Abnormal Bone Collagen Cross-Linking in Osteogenesis Imperfecta/Bruck Syndrome Caused by Compound Heterozygous PLOD2 Mutations.

Bruck syndrome (BS) is a congenital disorder characterized by joint flexion contractures, skeletal dysplasia, and increased bone fragility, which overlaps clinically with osteogenesis imperfecta (OI). On a genetic level, BS is caused by biallelic mutations in either FKBP10 or PLOD2. PLOD2 encodes the lysyl hydroxylase 2 (LH2) enzyme, which is responsible for the hydroxylation of cross-linking lysine residues in fibrillar collagen telopeptide domains. This modification enables collagen to form chemically stable (permanent) intermolecular cross-links in the extracellular matrix. Normal bone collagen develops a unique mix of such stable and labile lysyl-oxidase-mediated cross-links, which contribute to bone strength, resistance to microdamage, and crack propagation, as well as the ordered deposition of mineral nanocrystals within the fibrillar collagen matrix. Bone from patients with BS caused by biallelic FKBP10 mutations has been shown to have abnormal collagen cross-linking; however, to date, no direct studies of human bone from BS caused by PLOD2 mutations have been reported. Here the results from a study of a 4-year-old boy with BS caused by compound heterozygous mutations in PLOD2 are discussed. Diminished hydroxylation of type I collagen telopeptide lysines but normal hydroxylation at triple-helical sites was found. Consequently, stable trivalent cross-links were essentially absent. Instead, allysine aldol dimeric cross-links dominated as in normal skin collagen. Furthermore, in contrast to the patient's bone collagen, telopeptide lysines in cartilage type II collagen cross-linked peptides from the patient's urine were normally hydroxylated. These findings shed light on the complex mechanisms that control the unique posttranslational chemistry and cross-linking of bone collagen, and how, when defective, they can cause brittle bones and related connective tissue problems. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Delayed Postoperative Neurologic Deficits in Spinal Deformity Surgery.

STUDY DESIGN: A cross-sectional survey of surgeon members of the Scoliosis Research Society (SRS). OBJECTIVE: This study sought to characterize the incidence, clinical presentation, diagnostic workup, treatment, and neurologic prognosis following delayed postoperative neurologic deficit (DPND) in patients undergoing spinal deformity surgery. SUMMARY OF BACKGROUND DATA: DPND is a potentially devastating condition following spinal surgery, characterized by the development of a neurological deficit within hours or days of the surgical procedure. To date, only case reports and small case series have been published on the topic. METHODS: We developed a survey to characterize DPND following spinal deformity surgery. This survey was distributed to surgeon members of the SRS through email and standard mail. The overall response rate was 38% (352/929). RESULTS: Our results suggest an estimated DPND incidence of 1 of 9910 cases (0.01%). Eighty-one surgeons (23%) experienced at least 1 DPND in the past 10 years (92 total cases). Most common diagnoses were scoliosis (69%), kyphosis (23%), and spondylolisthesis (14%); 20% were revision surgeries. The number of hours to deficit onset was as follows: 1 to 12 (36%), 13 to 24 (27%), 25 to 48 (27%), more than 48 (10%). The most commonly cited sources of injury included ischemic injury (38%) and cord compression (15%). Forty-one percent experienced complete neurologic recovery, 26% partial, and 33% no recovery. Twenty-one percent of patients achieved final neurologic status within 1 week, 38% by 1 month, and 73% by 6 months. Patients with compression-related DPND had a significantly greater likelihood of experiencing some neurologic recovery (≥1 ASIA Grade) than ischemia-related DPND (86% versus 51%, P = 0.049). CONCLUSIONS: DPND occurs at an estimated incidence of 0.01%. Sixty-three percent of DPND cases occurred within the first 24 hours and 90% within 48 hours. Complete (41%) or partial (26%) neurologic recovery may be expected, especially in compression-related DPND, emphasizing the need for perioperative vigilance, prompt recognition, and early intervention. LEVEL OF EVIDENCE: 4.

Detection and Nonoperative Management of Pediatric Developmental Dysplasia of the Hip in Infants up to Six Months of Age.

