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1.
BMC Musculoskelet Disord ; 22(1): 165, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568117

RESUMO

PURPOSE: To analyze how pedicle subtraction osteotomy (PSO) treatment of severe Scheuermann thoracolumbar kyphosis (STLK) using pedicle screw instrumentation affects sagittal spinopelvic parameters. BACKGROUND: The medical literature on the post-surgical effects of treatments such as Ponte osteotomy is limited, but suggests few effects on spinopelvic profiles. Currently, there is no research regarding changes in sagittal spinopelvic alignment upon PSO treatment in STLK patients. METHODS: We performed a retrospective study on 11 patients with severe STLK. These patients underwent posterior-only correction surgeries with PSO and pedicle screw instrumentation between 2012 to 2017 in a single institute. Patients were measured for the following spinopelvic parameters: global kyphosis (GK), thoracic kyphosis (TK), thoracolumbar kyphosis (TL), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), pelvic tile (PT), sacral slope (SS), and administered a Scoliosis Research Society-22 questionnaire (SRS-22) pre-operation, post-operation and at final follow-up. RESULTS: GK improved from a median of 74.1° to 40.0° after surgery, achieving a correction rate of 48.8% with a median correction loss of 0.8°. TK, TL and LL all showed significant difference (P < 0.05) and SVA improved 22.7 (11.6, 30.9) mm post operation. No significant difference was found in pelvic parameters (PI, PT, SS, all P < 0.05). The absolute value of LL- PI significantly improved from a median of 26.5° pre-operation to 6.1° at the final follow-up. 72.7% in this series showed an evident trend of thoracic and lumbar apices migrating closer to ideal physiological segments after surgery. Self-reported scores of pain, self-image, and mental health from SRS-22 revealed significant improvement at final follow-up (all P < 0.05). CONCLUSIONS: PSO treatment of severe STLK with pedicle screw instrumentation can improve spine alignment and help obtain a proper alignment of the spine and the pelvis.

2.
Global Spine J ; : 2192568221989291, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33611986

RESUMO

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: We aimed to evaluate the safety and validity of posterior vertebral column resection (pVCR) for severe thoracolumbar kyphosis (TLK) in the achondroplasia (ACH) patients. METHODS: Seven ACH patients (male: female = 6:1) who underwent pVCR procedures due to severe TLK from December 2008 to December 2017 in the authors' hospital were included in this retrospective study. Their mean follow-up duration was 67 ± 35 months. Their clinical characteristics, radiologic characteristics, surgical characteristics and surgical complications were reviewed. RESULTS: A total of 8 vertebrae were removed with an average of 5 ± 2 levels of decompression and 9 ± 2 segments instrumented. The mean correction rates of TLKs and the main curves were 73 ± 15% and 87 ± 6%, respectively. Five patients (71%) had preoperative neurological symptoms with a mean Japanese Orthopedic Association (JOA) score of 8 ± 3 points. Their neurological functions were all improved, with a recovery rate of 78 ± 32% for the JOA score at the last follow-up. Four patients (57%) suffered from surgical complications, including rod breakages (43%), neurological complications (28%), dural tears (14%), cerebrospinal fluid leaks (14%) and proximal junction kyphosis (14%). CONCLUSIONS: pVCR can offer a good correction for TLK and improve neurological function with extensive laminectomies in ACH patients. But the morbidity of surgical complications is relatively high. Therefore, it is a reserved surgical option for severe TLK in ACH patients by experienced spinal surgeons, especially with apical markedly hypoplastic vertebrae.

3.
J Int Med Res ; 49(2): 300060520979217, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33550895

RESUMO

The occurrence of a spinal epidural hematoma in patients with hemophilia A with high-titer VIII inhibitors is extremely rare and intractable. A 15-year-old male patient presented to our institution with acute back pain and progressive sensorimotor disorder of the bilateral lower extremities. He had hemophilia A with high-titer VIII inhibitors and had experienced recurrent hemorrhagic episodes for many years. Prompt magnetic resonance imaging revealed a spinal epidural hematoma. We administered bypassing agent therapy with prothrombin complex concentrates and performed intensive neurological monitoring. The neurological dysfunction improved with days, and the patient recovered completely within 3 weeks. Magnetic resonance imaging 1 year later showed that the hematoma had been completely absorbed. Spinal epidural hematomas in patients with hemophilia A with high-titer inhibitors can be successfully treated using prothrombin complex concentrates. Multidisciplinary discussions based on intensive neurological monitoring should be performed as early in the clinical course as possible.

