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1.
World Neurosurg ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33529764

RESUMO

OBJECTIVE: To report the clinical use of uniplanar cannulated pedicle screws for the correction of Lenke type 1 AIS, and its safety and clinical outcomes were also evaluated. METHODS: 68 patients with Lenke type 1 AIS were retrospective analysed, among which 38 patients were treated with uniplanar cannulated screws at the concave side of periapical levels and multiaxial screws at the other levels (group A). The remaining 30 patients were treated with all multiaxial screws (group B). The preoperative and postoperative radiographic parameters, axial vertebral rotation, and the safety of the pedicle screws were evaluated. RESULTS: Preoperative data was comparable between two groups. The postoperative proximal thoracic curve, main thoracic curve, thoracolumbar/lumbar curve, and apical vertebral rotation were significantly improved in both group (P<0.05). The coronal correction rates in group A and B were 83% and 81.9% (P=0.723). The derotation rates in group A and B were 60.8% and 43.2% (P<0.05). The rotation classification in the group A was also better than group B. The misplacement rate in group A and B was 7.9% and 11.8% (P<0.05), and the total misplacement rate on the concave side (11.4%) was higher than that of convex side (8.4%). On the concave side, the misplacement rate in group A and B was 9.7% and 12.3%. On the convex side, the misplacement rate in group A and B was 5.9% and 11.1% (P<0.05). CONCLUSIONS: Collectively, uniplanar cannulated pedicle screws could effectively increase the accuracy of pedicle screws and facilitate the derotation of the apical vertebra compared with the multiaxial pedicle screws.

2.
Am J Hum Genet ; 108(2): 337-345, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434492

RESUMO

Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidades
3.
Orphanet J Rare Dis ; 15(1): 288, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33054853

RESUMO

BACKGROUND: Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly. RESULTS: We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients' blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype-phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005). CONCLUSIONS: Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.

4.
Orphanet J Rare Dis ; 15(1): 250, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933559

RESUMO

BACKGROUND: We previously reported a novel clinically distinguishable subtype of congenital scoliosis (CS), namely, TBX6-associated congenital scoliosis (TACS). We further developed the TBX6-associated CS risk score (TACScore), a multivariate phenotype-based model to predict TACS according to the patient's clinical manifestations. In this study, we aimed to evaluate whether using the TACScore as a screening method prior to performing whole-exome sequencing (WES) is more cost-effective than using WES as the first-line genetic test for CS. METHODS: We retrospectively collected the molecular data of 416 CS patients in the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study. A decision tree was constructed to estimate the cost and the diagnostic time required for the two alternative strategies (TACScore versus WES). Bootstrapping simulations and sensitivity analyses were performed to examine the distributions and robustness of the estimates. The economic evaluation considered both the health care payer and the personal budget perspectives. RESULTS: From the health care payer perspective, the strategy of using the TACScore as the primary screening method resulted in an average cost of $1074.2 (95%CI: $1044.8 to $1103.5) and an average diagnostic duration of 38.7d (95%CI: 37.8d to 39.6d) to obtain a molecular diagnosis for each patient. In contrast, the corresponding values were $1169.6 (95%CI: $1166.9 to $1172.2) and 41.4d (95%CI: 41.1d to 41.7d) taking WES as the first-line test (P < 0.001). From the personal budget perspective, patients who were predicted to be positive by the TACScore received a result with an average cost of $715.1 (95%CI: $594.5 to $835.7) and an average diagnostic duration of 30.4d (95%CI: 26.3d to 34.6d). Comparatively, the strategy of WES as the first-line test was estimated to have significantly longer diagnostic time with an average of 44.0d (95%CI: 43.2d to 44.9d), and more expensive with an average of $1193.4 (95%CI: $1185.5 to $1201.3) (P < 0.001). In 100% of the bootstrapping simulations, the TACScore strategy was significantly less costly and more time-saving than WES. The sensitivity analyses revealed that the TACScore strategy remained cost-effective even when the cost per WES decreased to $8.8. CONCLUSIONS: This retrospective study provides clinicians with economic evidence to integrate the TACScore into clinical practice. The TACScore can be considered a cost-effective tool when it serves as a screening test prior to performing WES.

