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1.
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
2.
Pan Afr Med J ; 39: 96, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34466198

RESUMO

The MSX homeobox genes cause Goldenhar syndrome (GHS) or facio-auriculo-vertebral dysplasia, a rare developmental defect. Its exact etiology is still unknown. Its incidence lies between 1: 3500 and 1: 5600. In 85% of the cases, the unilateral face is affected. Typical clinical findings in a classic GHS include eye disorders, ear irregularities (with or without hearing loss), facial impairments, dental and oral ailments, cardiac syndromes, central nervous system (CNS) involvement, trachea and lung malformations, kidney and gastrointestinal defects, and skeletal alterations. This case report presents a follow-up case of Goldenhar Syndrome in a 12-year-old female, with no relevant family history, diagnosed with anotia on the left side, cyanosis, and facial asymmetry at birth. She presented with moderate growth failure, bilateral sclerosing mastoiditis and kyphoscoliosis. She underwent posterior scoliosis correction posterior instrumented fusion from D1 to D11.


Assuntos
Síndrome de Goldenhar/diagnóstico , Escoliose/etiologia , Fusão Vertebral , Anormalidades Múltiplas/fisiopatologia , Criança , Feminino , Seguimentos , Síndrome de Goldenhar/fisiopatologia , Transtornos do Crescimento/etiologia , Humanos , Cifose/etiologia , Mastoidite/etiologia , Escoliose/cirurgia
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 841-844, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487526

RESUMO

OBJECTIVE: To analyze the phenotype and genetic variant of a fetus with dysplasia of cerebellar vermis. METHODS: Gestational status and family history of the gravida was taken in combination with the imaging results of the fetus. Following elected abortion, fetal tissue and peripheral blood samples of the couple were collected for the extraction of genome DNA. Whole exome sequencing was carried out to screen potential variant associated with the phenotype of the proband. Specific PCR primers were designed to verify the results by Sanger sequencing. RESULTS: Prenatal ultrasound revealed that the fetal vermis cerebellum was poorly developed, which was similar to the previous pregnancy. Whole exome sequencing revealed that the fetus has carried compound heterozygous variants of the CPLANE1 gene, namely c.7978C>T and c.7169delT, which were respectively inherited from the husband and wife. CONCLUSION: The c.7978C>T and c.7169delT compound heterozygous variants of the CPLANE1 gene probably underlay the dysplasia of cerebellar vermis in the fetus, which has provided a basis for genetic counseling and prenatal diagnosis.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Anormalidades do Olho/genética , Feminino , Feto , Humanos , Mutação , Fenótipo , Gravidez , Retina/anormalidades
4.
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
5.
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
6.
Nat Commun ; 12(1): 5013, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408147

RESUMO

Human families with chromosomal rearrangements at 2q31, where the human HOXD locus maps, display mesomelic dysplasia, a severe shortening and bending of the limb. In mice, the dominant Ulnaless inversion of the HoxD cluster produces a similar phenotype suggesting the same origin for these malformations in humans and mice. Here we engineer 1 Mb inversion including the HoxD gene cluster, which positioned Hoxd13 close to proximal limb enhancers. Using this model, we show that these enhancers contact and activate Hoxd13 in proximal cells, inducing the formation of mesomelic dysplasia. We show that a secondary Hoxd13 null mutation in-cis with the inversion completely rescues the alterations, demonstrating that ectopic HOXD13 is directly responsible for this bone anomaly. Single-cell expression analysis and evaluation of HOXD13 binding sites suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Homeodomínio/genética , Deformidades Congênitas dos Membros/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/metabolismo , Animais , Doenças do Desenvolvimento Ósseo/embriologia , Doenças do Desenvolvimento Ósseo/metabolismo , Modelos Animais de Doenças , Feminino , Deleção de Genes , Proteínas de Homeodomínio/metabolismo , Humanos , Deformidades Congênitas dos Membros/embriologia , Deformidades Congênitas dos Membros/metabolismo , Mutação com Perda de Função , Masculino , Camundongos Endogâmicos C57BL , Família Multigênica , Fatores de Transcrição/metabolismo
7.
Medicine (Baltimore) ; 100(30): e26687, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34397695