Detection and Nonoperative Management of Pediatric Developmental Dysplasia of the Hip in Infants up to Six Months of Age: Evidence-Based Clinical Practice Guideline is based on a systematic review of the current scientific and clinical research. This guideline has been endorsed by the Society of Diagnostic Medical Sonography, the Society for Pediatric Radiology, American Academy of Pediatrics, and the Pediatric Orthopaedic Society of North America. The purpose of this clinical practice guideline is to help improve treatment and management based on the current evidence. This guideline contains nine recommendations, including both diagnosis and treatment. In addition, the work group highlighted the need for better research in the early diagnosis and treatment of developmental dysplasia of the hip.

Spine Computed Tomography Radiation Dose Reduction: Protocol Refinement Based on Measurement Variation at Simulated Lower Radiation Acquisitions.

STUDY DESIGN: Retrospective dose-simulation comparison. OBJECTIVE: To determine if sufficient detail for preoperative analysis of bony anatomy can be acquired at substantially lower doses than those typically used. SUMMARY OF BACKGROUND DATA: Computed tomography (CT) is a preoperative planning tool for spinal surgery. The pediatric population is at risk to express the harmful effects of ionizing radiation. Preoperative CT scans are presently performed at standard pediatric radiation doses not tailored for surgical planning. METHODS: We used the validated GE Noise Injection software to retrospectively modify existing spine and chest CT scans from 10 patients to create CT images that simulated a standard dose (100%), 50% dose, and 25% dose scans. 4 orthopedic surgeons and a pediatric radiologist, blinded to dose, measured minimum medial-lateral pedicle width and maximum anterior-posterior bony length along the axis of presumed pedicle screw placement. A total of 90 axial images were generated to create our sample set. Measurements were evaluated for accuracy, precision, and consistency. RESULTS: For any given rater, there was no clinically relevant difference between measurements at the different dose levels and no apparent degradation in precision at the different dose levels. Consistent variation was observed between raters, the likely result of individual differences in measurement approach. CONCLUSION: Spinal CT scans done for preoperative planning can be performed at 25% of current radiation doses without a loss in surgical planning measurement accuracy or precision. These 25% dose-reduced scans would have average Computed Tomography Dose Index volume dose levels of roughly 1.0 to 2.5 mGy (depending on patient size) and size-specific dose estimates of roughly 2.5 mGy representing a substantial dose savings compared to current practice for many sites. Standardization of consistent landmarks may be useful to further improve inter-rater concordance.

Injection-induced gluteus muscle contractures: diagnosis with the "reverse Ober test" and surgical management.

BACKGROUND: Adoption rates are increasing in the United States and other developed countries. A large proportion of adopted children have been found to have unsuspected medical diagnoses, including orthopedic problems. One condition, termed injection-induced gluteus maximus contracture, has been previously described in several case series and can be difficult to diagnose if unfamiliar with this condition. By reviewing the etiology and pathoanatomy of this problem, as well as the typical examination findings, including the near-pathognomonic-positive "reverse Ober test," treating providers will be better prepared to recognize and properly treat this condition. METHODS: This is a retrospective review of 4 patients treated at our institution for injection-induced gluteus maximus contracture. Patient history, physical examination findings, and treatment outcomes were recorded. All had undergone surgical treatment through a longitudinal incision along the posterior margin of the iliotibial band, with division of thickened, contracted gluteus tissue down to the ischial tuberosity. RESULTS: All 4 of the patients were adopted from orphanages in developing countries. Chief complaints of the patients varied, but physical examination findings were very consistent. Three of the 4 patients had undergone rotational osteotomies for presumed femoral retroversion before their diagnosis and treatment for injection-induced gluteus maximus contracture. All patients had concave, atrophic buttock contours and numerous punctate buttock scars. All walked with an out-toed gait and had marked apparent femoral retroversion. Each patient was found to have full hip adduction when the hip was extended but a hip abduction contracture when the hip was flexed. This finding of increasing abduction as an extended/adducted hip is flexed to 90 degrees is described as a positive "reverse Ober test." After surgical treatment, all hips could adduct to neutral from full extension to full flexion. CONCLUSIONS: Although common in some countries, such as Russia and China, injection-induced gluteus muscle contractures are seldom seen in the United States and other developed countries. Diagnosis of this condition can be difficult leading to inappropriate treatment. Knowledge of the clinical presentation typical of a gluteus contracture and of the pathognomonic finding of a "reverse Ober test" can facilitate an effective surgical procedure to correct the associated functional impairment. LEVEL OF EVIDENCE: Level IV: retrospective case series.