5.
Mol Genet Genomic Med ; 8(10): e1453, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32815649

RESUMO

BACKGROUND: Congenital scoliosis (CS) is a spinal deformity due to vertebral malformations. Although insufficiency of TBX6 dosage contributes to a substantial proportion of CS, the molecular etiology for the majority of CS remains largely unknown. TBX6-mediated genes involved in the process of somitogenesis represent promising candidates. METHODS: Individuals affected with CS and without a positive genetic finding were referred to this study. Proband-only exome sequencing (ES) were performed on the recruited individuals, followed by analysis of TBX6-mediated candidate genes, namely MEOX1, MEOX2, MESP2, MYOD1, MYF5, RIPPLY1, and RIPPLY2. RESULTS: A total of 584 patients with CS of unknown molecular etiology were recruited. After ES analysis, protein-truncating variants in RIPPLY1 and MYF5 were identified from two individuals, respectively. In addition, we identified five deleterious missense variants (MYOD1, n = 4; RIPPLY2, n = 1) in TBX6-mediated genes. We observed a significant mutational burden of MYOD1 in CS (p = 0.032) compared with the in-house controls (n = 1854). Moreover, a potential oligogenic disease-causing mode was proposed based on the observed mutational co-existence of MYOD1/MEOX1 and MYOD1/RIPPLY1. CONCLUSION: Our study characterized the mutational spectrum of TBX6-mediated genes, prioritized core candidate genes/variants, and provided insight into a potential oligogenic disease-causing mode in CS.

6.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

7.
BMC Med Genet ; 21(1): 115, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460719

RESUMO

BACKGROUND: Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations. METHODS: We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed. RESULTS: An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family. CONCLUSIONS: Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.


Assuntos
Proteína de Matriz Oligomérica de Cartilagem/genética , Família , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Adolescente , Adulto , Idoso , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Proteína de Matriz Oligomérica de Cartilagem/química , Criança , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Relação Estrutura-Atividade , Sequenciamento Completo do Exoma , Adulto Jovem
8.
BMC Musculoskelet Disord ; 21(1): 220, 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32278351

RESUMO

BACKGROUND: Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. METHODS: We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. RESULTS: We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. CONCLUSIONS: Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

9.
Med Sci Monit ; 26: e921611, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32218412

RESUMO

BACKGROUND Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, but its etiology is unclear. Multiple genetic mutations have been reported to be associated with AIS. MATERIAL AND METHODS We enrolled a cohort of 113 surgically treated AIS patients with available parental subjects from the Peking Union Medical College Hospital. We performed whole-exome sequencing in 10 trio families and whole-genome sequencing in 103 singleton patients. Luciferase assay was used to detect the functional alterations of candidate ESR1 and ESR2 variants. RESULTS Using a de novo strategy, a missense variant in ESR1 (c.868A>G) was selected as a candidate gene for AIS. The main Cobb angle of this patient was 41° (T6-T10). Another potential pathogenic variant in ESR2 (c.236T>C) was identified. The main curve of the patient was 45° at T10-L3. The transactivation capacities of the mutated ESR1 and ESR2 protein were both significantly decreased (p=0.026 and 0.014, respectively). CONCLUSIONS Potential pathogenic variants in ESR1 and ESR2 were identified in 113 AIS patients, suggesting that genetic mutations in ESR1/2 were associated with the risk of AIS.

10.
J Med Genet ; 57(6): 371-379, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31888956

RESUMO

BACKGROUND: Congenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs. METHODS AND RESULTS: Patients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3 ) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae. CONCLUSION: Our findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

11.
Hum Mutat ; 41(1): 182-195, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31471994

RESUMO

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

12.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.