RESUMO

RATIONALE: Escobar syndrome (ES) is an autosomal recessive disorder. It is highly characterized by facial abnormalities, congenital diaphragmatic muscle weakness, myasthenic-like features, and skin pterygiums on multiple body legions. ES is a rare condition associated with many external and internal abnormalities. The internal malformations described in ES affect many organs including the heart, lungs, esophagus, liver, spleen, and intestine. The purpose of this paper is to explore the cardiac manifestations associated with ES. PATIENT CONCERNS: A 3.5-year-old girl, who was born for double first cousins, was admitted to the hospital for neuromuscular evaluation of multiple congenital contractures. DIAGNOSIS: The girl was diagnosed with ES and isolated dextrocardia which is a rare cardiac manifestation. However, to the best of our knowledge, no similar cases have been reported to date, and this case is thus believed to be very rare. INTERVENTIONS: The patient underwent an operative intervention to correct the bilateral fixed flexion deformity at her knees which was related to the posterior bilateral fibrotic bands/pterygia. OUTCOMES: Post-operatively, complete knee extension was obtained, the patient was fitted with a cast and extension night splint. She was discharged alive and had no complications. The patient was followed regularly in the orthopedic clinic and had periodic physiotherapy sessions. CONCLUSIONS: ES and isolated dextrocardia concurrence in the presented case resulted from different pathogenic mechanisms. Our findings suggest that ES might be caused by dysfunction in the acetylcholine receptor throughout fetal life, which may have affected muscle strength and movement. Other cardiac conditions include hypoplastic left-sided heart, Hypertrophic cardiomyopathy, patent ductus arteriosus, and heterotaxia.


Assuntos
Cardiopatias/etiologia , Hipertermia Maligna/complicações , Anormalidades da Pele/complicações , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Pré-Escolar , Contratura/etiologia , Permeabilidade do Canal Arterial/etiologia , Feminino , Cardiopatias/fisiopatologia , Humanos , Hipertermia Maligna/genética , Hipertermia Maligna/fisiopatologia , Arábia Saudita , Anormalidades da Pele/genética , Anormalidades da Pele/fisiopatologia
8.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360805

RESUMO

FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.


Assuntos
Anormalidades Múltiplas , Caseína Quinase I , Fissura Palatina , Exoftalmia , Proteínas da Matriz Extracelular , Variação Genética , Microcefalia , Osteosclerose , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Fissura Palatina/genética , Fissura Palatina/metabolismo , Fissura Palatina/mortalidade , Fissura Palatina/patologia , Exoftalmia/genética , Exoftalmia/metabolismo , Exoftalmia/mortalidade , Exoftalmia/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/mortalidade , Microcefalia/patologia , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/mortalidade , Osteosclerose/patologia
9.
Rev Med Liege ; 76(7-8): 625-628, 2021 Jul.
Artigo em Francês | MEDLINE | ID: mdl-34357716

RESUMO

KBG syndrome, named after the initials of the first 3 families reported, is a rare genetic syndrome caused by a deletion or a mutation of ANKRD11 (ankyrin repeat domain-containing protein 11) gene. Its prevalence is probably underestimated because of a variable expressivity; moreover, most of its clinical characteristics are not specific. There is no consensus about its diagnostic criteria. Ophthalmologic manifestations have sometimes been described among more frequent clinical signs. Early detection is critical and multidisciplinary care is requested in order to ensure the patient's independence. We report the case of a 16 years old boy diagnosed with a KBG syndrome after more than one year of genetic research, motivated by a short stature, high refractive errors and bilateral corneal clouding.


