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Mutations in COL1A1/A2 and CREB3L1 are associated with oligodontia in osteogenesis imperfecta.

COL1A1/A2 和 CREB3L1 的突变与成骨不全症中的少牙症相关。

  • 影响因子:4.06
  • DOI:10.1186/s13023-020-01361-4
  • 作者列表:"Andersson K","Malmgren B","Åström E","Nordgren A","Taylan F","Dahllöf G
  • 发表时间:2020-03-31

BACKGROUND:Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by an increased tendency for fractures throughout life. Autosomal dominant (AD) mutations in COL1A1 and COL1A2 are causative in approximately 85% of cases. In recent years, recessive variants in genes involved in collagen processing have been found. Hypodontia (< 6 missing permanent teeth) and oligodontia (≥ 6 missing permanent teeth) have previously been reported in individuals with OI. The aim of the present cross-sectional study was to investigate whether children and adolescents with OI and oligodontia and hypodontia also present with variants in other genes with potential effects on tooth development. The cohort comprised 10 individuals (7.7-19.9 years of age) with known COL1A1/A2 variants who we clinically and radiographically examined and further genetically evaluated by whole-genome sequencing. All study participants were treated at the Astrid Lindgren Children's Hospital at Karolinska University Hospital, Stockholm (Sweden's national multidisciplinary pediatric OI team). We evaluated a panel of genes that were associated with nonsyndromic and syndromic hypodontia or oligodontia as well as that had been found to be involved in tooth development in animal models. RESULTS:We detected a homozygous nonsense variant in CREB3L1, p.Tyr428*, c.1284C > A in one boy previously diagnosed with OI type III. COL1A1 and COL1A2 were the only two genes among 9 individuals which carried a pathogenic mutation. We found rare variants with unknown significance in several other genes related to tooth development. CONCLUSIONS:Our findings suggest that mutations in COL1A1, COL1A2, and CREB3L1 may cause hypodontia and oligodontia in OI. The findings cannot exclude additive effects from other modifying or interacting genes that may contribute to the severity of the expressed phenotype. Larger cohorts and further functional studies are needed.


背景: 成骨不全症 (OI) 是一种异质性结缔组织疾病,其特征是终生骨折倾向增加。在大约 85% 的病例中,COL1A1 和 COL1A2 的常染色体显性 (AD) 突变是致病因素。近年来,在参与胶原加工的基因中发现了隐性变异。以前在 OI 个体中报道过缺牙 (<6 颗恒牙缺失) 和少牙 (≥ 6 颗恒牙缺失)。本横断面研究的目的是调查 OI 和少牙和缺牙的儿童和青少年是否也存在对牙齿发育有潜在影响的其他基因的变异。该队列由 10 例已知 COL1A1/A2 变异的个体 (7.7-19.9 岁) 组成,我们通过全基因组测序对其进行了临床和影像学检查并进一步进行了遗传学评价。所有研究参与者均在斯德哥尔摩卡罗林斯卡大学医院的 Astrid Lindgren 儿童医院接受治疗 (瑞典国家多学科儿科 OI 团队)。我们在动物模型中评估了一组与非综合征性和综合征性缺牙或少牙症相关的基因,以及已发现参与牙齿发育的基因。 结果: 我们在 1 例既往诊断为 OI ⅲ 型的男孩中检测到 CREB3L1,p.Tyr428 *,c.1284C> a 纯合无义变异。COL1A1 和 COL1A2 是 9 个个体中仅有的两个携带致病性突变的基因。我们在与牙齿发育相关的其他几个基因中发现了意义未知的罕见变异。 结论: 我们的研究结果表明,COL1A1 、 COL1A2 和 CREB3L1 的突变可能导致 OI 的缺牙和少牙。该发现不能排除其他修饰或相互作用基因的加性效应,这些基因可能有助于表达表型的严重程度。需要更大的队列和进一步的功能研究。



作者列表:["Ghosh, Koushik","Salmon, Lucy J.","Heath, Emma","Pinczewski, Leo A.","Roe, Justin P."]