4.
BMC Musculoskelet Disord ; 22(1): 13, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402158

RESUMO

BACKGROUND: To assess the risk factors for blood transfusion in a great number of adolescent cases with different types of scoliosis who received scoliosis surgery. METHODS: Data of patients who were diagnosed as scoliosis and received one-stage posterior correction and spinal fusion from January 2014 to December 2017 were prospectively collected and retrospectively analyzed. Patients' demographic characteristics, segments of spinal fusion, Cobb angle of the major curve,osteotomy pattern, preoperative and postoperative levels of hemoglobin, and allogeneic blood transfusion (ABT) were recorded and analyzed. RESULTS: In this study, 722 cases with adolescent scoliosis were included, of whom 32.8% (237/722) received ABT. Risk factors included diagnosis: neurofibromatosis (OR = 5.592), syndromic (OR = 3.029),osteotomy: Ponte osteotomy (OR = 5.997), hemivertebrae resection (OR = 29.171), pedicle subtraction osteotomy (PSO)(OR = 8.712), vertebral column resection (VCR)(OR = 32.265);fusion segments (OR = 1.224) and intraoperative blood loss (OR = 1.004). In the subgroup analysis of cases with idiopathic scoliosis, Ponte osteotomy (OR = 6.086), length of segments of spinal fusion (OR = 1.293), and intraoperative blood loss (OR = 1.001) were found as risk factors for ABT. Results of receiver operating characteristic (ROC) curve analysis revealed that length of segments of spinal fusion equal to 11.5 vertebrae was the best cutoff value for cases with idiopathic scoliosis who did not receive osteotomy in both ABT group and non-ABT group. In the subgroup analysis of congenital scoliosis, Ponte osteotomy (OR = 5.087), hemivertebra resection (OR = 5.457), PSO (OR = 4.055), VCR (OR = 6.940), and intraoperative blood loss (OR = 1.004) were risk factors for ABT. CONCLUSIONS: Method of diagnosis, osteotomy pattern, segments of spinal fusion, and intraoperative blood loss were risk factors for ABT in cases with adolescent scoliosis. In cases with idiopathic scoliosis, Ponte osteotomy and segments of spinal fusion longer than 11.5 vertebrae were risk factors for ABT. In cases with congenital scoliosis, osteotomy pattern was the main risk factor for ABT. LEVEL OF EVIDENCE: Level III.

5.
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.

6.
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.

7.
Spine J ; 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32805433

RESUMO

BACKGROUND CONTEXT: The lowest instrumented vertebra (LIV) determination in Lenke type 5 Adolescent Idiopathic Scoliosis (AIS) requires a thorough understanding and prediction of the correction force on the LIV from coronal, sagittal, and axial plane. Although many LIV selection criteria have been reported, none of them comprehensively evaluated the multidimensional characteristics of the LIV till now. PURPOSE: To develop and evaluate our LIV selection criteria in Lenke type 5 AIS patients using pedicle screw system via posterior approach. STUDY DESIGN: A retrospective study. PATIENT SAMPLE: All consecutive patients with Lenke 5 curves who were treated with one-stage selective lumbar fusion using complete pedicle screw system in our center from January 2006 to December 2017, with minimum 2-year follow-up. OUTCOME MEASURES: Age, gender and Risser grade, fused levels, operating time, intraoperative blood loss, complications, and Scoliosis Research Society (SRS)-22 questionnaires outcome were recorded. Coronal, sagittal, and axial parameters were measured from plain radiographs. METHODS: A total of 138 consecutive patients with Lenke 5 curves treated with selective lumbar fusion were retrospectively analyzed, with minimum 2-year follow-up. Our LIV selection criteria include: (1) the most cephalad vertebrae touched by central sacrum vertical line (CSVL); (2) Nash-Moe rotation being equal or less than grade I on the standing AP radiograph; (3) CSVL cross between the two pedicles of LIV on concave bending film; (4) not at the apex of kyphosis. Radiographic data, operative data, perioperative complications and SRS-22 outcomes were collected and analyzed. RESULTS: The mean follow-up period was 50.9±24.7 months. The thoracolumbar/lumbar curve was corrected from 46.9°±8.9° before surgery to 5.5°±2.6° at the final follow-up. The C7-CSVL was 19.7±6.2 mm before surgery and 5.2±3.4 mm at the final follow-up. The LIV translation was corrected from 22.3 ±5.4 mm before surgery to 4.8 ± 2.6 mm at the final follow-up, with the correction rate of 78.4%. The LIV tilt was corrected from 21.6 ± 4.4° before surgery to 2.6 ± 2.3° at the final follow up, with the correction rate of 87.9%. Our LIV saved 0.3 level than SRS-last barely touching vertebra, 0.6 level than SRS-last substantially touching vertebra, 0.9 level than neutral vertebra, and 1.4 level than stable vertebra. CONCLUSION: The present study indicates using our LIV criteria, our study achieved the correction rate of thoracolumbar/lumbar curve as 88.9%, with the rate of adding on or coronal imbalance as 8.7% (12/138). The criteria may provide important guidance for preoperative decision-making in Lenke 5 AIS patients, and more multicenter prospective studies with larger samples are needed to further validate the findings of this study.