Assuntos
Deleção Cromossômica , Proteínas Repressoras , Anormalidades Múltiplas , Adolescente , Doenças do Desenvolvimento Ósseo , Facies , Humanos , Deficiência Intelectual , Masculino , Fenótipo , Proteínas Repressoras/genética , Anormalidades Dentárias
10.
Afr J Paediatr Surg ; 18(4): 219-223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341307

RESUMO

Background: Congenital heart defects (CHDs) are one of the most common associated anomalies in patients with an orofacial cleft (OFC). However, few studies have shown the association between cleft type and CHDs in our population. This study aimed to assess the prevalence of CHDs in a cohort of OFC patients at a tertiary health facility in Nigeria, as well as assess the risk of CHD by OFC type. Materials and Methods: This was a prospective study design. Patients with an OFC were consecutively enrolled at a single OFC treatment facility. All subjects were assessed by a paediatric cardiologist and had echocardiography done. They were categorised based on the presence of CHDs, as well as the OFC phenotypic type (cleft lip and/or alveolus, cleft lip and palate and cleft palate only). Statistical analysis was done using STATA version 14 (College Station, Texas), and significance was set at P < 0.05. Results: A total of 150 subjects enrolled in the study over a period of 2 years (2018-2020). The median age of subjects was 6 months (interquartile range: 2-24), and 54.7% were female. The prevalence of CHDs in the subjects reviewed was 30.7%. Based on the severity of CHDs, the majority presented with simple defects (95.6%). Overall, the most common presentation was patent foramen ovale (12.7%), followed by septal defects (8.0%). There was no significant association between cleft type and the odds of a CHD. Conclusion: The study reports a relatively high prevalence of CHDs in patients with OFC; however, there was no association between the risk of CHD by cleft type. Although a majority of CHDs may pose a low operative risk, cardiac evaluation is recommended for all cases of OFC to aid the identification of potentially high-risk cases.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cardiopatias Congênitas , Criança , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Lactente , Estudos Prospectivos
11.
Pan Afr Med J ; 39: 75, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422198

RESUMO

Hyperreactio luteinalis (HL) is a rare entity in which both ovaries are multicystic and enlarged under the action of human chorionic gonadotropin (hCG), mostly seen in the third trimester of pregnancy. This benign condition is usually asymptomatic and doesn't need any specific treatment, as the ovaries spontaneously reduce in size after birth. This is a case report of a 33-year-old woman diagnosed with hyperreactio luteinalis during the second trimester of her induced pregnancy. An ultrasound scan at 22 weeks of gestation revealed bilateral multicystic enlarged ovaries along with multiple fetal malformations and hydropsfetalis. Usually, HL is most commonly seen in situations in which there are high levels of hCG, but our patient had normal levels of hCG during all her pregnancy, which makes our case even rarer. In conclusion, the most important challenge when faced with HL is to differentiate between it and other differential diagnosis especially malignant tumors, because unlike them, this benign condition doesn't need surgical treatment.


Assuntos
Gonadotropina Coriônica/sangue , Cistos Ovarianos/diagnóstico por imagem , Complicações na Gravidez/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico por imagem , Adulto , Feminino , Humanos , Achados Incidentais , Gravidez , Segundo Trimestre da Gravidez , Ultrassonografia Pré-Natal
12.
Nat Commun ; 12(1): 4549, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315901

RESUMO

Germline pathogenic variants in DNMT3A were recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3A Overgrowth Syndrome/DOS). Somatic mutations in the DNMT3A gene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negative DNMT3AR882H mutation. A germline mouse model expressing the homologous Dnmt3aR878H mutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.