Best Practices in Intraoperative Neuromonitoring in Spine Deformity Surgery: Development of an Intraoperative Checklist to Optimize Response.

STUDY DESIGN: Consensus-based creation of a checklist and guideline. OBJECTIVE: To develop a consensus-based checklist to guide surgeon responses to intraoperative neuromonitoring (IONM) changes in patients with a stable spine and to develop a consensus-based best practice guideline for IONM practice in the United States. SUMMARY OF BACKGROUND DATA: Studies show that checklists enhance surgical team responses to crisis situations and improve patient outcomes. Currently, no widely accepted guidelines exist for the response to IONM changes in spine deformity surgery. METHODS: After a literature review of risk factors and recommendations for responding to IONM changes, 4 surveys were administered to 21 experienced spine surgeons and 1 neurologist experienced in IONM. Areas of equipoise were identified and the nominal group process was used to determine items to be included in the checklist. The authors reevaluated and modified the checklist at 3 face-to-face meetings over 12 months, including a period of clinical validation using a modified Delphi process. The group was also surveyed on current IONM practices at their institutions. This information and existing IONM position statements were used to create the IONM best practice guideline. RESULTS: Consensus was reached for the creation of 5 checklist headings containing 26 items to consider in the response to IONM changes. Consensus was reached on 5 statements for inclusion in the best practice guideline; the final guideline promotes a team approach and makes recommendations aimed at decreasing variability in neuromonitoring practices. CONCLUSIONS: The final products represent the consensus of a group of expert spine surgeons. The checklist includes the most important and high-yield items to consider when responding to IONM changes in patients with a stable spine, whereas the IONM guideline represents the group consensus on items that should be considered best practice among IONM teams with the appropriate resources.

Iatrogenic radiation exposure to patients with early onset spine and chest wall deformities.

STUDY DESIGN: Retrospective cohort series. OBJECTIVE: Characterize average iatrogenic radiation dose to a cohort of children with thoracic insufficiency syndrome (TIS) during assessment and treatment at a single center with vertically expandable prosthetic titanium rib. SUMMARY OF BACKGROUND DATA: Children with TIS undergo extensive evaluations to characterize their deformity. No standardized radiographical evaluation exists, but all reports use extensive imaging. The source and level of radiation these patients receive is not currently known. METHODS: We evaluated a retrospective consecutive cohort of 62 children who had surgical treatment of TIS at our center from 2001-2011. Typical care included obtaining serial radiographs, spine and chest computed tomographic (CT) scans, ventilation/perfusion scans, and magnetic resonance images. Epochs of treatment were divided into time of initial evaluation to the end of initial vertically expandable prosthetic titanium rib implantation with each subsequent epoch delineated by the next surgical intervention. The effective dose for each examination was estimated within millisieverts (mSv). Plain radiographs were calculated from references. Effective dose was directly estimated for CT scans since 2007 and an average of effective dose from 2007-2011 was used for scans before 2007. Effective dose from fluoroscopy was directly estimated. All doses were reported in mSv. RESULTS: A cohort of 62 children had a total of 447 procedures. There were a total of 290 CT scans, 4293 radiographs, 147 magnetic resonance images, and 134 ventilation/perfusion scans. The average accumulated effective dose was 59.6 mSv for children who had completed all treatment, 13.0 mSv up to initial surgery, and 3.2 mSv for each subsequent epoch of treatment. CT scans accounted for 74% of total radiation dose. CONCLUSION: Children managed for TIS using a consistent protocol received iatrogenic radiation doses that were on average 4 times the estimated average US background radiation exposure of 3 mSv/yr. CT scans comprised 74% of the total dose. LEVEL OF EVIDENCE: 3.

Classic bladder exstrophy: orthopaedic surgical considerations.