8.
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
9.
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.

10.
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.

11.
Chin Med J (Engl) ; 133(4): 483-493, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31972723

RESUMO

Etiology of adolescent idiopathic scoliosis (AIS), a complicated three-dimensional spinal deformity with early-onset, receives continuous attention but remains unclear. To gain an insight into AIS pathogenesis, this review searched PubMed database up to June 2019, using key words or medical subject headings terms including "adolescent idiopathic scoliosis," "scoliosis," "pathogenesis," "etiology," "genetics," "mesenchymal stem cells," and their combinations, summarized existing literatures and categorized the theories or hypothesis into nine aspects. These aspects include bone marrow mesenchymal stem cell studies, genetic studies, tissue analysis, spine biomechanics measurements, neurologic analysis, hormone studies, biochemical analysis, environmental factor analysis, and lifestyle explorations. These categories could be a guidance for further etiology or treatment researches to gain inspiration.

12.
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.

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.
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
15.
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
16.
J Bone Joint Surg Am ; 101(15): 1357-1365, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31393426

RESUMO

BACKGROUND: There have been many reports on the treatment of congenital kyphoscoliosis. However, congenital deformities in the cervicothoracic spine (C7-T1) have not been well described because of the rarity of these conditions. METHODS: The medical records and imaging studies of 25 children who were treated with 360° osteotomy for congenital deformities in the cervicothoracic spine (C7-T1) at a mean age of 11.4 years were reviewed. RESULTS: All 25 children presented with torticollis; 4 presented with neck pain; 10, with facial asymmetry; and 3, with preoperative neurological deficits. Twenty-three patients had congenital deformities in other regions of the spine. Six patients had a total of 8 intraspinal deformities. On average, the cervicothoracic curve was corrected from 53° preoperatively to 14° at the latest follow-up, the segmental kyphosis was corrected from 25° to 12°, and the head tilt improved from 25° to 5°. Nineteen patients had a total of 28 complications, including 1 transient cord injury together with a permanent C8 nerve root injury, 11 transient nerve root injuries, 1 transient Horner syndrome, 9 cases of decompensation of a compensatory curve, 2 implant failures, 2 cases of hemothorax, 1 dural tear, and 1 case of delayed wound-healing. CONCLUSIONS: Most congenital cervicothoracic deformities are fixed, and early surgical intervention may be needed. A 360° osteotomy is indicated for this type of rigid deformity and may provide satisfactory correction. However, 360° osteotomy in the cervicothoracic spine (C7-T1) is technically demanding with a higher risk of nerve root injuries, although most injuries tend to be transient. If the compensatory thoracic curve is severe and rigid, 1-stage or staged surgery in this region may be required. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Cifose/cirurgia , Osteotomia/métodos , Amplitude de Movimento Articular/fisiologia , Escoliose/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Criança , Estudos de Coortes , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/cirurgia , Bases de Dados Factuais , Feminino , Humanos , Cifose/congênito , Cifose/diagnóstico por imagem , Masculino , Duração da Cirurgia , Osteotomia/efeitos adversos , Posicionamento do Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Cuidados Pré-Operatórios/métodos , Prognóstico , Recuperação de Função Fisiológica , Estudos Retrospectivos , Medição de Risco , Escoliose/congênito , Escoliose/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Torcicolo/diagnóstico , Torcicolo/etiologia , Torcicolo/cirurgia
17.
Comput Struct Biotechnol J ; 17: 954-962, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360334