Assuntos
Anormalidades Múltiplas/genética , DNA (Citosina-5-)-Metiltransferases/genética , Epigênese Genética , Anormalidades Múltiplas/sangue , Adolescente , Adulto , Animais , Comportamento Animal , Peso Corporal/genética , Células da Medula Óssea/metabolismo , Criança , Pré-Escolar , Ilhas de CpG/genética , Metilação de DNA/genética , Feminino , Perfilação da Expressão Gênica , Mutação em Linhagem Germinativa/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Lactente , Leucemia/genética , Leucemia/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/genética , Fenótipo , Síndrome , Transcrição Genética
13.
A A Pract ; 15(7): e01503, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283818

RESUMO

Alström syndrome is a rare genetic condition that affects cardiac, respiratory, endocrine, hepatorenal, gastrointestinal, auditory, ophthalmic, and musculoskeletal systems. This multisystem syndrome poses significant anesthetic challenges, along with a high likelihood of perioperative adverse clinical outcomes. A literature review revealed no reports on the anesthetic management for emergency surgery in adults with Alström syndrome. We report the perioperative management of a patient with Alström syndrome who presented for an emergency laparotomy due to an ischemic bowel. This report highlights perioperative challenges in the management of this condition in the emergency setting.


Assuntos
Anormalidades Múltiplas , Anestésicos , Retinite Pigmentosa , Adulto , Humanos , Deficiência Intelectual , Síndrome
14.
Hum Genet ; 140(9): 1395-1401, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34313816

RESUMO

The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery.


Assuntos
Anormalidades Múltiplas/genética , Dano ao DNA , Genes Recessivos , Homozigoto , Proteínas Supressoras de Tumor/deficiência , Anormalidades Múltiplas/patologia , Criança , Humanos , Masculino
15.
Toxicol Appl Pharmacol ; 426: 115653, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302850

RESUMO

Peroxisome Proliferator Activated Receptors (PPARs) are transcription factors that regulate processes such as lipid and glucose metabolism. Synthetic PPAR ligands, designed as therapeutics for metabolic disease, provide a tool to assess the relationship between PPAR activity and pancreas development in vivo, an area that remains poorly characterized. Here, we aim to assess the effects of PPAR agonists and antagonists on gene expression, embryonic morphology and pancreas development in transgenic zebrafish embryos. To evaluate developmental perturbations, we assessed gross body and pancreas morphology at 4 days post fertilization (dpf) in response to developmental exposures with PPARα, PPARγ, and PPARß/δ agonists and antagonists at 0, 0.01, 0.1, 1, and 10 µM concentrations. All ligand exposures, with the exception of the PPARα agonist, resulted in significantly altered fish length and yolk sac area. PPARγ agonist and antagonist had higher incidence of darkened yolk sac and craniofacial deformities, whereas PPARα antagonist had higher incidence of pericardial edema and death. Significantly reduced endocrine pancreas area was observed in both PPARγ ligands and PPARα agonist exposed embryos, some of which also exhibited aberrant endocrine pancreas morphology. Both PPARß/δ ligands caused reduced exocrine pancreas length and novel aberrant phenotype, and disrupted gene expression of pancreatic targets pdx1, gcga, and try. Lipid staining was performed at 8 dpf and revealed altered lipid accumulation consistent with isoform function. These data indicate chronic exposure to synthetic ligands may induce morphological and pancreatic defects in zebrafish embryos.


Assuntos
Pâncreas/anormalidades , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Anormalidades Múltiplas , Animais , Animais Geneticamente Modificados , Anormalidades Craniofaciais , Embrião não Mamífero , Desenvolvimento Embrionário , Feminino , Expressão Gênica , Metabolismo dos Lipídeos , Masculino , Transdução de Sinais , Saco Vitelino/anormalidades , Peixe-Zebra/anormalidades , Peixe-Zebra/genética
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 663-666, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247373