Assuntos
Anormalidades Congênitas/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Escoliose/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Fator de Crescimento Transformador beta/genética
13.
Mol Genet Genomic Med ; 8(1): e1023, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

14.
Curr Gene Ther ; 19(4): 242-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31549955

RESUMO

OBJECTIVE: The genetic variations contributed to a substantial proportion of congenital vertebral malformations (CVM). SOX9 gene, a member of the SOX gene family, has been implicated in CVM. To study the SOX9 mutation in CVM patients is of great significance to explain the pathogenesis of scoliosis (the clinical manifestation of CVM) and to explore the pathogenesis of SOX9-related skeletal deformities. METHODS: A total of 50 singleton patients with CVM were included in this study. Exome Sequencing (ES) was performed on all the patients. The recurrent candidate variant of SOX9 gene was validated by Sanger sequencing. Luciferase assay was performed to investigate the functional changes of this variant. RESULTS: A recurrent rare heterozygous missense variant in SOX9 gene (NM_000346.3: c.1405A>G, p.M469V) which had not been reported previously was identified in three CVM patients who had the clinical findings of congenital scoliosis without deformities in other systems. This variant was absent from our in-house database and it was predicted to be deleterious (CADD = 24.5). The luciferase assay demonstrated that transactivation capacity of the mutated SOX9 protein was significantly lower than that of the wild-type for the two luciferase reporters (p = 0.0202, p = 0.0082, respectively). CONCLUSION: This SOX9 mutation (p.M469V) may contribute to CVM without other systematic deformity, which provides important implications and better understanding of phenotypic variability in SOX9-related skeletal deformities.


Assuntos
Anormalidades Congênitas/genética , Mutação de Sentido Incorreto , Fatores de Transcrição SOX9/genética , Doenças da Coluna Vertebral/genética , Coluna Vertebral/anormalidades , Adolescente , Criança , Pré-Escolar , China/epidemiologia , Anormalidades Congênitas/epidemiologia , Feminino , Heterozigoto , Humanos , Masculino , Prognóstico , Doenças da Coluna Vertebral/congênito , Doenças da Coluna Vertebral/epidemiologia , Coluna Vertebral/metabolismo , Coluna Vertebral/patologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31921798

RESUMO

Background: Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS. Methods: A female monozygotic (MZ) twin pair discordant for AIS were examined for whole-exome sequencing and epigenome difference. Sets of differentially methylated regions (DMRs) were validated using MethylTarget™ method in 20 AIS female patients and 20 healthy female controls. Results: Few exome difference but several potential DMRs were found between the MZ twins. We identified 313 hypermethylated DMRs and 397 hypomethylated DMRs, respectively. Most of them were enriched in the MAPK and PI3K-Akt signaling pathway, which may contribute to the discordance of AIS. Several DMRs related to scoliosis genes were tested, and the NDN: TSS-DMR (chr15:23932133-23932304, hg19) was confirmed in additional samples. The methylation level of this DMR was significantly higher in the AIS group than in the control group (p = 0.04). Conclusions: We described the epigenome difference in an AIS female discordant MZ twin pair using Whole Genome Bisulfite Sequencing (WGBS). The NDN: TSS-DMR had higher methylation level in female AIS, which can help elucidate the potential etiology of AIS.

16.
Medicine (Baltimore) ; 97(48): e12957, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508884

RESUMO

Case series study.To report the clinical outcomes of posterior temporary C1-2 fixation for 3-part fracture of the axis (Type II odontoid fracture according to Grauer classification combined with Hangman fracture).The 3-part fracture of the axis is rare and the treatment is controversy.A total of 8 patients with 3-part fracture of the axis were included in this study. X-rays, CT, and MRI prior to surgery were used to evaluate the cervical spine injury. Grauer classification, fracture angulation, and fracture translation were used to evaluate the fracture of dens. The neck disability index (NDI) and range of neck rotary motion were used to assess the neck function.The preoperative fracture angulation and fracture translation were 4.6 ±â€Š1.3° and 2.4 ±â€Š0.6 mm, respectively. The average operation time and blood loss were 109 ±â€Š27 minutes and 49 ±â€Š15 mL. No infection, vascular injuries or neural structure injuries was observed. All patients acquired bone healing at 5.9 ±â€Š2.0 months. The temporary instrumentation was removed at 10.8 ±â€Š1.3 months. The average NDI before and 2 days after removal of instrumentation were 10.1 ±â€Š4.0 and 7.1 ±â€Š3.0, respectively. At 1-year follow-up after instrumentation removal, the NDI was 1.8 ±â€Š0.7, which was much better than immediate NDI after instrumentation removal. The neck rotary motion (left rotation + right rotation) before and 2-day after instrumentation removal were 70.4 ±â€Š6.3° and 119.6 ±â€Š13.1°, respectively. At 1-year follow-up, the average neck rotary motion was 153.1 ±â€Š9.1°, which had significant different with rotary motion 2-day after the removal of temporary instrumentation.With regard to the high fracture fusion rates, low complications, and excellent predictable outcomes in patients treated with posterior temporary C1-2 pedicle screw fixation, the technique may be a suitable choice for 3-part fracture of the axis.


