13.
Eur J Hum Genet ; 27(3): 360-368, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30552424

RESUMO

Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.


Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Comunicação Interatrial/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Fenótipo , Proteínas com Domínio T/genética , Deformidades Congênitas das Extremidades Superiores/genética , Anormalidades Múltiplas/patologia , Diagnóstico Diferencial , Cardiopatias Congênitas/patologia , Comunicação Interatrial/patologia , Humanos , Lactente , Deformidades Congênitas das Extremidades Inferiores/patologia , Mutação , Deformidades Congênitas das Extremidades Superiores/patologia
14.
J Hum Genet ; 64(3): 261-264, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30531807

RESUMO

Spondylocostal dysostosis (SCDO) is a heterogeneous group of skeletal disorders characterized by multiple segmentation defects involving vertebrae and ribs. Seven disease genes have been reported as causal genes for SCDO: DLL3, MESP2, TBX6, HES7, RIPPLY2, DMRT2, and LFNG. Here we report a Japanese SCDO case with multiple severe vertebral anomalies from cervical to sacral spine. The patient was a compound heterozygote for c.372delG (p.K124Nfs*) and c.601G>A (p.D201N) variants of LFNG, which encodes a glycosyltransferase (O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase). The missense variant was in the DxD motif, an active-site motif of the glycosyltransferase, and its loss of the enzyme function was confirmed by an in vitro enzyme assay. This is the second report of LFNG mutations in SCDO.


Assuntos
Anormalidades Múltiplas/genética , Glicosiltransferases/genética , Hérnia Diafragmática/genética , Hexosiltransferases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Mutação , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Hérnia Diafragmática/patologia , Humanos , Lactente , Masculino , Prognóstico , Homologia de Sequência
15.
Mol Med Rep ; 18(3): 3153-3158, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30066947

RESUMO

Keratosis pilaris (KP) and nevus comedonicus (NC) are congenital keratinized dermatoses; however, the exact etiology of these two diseases is unclear. The objective of the present study was to identify the disease­causing genes and their association with functional alterations in the development of KP and NC. Peripheral blood samples of one KP family, two NC families and 100 unrelated healthy controls were collected. The genomic sequences of 147 genes associated with 143 genetic skin diseases were initially analyzed from the KP proband using a custom­designed GeneChip. A novel heterozygous missense mutation in the ATP­binding cassette sub­family A member 12 (ABCA12) gene, designated c.6694G>T (p.Asp2232Tyr), was identified in the KP proband and confirmed by Sanger sequencing. The same mutation was also present in the affected family members but not in the healthy family members, the two patients with NC or population­matched controls. The predictions provided by PolyPhen­2 and SIFT analyses suggested that the mutation may produce a damaged protein. The region surrounding the mutation is the extra­membrane domain, which is conserved among particular species, as suggested by ClustalX; however, no ABCA12 mutations were reported in the patients with NC. As observed by immunofluorescence, ABCA12 expression was upregulated in the sebaceous glands of the patients with NC compared with that of normal controls. In summary, ABCA12­associated mutations or alterations in expression may exhibit causative or contributive effects to the development of keratinized dermatoses, including KP and NC.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Anormalidades Múltiplas/genética , Doença de Darier/genética , Sobrancelhas/anormalidades , Mutação de Sentido Incorreto , Dermatopatias/genética , Regulação para Cima , Transportadores de Cassetes de Ligação de ATP/análise , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Criança , Doença de Darier/patologia , Sobrancelhas/patologia , Feminino , Humanos , Masculino , Linhagem , Glândulas Sebáceas/metabolismo , Glândulas Sebáceas/patologia , Pele/patologia , Dermatopatias/patologia , Adulto Jovem
16.
Bull Exp Biol Med ; 165(2): 288-291, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29926279

RESUMO

We explored the possibility of using postmortem MRI for the diagnostics of lung hypoplasia associated with innate diaphragmatic hernia in neonates. The main experimental group consisted of 17 newborns with innate diaphragmatic hernia including 10 non-operated newborns and 7 newborns died after surgery for innate diaphragmatic hernia. It was demonstrated that postmortem MRI allows objective quantitative assessment of the absolute and relative dimensions of the lungs in the thoracic cavity and thereby reveals their hypoplasia, which contributes to the determination of tanatogenesis. Surgery for congenital diaphragmatic hernia leads to an increase in the mass and volume of the lungs, but does not always eliminate their hypoplasia.