RESUMO

OBJECTIVE: To explore gender difference in the clinical manifestations of two children with Keishi-Bukuryo-Gan syndrome (KBGS). METHODS: Clinical manifestations of the two children were reviewed. Genetic testing was carried out through next generation sequencing (NGS). Treatment was summarized, and the prognosis was followed up. RESULTS: Both children showed particular appearance including megatooth, abnormal hair distribution, hands' abnormality and language development delay. NGS revealed that both children have carried pathogenic variants of the ANKRD11 gene (c.1903_1907del and c.4911delT), which resulted in shifting of amino acid sequences starting from the Lysine and Proline at positions 635 and 1638, respectively. The female patient exhibited central precocious puberty. Her height has increased by 13 cm, and sex characteristics has retracted after treatment with leuprorelin for 23 months and recombinant human growth hormone for 1 month. CONCLUSION: Comparison of the two cases with different genders and summary of previously reported cases found that male KBGS patients have more obvious dysmorphisms such as triangular face, synophrys, ocular hypertelorism and vertebral body abnormality, with higher morbidity of epilepsy, mental retardation, autism, congenital heart disease, immune thrombocytopenia and other complications. KBGS is an autosomal dominant disease featuring more evident peculiar appearance and global development delay. Male patients often have multi-system involvement, and multidisciplinary cooperation is required for early recognition of particular features in order to improve the prognosis.


Assuntos
Deficiência Intelectual , Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Criança , Facies , Feminino , Humanos , Masculino , Fenótipo , Proteínas Repressoras/genética , Caracteres Sexuais , Anormalidades Dentárias
17.
Nat Commun ; 12(1): 4050, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193871

RESUMO

The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.


Assuntos
Anormalidades Múltiplas/patologia , Proteínas de Transporte/metabolismo , Anormalidades Craniofaciais/patologia , Dano ao DNA , Deformidades Congênitas da Mão/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Deficiência Intelectual/patologia , Mutação , Unhas Malformadas/patologia , Células-Tronco Neurais/patologia , Proteínas Nucleares/metabolismo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Proteínas de Transporte/genética , Células Cultivadas , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Unhas Malformadas/genética , Unhas Malformadas/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Nucleares/genética , Organoides
19.
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
20.
J Pediatr Surg ; 56(10): 1803-1810, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34167803

RESUMO

AIM: To evaluate the correlation between sacral/vertebral anomalies and spinal cord anomalies (SCA) on MRI, in patients with anorectal malformation (ARM). METHODS: Patients with ARM consecutively treated between January 1999 and August 2019 were included. Radiological imaging of sacrum and spine were retrospectively analyzed and correlated to the presence of SCA at MRI. Fisher's exact test and X2 test were used as appropriate; p<0.05 was considered statistically significant. RESULTS: 348 patients with ARM were enrolled in the study, 147 presented SCA at MRI. 144 patients showed spinal bone anomalies, isolated vertebral and sacral anomalies were found in 17,6% and 35% respectively. Higher level of ARM was associated with a significant higher prevalence of sacral and vertebral anomalies. A significant correlation was found between the "level" of ARM and the presence of SCA (p<0.05). Sacral anomalies were significantly correlated with the presence of SCA at MRI (p<0.05). SCA were found in 70% of patients with vertebral anomalies (VA) and in 76% of patients with sacral anomalies. The presence of multiple malformations (vertebral and sacral anomalies) are strictly related to the presence of SCA. However, the absence of spinal bone anomalies does not exclude the presence of SCA. SD was the most represented type of SCA (n=94/147), of those 96% had fatty filum. Neurological or neurourological symptoms were detected in 11,5% patients (n=17) with SCA and required neurosurgical intervention. CONCLUSIONS: Our data confirm the strong relation between sacral or vertebral anomalies and SCA. However, in our series also patients without sacral/vertebral anomalies had SCA at MRI. Our results suggest that, despite the presence or absence of spinal anomalies, spinal cord MRI should be performed in all children with ARM, to allow a correct multidisciplinary follow-up and treatment. In fact, most patients with spinal bone and SCA are asymptomatic, but could develop clinical manifestations during their growth.


Assuntos
Anormalidades Múltiplas , Malformações Anorretais , Anormalidades Musculoesqueléticas , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/epidemiologia , Criança , Humanos , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Medula Espinal
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