Assuntos
Vértebra Cervical Áxis/lesões , Vértebra Cervical Áxis/cirurgia , Fixação Interna de Fraturas/métodos , Fraturas da Coluna Vertebral/cirurgia , Adulto , Idoso , Vértebra Cervical Áxis/diagnóstico por imagem , Perda Sanguínea Cirúrgica , Feminino , Consolidação da Fratura , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Processo Odontoide/lesões , Processo Odontoide/cirurgia , Duração da Cirurgia , Parafusos Pediculares , Amplitude de Movimento Articular , Tomografia Computadorizada por Raios X
17.
J Orthop Surg Res ; 13(1): 3, 2018 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-29310670

RESUMO

BACKGROUND: Recently, the excellent outcomes of temporary fixation of C1-2 without fusion in the treatment of odontoid fracture had been reported. It is still unclear if this technique could achieve the equivalent outcomes as the golden standard technique of anterior screw fixation. The objective of this study is to compare the clinical outcome of two treatments of fresh type II odontoid fracture: anterior cannulated screws fixation (ACSF) versus posterior instrumentation of C1-2 without fusion (PIWF). METHODS: This is a retrospective study. This series included 28 males and 8 females, and the mean age was 41.5 years (range, 22 to 70 years). Eleven patients were treated with ACSF, and 25 patients with PIWF. For PIWF, the implants were removed after fracture union was confirmed at 0.75~1.5 years later. All patients underwent preoperative and serial postoperative clinical examinations at approximately 3 months, 6 months, and annually thereafter. The neck disability index (NDI) was used to assess the neck discomfort caused by the operation. The range of rotary motion was evaluated at each visit. All fractures were reassessed postoperatively with serial X-films and CT scans of the cervical spine at each follow-up visit, to evaluate screw position, fracture alignment, and fusion status. RESULTS: All patients achieved immediate spinal stabilization after surgery, and none experienced neurologic deterioration. The follow-up periods ranged from 24 to 60 months. The average range of neck rotation was dramatically lost in PIWF after fixation (46° and 89° respectively in ACSF and PIWF), and recovered to 83° after the implant was removed. The NDI in PIWF was statistically higher than that in ACSF (5 and 13% respectively in ACSF and PIWF) after the first operation and decreased to 8% 1 year after the secondary operation. The fusion rates were 90.9 and 96% respectively in ACSF and PIWF. Both groups had a case of fracture non-union. CONCLUSIONS: For fresh type II odontoid fractures, high rate of fracture union can be achieved by both ACSF and PIWF. For most fresh type II odontoid fractures, anterior screw fixation was the best option for its simplicity and preservation of normal atlanto-axial rotary function. Posterior instrumentation without fusion could preserve most of the atlanto-axial rotary function and lead to moderate neck discomfort and is also a good alternative if anterior screw fixation is contraindicated.