Assuntos
Anormalidades Múltiplas/diagnóstico , Pneumopatias/diagnóstico , Pulmão/anormalidades , Imagem por Ressonância Magnética/métodos , Anormalidades Múltiplas/patologia , Autopsia/métodos , Feminino , Hérnias Diafragmáticas Congênitas/complicações , Hérnias Diafragmáticas Congênitas/diagnóstico , Hérnias Diafragmáticas Congênitas/patologia , Humanos , Lactente , Morte do Lactente , Recém-Nascido , Pulmão/patologia , Pneumopatias/complicações , Pneumopatias/patologia , Medidas de Volume Pulmonar/métodos , Masculino , Valor Preditivo dos Testes , Natimorto
17.
BMJ Case Rep ; 20182018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29898907

RESUMO

Aortopulmonary window (APW) is rare a congenital heart disease accounting for 0.1%-0.2% of all congenital heart defects. The 35% of the APW has been associated with wide variety of other structural heart diseases such as ventricular septal defect, persistent ductus arteriosus, arch anomalies and coronary artery anomalies. To the best of our knowledge, only six cases of APW with pulmonary atresia with ventricular septal defect has been described in the literature. It resembles the type 1 truncus arteriosus, and differentiation from this condition is important prior to surgical correction. We present a case of 14-year-old girl child; she was diagnosed with APW with pulmonary atresia with ventricular septal defect and D transposition of great arteries with the help of echocardiography, cardiac catheterisation and cardiac CT.


Assuntos
Anormalidades Múltiplas/patologia , Defeito do Septo Aortopulmonar/patologia , Comunicação Interventricular/patologia , Atresia Pulmonar/patologia , Transposição dos Grandes Vasos/patologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Assistência ao Convalescente , Defeito do Septo Aortopulmonar/diagnóstico por imagem , Defeito do Septo Aortopulmonar/tratamento farmacológico , Defeito do Septo Aortopulmonar/fisiopatologia , Cateterismo Cardíaco/métodos , Ecocardiografia/métodos , Eletrocardiografia/métodos , Feminino , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/tratamento farmacológico , Comunicação Interventricular/fisiopatologia , Humanos , Atresia Pulmonar/diagnóstico por imagem , Atresia Pulmonar/tratamento farmacológico , Atresia Pulmonar/fisiopatologia , Doenças Raras , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/tratamento farmacológico , Transposição dos Grandes Vasos/fisiopatologia , Resultado do Tratamento
18.
BMJ Case Rep ; 20182018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29754139

RESUMO

Body-stalk anomaly is a sporadic and rare maldevelopment disorder characterised by large abdominal wall defect, spinal deformity and rudimentary umbilical cord. It is considered a lethal condition as there are only few reports of survival but there was at least one case of long-term survival after neonatal surgery.Differential diagnosis includes isolated omphalocele or gastroschisis, short umbilical cord, amniotic band, limb body-wall complex and other polymalformative syndromes.There are few reports about the expectant prenatal management of the body stalk anomaly as the majority of prenatal diagnosed cases undergo early elective termination. Twin pregnancies discordant for the anomaly represent a challenge to prenatal management as a healthy fetus should also be considered.We describe a case of dichorionic-diamniotic twins discordant for body stalk anomaly which underwent selective feticide of the affected fetus late in pregnancy, in accordance with parents' decision focused on the neonatal well-being of the unaffected twin.