RESUMO

Genetic factors play a substantial role in the etiology of skeletal diseases, which involve 1) defects in skeletal development, including intramembranous ossification and endochondral ossification; 2) defects in skeletal metabolism, including late bone growth and bone remodeling; 3) defects in early developmental processes related to skeletal diseases, such as neural crest cell (NCC) and cilia functions; 4) disturbance of the cellular signaling pathways which potentially affect bone growth. Efficient and high-throughput genetic methods have enabled the exploration and verification of disease-causing genes and variants. Animal models including mouse and zebrafish have been extensively used in functional mechanism studies of causal genes and variants. The conventional approaches of generating mutant animal models include spontaneous mutagenesis, random integration, and targeted integration via mouse embryonic stem cells. These approaches are costly and time-consuming. Recent development and application of gene-editing tools, especially the CRISPR/Cas9 system, has significantly accelerated the process of gene-editing in diverse organisms. Here we review both mice and zebrafish models of human skeletal diseases generated by CRISPR/Cas9 system, and their contributions to deciphering the underpins of disease mechanisms.

18.
Spine J ; 19(9): 1584-1596, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31100472

RESUMO

BACKGROUND CONTEXT: Coexistence of abnormal skeletal growth and reduced bone mineral density in the context of adolescent idiopathic scoliosis (AIS) suggests disturbed bone metabolism existing in such patients. Our previous study suggested increased proliferation ability and decreased osteogenic differentiation ability of bone marrow mesenchymal stem cells (BM-MSCs) of AIS. PURPOSE: To explore the differential miRNA expression profile, Go (gene ontology) terms and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in BM-MSCs of AIS and non-AIS controls were conducted using microarray approach and bioinformatics analyses. STUDY DESIGN: miRNA microarray approach and bioinformatics analysis. METHODS: The differentially expressed miRNAs (DEMs) of BM-MSCs from AIS patients compared with those from healthy individuals were analyzed using a microarray analysis. Comprehensive bioinformatics analyses were then used to enrich datasets for gene ontology and pathway. Based on the interaction network analysis of DEMs contained in significant pathways, 12 potential crucial miRNAs were selected for validation by RT-PCR. RESULTS: The study identified 54 previously unrecognized DEMs (12 upregulated, 42 downregulated) in BM-MSCs from AIS patients. These miRNAs are involved in multiple biological processes, including small GTPase-mediated signal transduction, DNA-dependent transcription, cytokinesis, cell adhesion, transmembrane transport, response to hypoxia, etc. Pathway analysis of these new identified miRNAs revealed dysregulated MAPK signaling pathway, PI3K-Akt signaling pathway, calcium signaling pathway, Notch signaling pathway, and ubiquitin-mediated proteolysis pathway, all of which have been reported to play important role in regulating the osteogenic or adipogenic differentiation of MSCs. Furthermore, interaction networks analysis indicated that seven most significant central miRNAs, including miR-17-5p, miR-106a-5p, miR-106b-5p, miR-16-5p, miR-93-5p, miR-15a-5p, and miR-181b-5p may play essential roles in AIS pathogenesis and accompanied osteopenia. CONCLUSION: The current study reports the differential miRNAs expression profiles of BM-MSCs from AIS patients and related pathways for the first time. The identification of these candidate miRNAs provides a deep insight into the pathogenesis of AIS and the accompanying generalized osteopenia.