Assuntos
Parafusos Ósseos , Fixação Interna de Fraturas/métodos , Processo Odontoide/lesões , Fraturas da Coluna Vertebral/cirurgia , Adulto , Idoso , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Feminino , Fixação Interna de Fraturas/instrumentação , Consolidação da Fratura , Movimentos da Cabeça , Humanos , Masculino , Pessoa de Meia-Idade , Processo Odontoide/diagnóstico por imagem , Processo Odontoide/cirurgia , Radiografia , Amplitude de Movimento Articular , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fusão Vertebral , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
18.
J Neurosurg Spine ; 28(3): 317-325, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29303471

RESUMO

OBJECTIVE This study aimed to evaluate the clinical outcomes of percutaneous endoscopic transforaminal discectomy (PETD), microendoscopic discectomy (MED), and microdiscectomy (MD) for treatment of symptomatic lumbar disc herniation (LDH). METHODS One hundred ninety-two patients with symptomatic LDH at L3-4 and L4-5 were included in this study. The mean (± SD) age of patients was 34.2 ± 2.6 years (range 18-62 years). The patients were divided into groups as follows: group A was treated with PETD and included 60 patients (31 men and 29 women) with a mean age of 36.2 years; group B was treated with MED and included 63 patients (32 men and 31 women) with a mean age of 33.1 years; and group C was treated with MD and included 69 patients (36 men and 33 women) with a mean age of 34.0 years. The Japanese Orthopaedic Association (JOA) scale for low-back pain (LBP), Oswestry Disability Index (ODI), creatine phosphokinase activity 3 days after surgery, and visual analog scale (VAS) scores for LBP and leg pain were used for evaluation of clinical results. RESULTS There were no significant differences in mean preoperative JOA score, ODI score, and VAS scores for LBP and leg pain among groups A, B, and C. Incision length, duration of the operation, blood loss, creatine phosphokinase, length of hospital stay, and postoperative incision pain according to the VAS were best in the PETD group (p < 0.05). The number of seconds of intraoperative fluoroscopy was highest in the PETD group (p < 0.05), whereas there was no difference between the MED and MD groups. Three cases from the MED group and 2 cases from the MD group had an intraoperative durotomy. No CSF leakage was observed after surgery. One case from the MED group and 3 cases from the MD group had incision infections. There were no neurological deficits related to the surgeries in any of the groups. Fifty-five (91.6%), 59 (93.7%), and 62 patients (89.9%) had at least 2 years of follow-up in groups A, B, and C, respectively. At the last follow-up, JOA scores, VAS scores of LBP and leg pain, and ODI scores were significantly better than preoperative correlates in all groups. There were no differences among the 3 groups in JOA scores, JOA recovery rate, ODI scores, and VAS scores for leg pain. The VAS score for LBP was best in the PETD group (p < 0.05). No lumbar instability was observed in any group. Three cases (5.5%) in the PETD group had recurrent LDH, and 2 recurrent cases (3.4%) were confirmed in the MED group. CONCLUSIONS PETD, MED, and MD were all reliable techniques for the treatment of symptomatic LDH. With a restricted indication, PETD can result in rapid recovery and better clinical results after at least 2 years of follow-up.


Assuntos
Discotomia Percutânea , Discotomia , Degeneração do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Adulto , Discotomia/efeitos adversos , Discotomia/métodos , Discotomia Percutânea/efeitos adversos , Discotomia Percutânea/métodos , Endoscopia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Resultado do Tratamento
19.
J Orthop Sci ; 22(2): 254-259, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28025024