Assuntos
Parede Abdominal/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Redução de Gravidez Multifetal , Diagnóstico Pré-Natal , Coluna Vertebral/anormalidades , Cordão Umbilical/anormalidades , Parede Abdominal/diagnóstico por imagem , Parede Abdominal/embriologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adulto , Cordocentese , Feminino , Aconselhamento Genético , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Gravidez de Gêmeos , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/embriologia , Cordão Umbilical/diagnóstico por imagem , Cordão Umbilical/embriologia
19.
J Clin Neurosci ; 53: 247-249, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29731280

RESUMO

Klippel-Feil syndrome (KFS) is defined as congenital fusion of two or more cervical vertebrae resulting from a segmentation failure in the developing spine. According to Samartzis et al., the most commonly fused segments are found at C2/3 (74.1%) and C6/7 (70.4%). In patients with C2/3 fusion, especially when there is additional C1 occipitalization, several secondary anomalies including atlantoaxial dislocation (AAD), basilar invagination (BI), Chiari malformation, and syringomyelia can be identified. In this report, we present a case of a 12-year-old patient with C2/3 and occipitalization and a "Full-Spectrum" presentation of associated CVJ abnormalities including C0/1 fusion, AAD, BI, Chiari malformation, syringomyelia, myelopathy and cranial neuropathy received neurological decompression of the cervico-medullary junction by posterior reduction of the AAD and reconstruction of her CVJ using an unconventional hybrid construct due to a high-riding right vertebral artery in C2. To our knowledge, her "Full-Spectrum" presentation may include the most categories of concomitant abnormalities in the literature. In addition, She received neurological decompression of the cervico-medullary junction using an unconventional hybrid construct due to a high-riding vertebral artery in C2. Three months after the surgery, all of her symptoms recovered significantly. Neither Chiari malformation nor syringomyelia could be identified by MRI two years after the surgery. At the last follow-up (4 years), the patient became completely asymptomatic.


Assuntos
Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/cirurgia , Síndrome de Klippel-Feil/complicações , Síndrome de Klippel-Feil/cirurgia , Anormalidades Múltiplas/patologia , Malformação de Arnold-Chiari/etiologia , Malformação de Arnold-Chiari/cirurgia , Articulação Atlantoaxial/patologia , Articulação Atlantoaxial/cirurgia , Vértebras Cervicais/cirurgia , Criança , Descompressão Cirúrgica/métodos , Feminino , Humanos , Luxações Articulares/etiologia , Luxações Articulares/cirurgia , Síndrome de Klippel-Feil/patologia , Procedimentos Neurocirúrgicos/métodos , Doenças da Medula Espinal/etiologia , Doenças da Medula Espinal/cirurgia , Siringomielia/etiologia , Siringomielia/cirurgia
20.
J Drugs Dermatol ; 17(5): 554-556, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29742188

RESUMO

Chlorine dioxide complex™ is a new molecule to dermatology that is a unique, non-toxic, broad spectrum anti-microbial and keratolytic compound. Chlorine dioxide has been used as an antiseptic in industrial settings for decades, primarily in water treatment facilities for municipal water supplies and food preparation. The compound has exceptional antiseptic properties with no known potential for development of resistance. It is a true keratolytic and anti-inflammatory, but is non-toxic to human tissue due to its unique mechanism of action. Chlorine dioxide's use in consumer products was previously limited because it is inherently an unstable molecule that had to be used quickly after it was produced. However, the recent development of a complexed form of chlorine dioxide that retains its antimicrobial and keratolytic activity has allowed the development of products (AsepticMD, Aseptic Plus, Nashville, TN) that take advantage of the properties of this unique molecule. Here we report a case series demonstrating its efficacy as a cleanser in keratosis pilaris. J Drugs Dermatol. 2018;17(5):554-556.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Compostos Clorados/uso terapêutico , Doença de Darier/tratamento farmacológico , Detergentes/uso terapêutico , Sobrancelhas/anormalidades , Óxidos/uso terapêutico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Compostos Clorados/administração & dosagem , Doença de Darier/patologia , Detergentes/administração & dosagem , Sobrancelhas/patologia , Feminino , Humanos , Masculino , Óxidos/administração & dosagem , Resultado do Tratamento , Adulto Jovem
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