Assuntos
Células da Medula Óssea/metabolismo , Redes Reguladoras de Genes , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Escoliose/genética , Adolescente , Feminino , Humanos , Masculino , Osteogênese , Escoliose/metabolismo
19.
Spine J ; 19(9): 1518-1528, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30940502

RESUMO

BACKGROUND: The original Peking Union Medical College (PUMC) classification of adolescent idiopathic scoliosis (AIS) is one system to combine each type with corresponding surgical fusion guidance, presenting comparable interobserver reliability, and reproducibility with Lenke classification. However, during its application in previous over 10 years, we found 2 main problems of this classification, which required modification. PURPOSE: (1) To evaluate the interobserver and intraobserver reliability, (2) to assess the effects of the added fusion criteria of proximal thoracic (PT) curve on improving postoperative shoulder balance of the modified PUMC classification of AIS. STUDY DESIGN/SETTING: Retrospective analysis of our AIS cohort and prospective validation of its effectiveness. PATIENT SAMPLE: Fifty sets of preoperative radiographs of AIS patients were randomly chosen from our AIS database. Furthermore, 46 consecutive AIS cases with PT curve were enrolled who underwent surgeries in our center from July 2007 to July 2013, with at least 2-year follow-up. OUTCOME MEASURES: The classification results of 50 sets of preoperative radiographs by 5 surgeons. The shoulder balance was evaluated using radiographic shoulder height. METHODS: Five surgeons independently evaluated and classified presurgical radiographs of 50 AIS patients based on the modified PUMC classification. Inter- and intraobserver reliabilities were calculated. Furthermore, the post-op shoulder balance was investigated in 46 consecutive cases of AIS with PT curve who were treated strictly based on the modified PUMC classification. RESULTS: The Kappa coefficients of inter- and intraobserver reliability of the overall modified PUMC classification are 0.889 and 0.865, respectively. The Kappa coefficients of inter- and intraobserver reliability for the type II are 0.791 and 0.746, respectively. In addition, the shoulder balance rate of the 46 AIS patients with PT curve at the final follow-up was 95.7%. CONCLUSIONS: Modified PUMC classification presents incremental improvement compared to our original published version, with high interobserver and intraobserver reliability and better performance of postoperative shoulder balance. Furthermore, the modified PUMC classification provides corresponding surgical fusion guidance for each subtype. Multicenter prospective studies with larger samples are still needed to further improve this system.


Assuntos
Guias de Prática Clínica como Assunto , Radiografia/normas , Escoliose/classificação , Adolescente , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Escoliose/patologia , Escoliose/cirurgia , Fusão Vertebral/efeitos adversos , Fusão Vertebral/métodos , Fusão Vertebral/normas
20.
J Neurosurg Pediatr ; : 1-8, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875682

RESUMO

OBJECTIVEConcerns remain over the influence of pedicle screw instrumentation on the growth potential of an immature spine. Previous studies have reported discrepancies between animal experiments and clinical studies. The authors' objective was to explore the influence of pedicle screw instrumentation on the growth of an immature spine at a very young age.METHODSIndividuals who met the authors' criteria were included. Anteroposterior diameter of the vertebral body; pedicle length on both sides; and anteroposterior diameter, transverse diameter, and area of the spinal canal were measured on CT images before surgery and at the final follow-up. Parameters of instrumented vertebrae and adjacent noninstrumented vertebrae were compared. The growth value and growth percentage of each parameter were calculated. Subgroup comparisons were made in thoracic vertebrae and lumbar vertebrae. Statistical analyses were performed.RESULTSThirteen patients with a congenital spinal deformity were included in the study. The average age at surgery was 3.4 (range 2-5) years, and the average follow-up was 7.2 (range 5-11) years. Osteotomy and short instrumentation with pedicle screws were performed in each case. A total of 69 segments were measured, including 43 instrumented vertebrae and 26 immediately adjacent noninstrumented vertebrae. Significant increases in all parameters were noted at the final follow-up. In instrumented vertebrae, growth of the pedicle length and the anteroposterior diameter and area of the spinal canal increased significantly, while growth of the anteroposterior diameter of the vertebral body decreased significantly compared with noninstrumented vertebrae. Similar results were noted in the lumbar region. The shape-change phenomenon was found in noninstrumented vertebrae but was not apparent in instrumented vertebrae.CONCLUSIONSPedicle screw instrumentation may slow down growth of the vertebral body, indirectly speed up growth of the spinal canal, and hinder the shape-change phenomenon of the lumbar spinal canal. However, the influences were quite slight, and significant development did occur in instrumented vertebrae. Therefore, pedicle screw instrumentation may not have much effect on the growth of immature vertebrae in children younger than 5 years.

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