Classic bladder exstrophy is an embryologic malformation that results in complex deficiency of the anterior midline, with urogenital and skeletal manifestations. Urogenital reconstruction is a challenging procedure that can be facilitated by closure of the bony pelvic ring by an orthopaedic team. Surgical options include a multiyear staged approach and the single-stage complete repair for exstrophy. The goals of urologic surgery include closure of the bladder and abdominal wall with eventual bladder continence, preservation of renal function, and cosmetic and functional reconstruction of the genitalia. Pelvic osteotomy is done at the time of bladder closure in the patient in whom the anterior pelvis cannot be approximated without tension. Traction or spica casting is used postoperatively. Good outcomes are probable with appropriate management at specialized treatment centers.

VEPTR™ growing rods for early-onset neuromuscular scoliosis: feasible and effective.

BACKGROUND: The Vertical Expandable Prosthetic Titanium Rib (VEPTR™; Synthes North America, West Chester, PA) reportedly controls spinal deformity associated with constrictive chest wall conditions. QUESTIONS/PURPOSES: We asked whether spine-to-spine constructs using VEPTR™ instrumentation in combination with standard spinal instrumentation could be deployed to salvage failed rib-to-spine constructs used originally in patients with constricted chest walls and to primarily treat progressive spinal deformity without chest wall abnormalities. PATIENTS AND METHODS: Fifty patients were treated with VEPTR™ constructs for thoracic insufficiency syndrome at our center between 2001 and 2007. Fourteen of these 50 patients had placement of a spine-to-spine construct using a VEPTR™ implant in combination with standard spinal implants and are the subject of this retrospective review. Five had prior rib-based VEPTR™ or growing implants with an average of two failures before this surgery. Radiographic variables, preceding treatment, complications, and changes in ambulatory status, were recorded. The minimum followup was 2 years (mean, 35 months; range, 2-4 years). RESULTS: After an average of five expansions in these 14 patients, positive changes were recorded for Cobb angle, T1-S1 height, sagittal balance, and space available for the lung. Complications included two rod fractures, two superficial infections, and one deep infection with rod removal. CONCLUSIONS: VEPTR™ instrumentation as a spine-to-spine growing-rod construct demonstrated ease of implantation and expansion, with complication rates similar to other reported devices. This study suggests growing constructs using VEPTR™ can be used with relatively few complications and extends the potential uses of this instrumentation system.

Effects of anesthetic regimens and other confounding factors affecting the interpretation of motor evoked potentials during pediatric spine surgery.

Children undergoing corrective spine surgery are at risk of serious neurologic injury. Monitoring transcranial electric motor evoked potentials (TCeMEPs) during these procedures may identify and help prevent injury to motor pathways. The difficulty in obtaining consistent motor evoked potential (MEP) responses during pediatric spine surgery can result in part to the suppression of evoked responses caused by volatile inhalational anesthetics, elevated levels of propofol, and/or physiologic variables. Data obtained from 140 pediatric patients who underwent spine surgery with MEP monitoring were retrospectively analyzed and evaluated for age and anesthetic effects on stimulation variables. MEPs acquired under inhalational anesthetic agents required greater stimulation compared to intravenous propofol anesthesia. Additionally, the responses were more variable when inhalational agents were used. These effects were more prominent in younger age patients. The number of alerts of MEP loss or reduction related to anesthetic levels or blood pressure changes was higher under inhalational agents.

Efficacy of intraoperative neurologic monitoring in surgery involving a vertical expandable prosthetic titanium rib for early-onset spinal deformity.