METHODS:Purpose To determine outcomes of transphyseal ACL reconstruction using a living parental hamstring tendon allograft in a consecutive series of 100 children. Methods One hundred consecutive juveniles undergoing ACL reconstruction with a living parental hamstring allograft were recruited prospectively and reviewed 2 years after ACL reconstruction with IKDC Knee Ligament Evaluation, and KT1000 instrumented laxity testing. Skeletally immature participants obtained annual radiographs until skeletal maturity, and long leg alignment radiographs at 2 years. Radiographic Posterior tibial slope was recorded. Results Of 100 juveniles, the median age was 14 years (range 8–16) and 68% male. At surgery, 30 juveniles were graded Tanner 1 or 2, 21 were Tanner 3 and 49 were Tanner 4 or 5. There were no cases of iatrogenic physeal injury or leg length discrepancy on long leg radiographs at 2 years, despite a median increase in height of 8 cm. Twelve patients had an ACL graft rupture and 9 had a contralateral ACL injury. Of those without further ACL injury, 82% returned to competitive sports, IKDC ligament evaluation was normal in 52% and nearly normal in 48%. The median side to side difference on manual maximum testing with the KT1000 was 2 mm (range − 1 to 5). A radiographic PTS of 12° or more was observed in 49%. Conclusions ACL reconstruction in the juvenile with living parental hamstring tendon allograft is a viable procedure associated with excellent clinical stability, patient-reported outcomes and return to sport over 2 years. Further ACL injury to the reconstructed and the contralateral knee remains a significant risk, with identical prevalence observed between the reconstructed and contralateral ACL between 12 and 24 months after surgery. Level of evidence III (Cohort Study).

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作者列表:["Skvortsov, D.","Kaurkin, S.","Goncharov, E.","Akhpashev, A."]

METHODS:Purpose The purpose of the study was to investigate the biomechanics of walking and of the knee joint in the acute phase of ACL injury. Methods We examined 18 patients with acute ACL injuries and 20 healthy adults as controls. The biomechanics of the knee joint and of walking was assessed by 5 inertial sensors fixed with special cuffs to the lower back, the lower third of the thigh, and the lower third of the shank of the right and left legs. The movements and temporal characteristics were recorded while the subject was walking 10 m at a comfortable pace. Based on the results of examination, the patients were divided into two groups: with severe function impairment (6 patients) and with moderate function impairment (12 patients). Results It was found that in the first days post-trauma, not only the knee function was reduced, but the function of the entire lower limb as well. This led to a functional asymmetry. The kinematics of movements in the joints changed in accordance with slower walking. The walking became not only slower, but it was also associated with a decreased impact load in the weight acceptance phase. At later dates, the functional impairments were less pronounced. The total range of flexion motion did not exceed 20 degrees in the first group and 55 degrees in the second one. The injured joint developed functional immobilization within the first days post-injury. This was a guarding response by additional muscle strain to prevent unusual and limit physiological movements in the knee joint. The movements in the knee joint while walking were of small amplitude, rocking, and occurred only under load. The amplitude of the main flexion in the swing phase was reduced. Conclusion The stage of an ACL injury should be assessed not only based on the time post-trauma, but also taking account of the functional parameter—the knee range of flexion while walking. According to our findings, the only factor that had influenced the functional condition of the KJ was the duration of joint immobilization after trauma.

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作者列表:["Theopold, Jan","Schleifenbaum, Stefan","Georgi, Alexander","Schmidt, Michael","Henkelmann, Ralf","Osterhoff, Georg","Hepp, Pierre"]

METHODS:Purpose Numerous techniques have been described for the tibial-sided graft preparation in anterior cruciate ligament (ACL) reconstruction. The use of less suture material for graft preparation is thought to improve ingrowth and to reduce the risk for infection. At the same time, the suture construct should be strong enough to resist the surgeon’s pull during tensioning of the transplant. Methods In total, 39 fresh-frozen procine deep flexor tendons were used and prepared as four-strand grafts. In the three-suture group ( n  = 19), graft preparation was performed using three tibial-sided sutures, with each tendon end sutured separately. In the one-suture group ( n  = 20), a modified graft preparation using only one tibial-sided suture was applied. Each sample underwent load-to-failure testing ( N _max) after cyclic pre-loading. To estimate intraoperative tension forces acting on the tibial-sided suture constructs, the maximal tension force of 26 volunteers on such a construct was measured using a load cell. Results The biomechanical testing of the two different suture constructs showed a significantly higher load-to-failure for the three-suture group (711 N ± 91 N) compared to the one-suture group (347 N ± 24 N) ( p  = 0.0001). In both groups, the mode of failure was a tear of the suture in all samples. A failure of the suture–tendon interface was not observed in any case. The median maximal tension force on the construct applied by the 26 volunteers was 134 N (range 73–182 N). Conclusion The presented single-suture tendon graft preparation resisted to smaller failure loads than the conventional three-suture technique. However, no failures in the suture–tendon interface were seen and the failure loads observed were far beyond the tension forces that can be expected intraoperatively. Hence, the single-suture graft preparation technique may be a valuable alternative to the conventional technique.

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