RESUMO

OBJECTIVE: We collected the radiographic and clinical data of 129 AIS patients (Lenke type 1-6) to analyze the characteristics of cervical sagittal alignment in adolescent idiopathic scoliosis patients and the correlations between cervical sagittal alignment and global sagittal alignment, and clinical symptoms. METHODS: 129 patients with AIS and 48 adolescent volunteers were included in this study. The angles of the main thoracic curve, proximal thoracic curve, thoracolumbar curve, lumbar curve, C2-7 Cobb angle, T5-12 Cobb angle, L1-5 Cobb angle, pelvic incidence, pelvic tilt, sacrum slop, C2-7 sagittal vertical axis, C7-S1 sagittal vertical axis, and T1 pelvic angle were included in radiographic measurements. In addition, a 10-cm Visual Analogue Score was used to assess neck pain. Pearson correlation coefficients and t-test were used for statistical analysis. RESULTS: In the AIS group, C2-7 Cobb angle increased significantly compared with the control group, and it was significantly correlated with T5-12 Cobb angle and L1-5 Cobb angle. There was no significant correlation between C2-7 Cobb angle and coronal curvature in each Lenke type of patients. In the C2-7 SVA ≥ 3 cm group, C2-7 Cobb angle was related to T5-12 Cobb angle, L1-5 Cobb angle, pelvic incidence, and sacrum slop. In the cervical kyphosis group, T5-12 Cobb angle was significantly lower than that of the C2-7 Cobb angle ≥0 group. The C2-7 Cobb angle in the group with T5-12 Cobb angle >30° increased significantly compared with that in the group with T5-12 Cobb angle ≤30°. The Visual Analogue Score of neck pain of the cervical imbalance group was significantly higher than that of the cervical balance group. CONCLUSIONS: The cervical sagittal alignment in AIS patients was related with thoracic kyphosis and lumbar lordosis, especially with thoracic kyphosis, but not with the coronal angle of thoracic and lumbar spine, and pelvic parameters.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Cervicalgia/diagnóstico por imagem , Medição da Dor , Escoliose/diagnóstico por imagem , Adolescente , Estudos de Casos e Controles , Feminino , Humanos , Cifose/complicações , Cifose/diagnóstico por imagem , Cifose/fisiopatologia , Lordose/complicações , Lordose/diagnóstico por imagem , Lordose/fisiopatologia , Masculino , Cervicalgia/etiologia , Procedimentos Ortopédicos/métodos , Prognóstico , Radiografia/métodos , Valores de Referência , Estudos Retrospectivos , Escoliose/complicações , Escoliose/cirurgia
20.
J Neurosurg Spine ; 23(1): 42-8, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25909274

RESUMO

OBJECT: The purpose of this study was to determine the efficacy of a modified vertebral column resection for the treatment of thoracolumbar angular kyphosis. METHODS: A total of 13 patients (8 male, 5 female) with thoracolumbar kyphosis (kyphotic angle > 60°) were included in this study (Group A). There were 3 patients with failure of spinal formation (Type 1 deformity), 6 patients with old thoracic or lumbar compression fracture, and 4 patients with old spinal tuberculosis (including 1 case of T3-5 vertebral malunion). The average preoperative kyphotic angle was 67.3° (range 62°-75°). Each patient underwent an expanded eggshell procedure combined with the closing-opening technique for the treatment of thoracolumbar angular kyphosis. Sixteen patients who were previously treated with a closing-opening wedge osteotomy in the same spine classification group (kyphotic angle > 60°) were used as a control group (Group B). RESULTS: In Group A, the average (± SD) operative time was 400 ± 60 minutes, and the average blood loss was 960 ± 120 ml. There were no surgery-related complications observed during or after the operations. The average local kyphotic angle was 20.3° (range 18°-24.5°), and the average correction rate was 68.7%. In Group B, the average operative time was 470 ± 90 minutes, and the average blood loss was 2600 ± 1600 ml (range 1200-8200 ml). There were segmental vessels and spinal canal venous plexus injury in 1 case, spinal cord injury in 1 case, dural tearing in 2 cases, pleural rupture in 2 cases, and hemothorax and pneumothorax in 1 case. Each patient had more than 2 years of follow-up. At the latest follow-up examination, the average regional kyphotic angle was 19.9° ± 9.1° (range 19°-34°), and there was no significant loss of correction (p > 0.05). There was greater blood loss and a higher complication rate in Group B than in Group A (p < 0.05). CONCLUSIONS: An expanded eggshell procedure combined with the closing-opening technique for the treatment of thoracolumbar angular kyphosis resulted in significant reduction of the kyphotic angle, few complications, and good follow-up results. However, a larger series of patients and long-term follow-up results is still required to verify the effectiveness and safety of this method.


Assuntos
Cifose/cirurgia , Vértebras Lombares/cirurgia , Procedimentos Neurocirúrgicos , Vértebras Torácicas/cirurgia , Adolescente , Adulto , Feminino , Humanos , Cifose/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Medição da Dor , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
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