BACKGROUND: The vertical expandable prosthetic titanium rib (VEPTR) device is used in the treatment of thoracic insufficiency syndrome and certain types of early-onset spinal deformity. The purpose of this study was to evaluate the risk of neurologic injury during surgical procedures involving use of the VEPTR and to determine the efficacy of intraoperative spinal cord neuromonitoring. METHODS: Data were collected prospectively during a multicenter study. Surgical procedures were divided into three categories: primary device implantation, device exchange, and device lengthening. Further retrospective evaluation was undertaken in cases of neurologic injury or changes detected with neuromonitoring. RESULTS: There were 1736 consecutive VEPTR procedures at six centers: 327 (in 299 patients) consisted of a primary device implantation, 224 were a device exchange, and 1185 were a device lengthening. Perioperative clinical neurologic injury was noted in eight (0.5%) of the 1736 cases: these injuries were identified after five (1.5%) of the 327 procedures for primary device implantation, three (1.3%) of the 224 device exchanges, and none of the 1185 device-lengthening procedures. Of the eight cases of neurologic injury, six involved the upper extremity and two involved the lower extremity. The neurologic deficit was temporary in seven patients and permanent in one patient, who had persistent neurogenic arm and hand pain. Intraoperative neuromonitoring demonstrated changes during six (0.3%) of the 1736 procedures: five (1.5%) of the 327 procedures for primary device implantation and one (0.08%) of the 1185 device-lengthening procedures. The surgery was altered in all six cases, with resolution of the monitoring changes in five cases and persistent signal changes and a neurologic deficit (upper-extremity brachial plexopathy) in one. Two patients had false-negative results of monitoring of somatosensory evoked potentials, and one had false-negative results of monitoring of somatosensory evoked potentials and motor evoked potentials during implant surgery; two had a brachial plexopathy and one had monoplegia postoperatively, with all three recovering. CONCLUSIONS: Neurologic injury during VEPTR surgery occurs much more frequently in the upper extremities than in the lower extremities. The rates of potential neurologic injuries (neurologic injuries plus instances of changes detected by monitoring) during primary implantation of the VEPTR (2.8%) and during exchange of the VEPTR (1.3%) justify the use of intraoperative neuromonitoring of the upper and lower extremities during those procedures. As neuromonitoring did not demonstrate any changes in children without a previous VEPTR-related monitoring change and there were no neurologic injuries during more than 1000 VEPTR-lengthening procedures, intraoperative neuromonitoring may not be necessary during those procedures in children without a history of a neurologic deficit during VEPTR surgery.

The use of polymerase chain reaction for the detection and speciation of bacterial bone and joint infection in children.

We evaluated 36 consecutive patients presenting with signs and symptoms of bacterial bone and joint infection and 10 control patients using bacterial cultures of blood and the presumed site of infection compared with polymerase chain reaction (PCR) techniques using a universal primer and restriction endonuclease digestion. Of the 28 patients with definitive clinical and/or laboratory evidence of bacterial infection, 16 patients had positive bacterial cultures and 12 were PCR-positive. Twenty of 28 patients were either PCR- or culture-positive. Nine of the 16 subjects who had culture-positive samples also had PCR-positive samples (8 positive for the same organism and 1 with 2 organisms identified by culture, but only a single organism by PCR. Six culture positive patients were PCR-negative. Of the 12 patients who were culture-negative, 4 had bacterial genomic material present indicating infection. We conclude that current PCR methods are not superior to standard bacterial culture methods when applied to children with presumed bone or joint infections, but that PCR may complement existing microbiologic cultures for detection of bone and joint infections in children.

Health-related quality of life in children with thoracic insufficiency syndrome.

BACKGROUND: The traditional techniques to treat thoracic insufficiency syndrome (TIS) are not able to stabilize or improve chest wall size or pulmonary function while allowing spine growth. To this end, vertical expandable prosthetic titanium rib (VEPTR) was specifically designed to treat TIS by allowing growth of the thoracic cavity and control/correction of spine deformity. The purpose of this study was to determine quality of life (QOL) of children with TIS and its impact on their parents before and after implantation of the VEPTR and also compare these results to those of healthy children. METHODS: As part of the original multicenter evaluation of the VEPTR, a Child Health Questionnaire (CHQ) was collected preoperatively on 45 patients who were subsequently treated with expansion thoracoplasty using the VEPTR. The average age was 8.2 +/- 2.6 years, and the parent form of the CHQ was filled out by the primary caretaker. Patients were divided into 3 diagnostic categories: rib fusion (n = 15), hypoplastic thorax syndromes (n = 17), and progressive spinal deformity (n = 13). RESULTS: There were significant differences between the study patients and healthy children in physical domains. Compared with parents of healthy children, parents of children with TIS experienced more limitations on their time and emotional lives due to their children's health problems. There were no significant differences in CHQ before and after the surgery except for a significant decrease in the self-esteem among a subgroup of patients with hypoplastic thorax syndromes. There were no significant differences in postoperative QOL between patients who had VEPTR-related complications and patients who did not have the complications. CONCLUSIONS: The children with TIS had lower physical scores and higher caregiver burden scores than healthy children. However, the scores in psychosocial domains were similar to those in healthy children. Our study demonstrated that QOL of children and burden of care in their parents remained the same after VEPTR instrumentation. Children's QOL seemed to be not affected by whether they had VEPTR-related complications or not.

Vertical expandable prosthetic titanium rib for thoracic insufficiency syndrome: a new method to treat an old problem.

PURPOSE: The vertical expandable prosthetic titanium rib (VEPTR) thoracoplasty is a new technique devised for the treatment children with thoracic insufficiency syndrome. This study describes our initial experience with this device. METHODS: This is a retrospective chart review of all children undergoing VEPTR placement between October 2001 and December 2005. RESULTS: Twenty-two patients had 36 VEPTR devices placed. Two patients had Jeune syndrome, 19 had scoliosis, and 1 had a chest wall resection for tumor. Most had associated carbon dioxide retention, pulmonary restrictive disease, or respiratory failure. Eleven patients had multiple fused ribs requiring opening thoracostomy. All but the most recent patients have undergone sequential VEPTR expansion. All children had intraoperative spinal cord monitoring (somatosensory evoked potential). Four experienced intraoperative somatosensory evoked potential changes that resolved with decreased VEPTR expansion. Seven VEPTR devices required revision for erosion through the bone or dislodgment and 3 were removed. Five were outgrown and removed or replaced. One eroded soft tissue causing superficial infection that resolved with operative revision. Postoperative ventilation/perfusion scans improved most in younger children. Two of three children with carbon dioxide retention pre-VEPTR had carbon dioxide reduction post-VEPTR. CONCLUSIONS: Vertical expandable prosthetic titanium rib (VEPTR) is a new and safe method to treat children with thoracic insufficiency syndrome. The VEPTR may decrease carbon dioxide retention in some patients and may be most beneficial in younger children.

Use of the StepWatch activity monitor for characterization of normal activity levels of children.

Clinical and research measures for walking activity measure capacity and performance. Existing tools such as 3-dimensional gait analysis and validated gross motor instruments examine capacity but do not measure performance. We defined normal activity levels for 20 children ages 5-7 and 9-11 years using the StepWatch Activity Monitor (SAM). Average daily step counts varied widely by age and sex (mean 7604 +/- 2485), but the percent time spent at high, medium, and low levels of activity was very consistent regardless of age or sex of the child.

Gait abnormalities following slipped capital femoral epiphysis.

The authors evaluated 30 subjects with treated unilateral slipped capital femoral epiphysis and a range of severity from mild to severe to characterize gait and strength abnormalities using instrumented three-dimensional gait analysis and isokinetic muscle testing. For slip angles less than 30 degrees, kinematic, kinetic, and strength variables were not significantly different from age- and weight-matched controls. For moderate to severe slips, as slip angle increased, passive hip flexion, hip abduction, and internal rotation in the flexed and extended positions decreased significantly. Persistent pelvic obliquity, medial lateral trunk sway, and trunk obliquity in stance increased, as did extension, adduction, and external rotation during gait. Gait velocity and step length decreased with increased amount of time spent in double limb stance. Hip abductor moment, hip extension moment, knee flexion moment, and ankle dorsiflexion moment were all decreased on the involved side. Hip and knee strength also decreased with increasing slip severity. All of these changes were present on the affected and to a lesser degree the unaffected side. Body center of mass translation or pelvic obliquity in mid-stance greater than one standard deviation above normal correlated well with the impression of compensated or uncompensated Trendelenburg gait.

Gene targeting in stem cells from individuals with osteogenesis imperfecta.

Adult stem cells offer the potential to treat many diseases through a combination of ex vivo genetic manipulation and autologous transplantation. Mesenchymal stem cells (MSCs, also referred to as marrow stromal cells) are adult stem cells that can be isolated as proliferating, adherent cells from bones. MSCs can differentiate into multiple cell types present in several tissues, including bone, fat, cartilage, and muscle, making them ideal candidates for a variety of cell-based therapies. Here, we have used adeno-associated virus vectors to disrupt dominant-negative mutant COL1A1 collagen genes in MSCs from individuals with the brittle bone disorder osteogenesis imperfecta, demonstrating successful gene targeting in adult human stem cells.