Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders: Results from the largest cohort to date.

Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019-April 2022). Median (range) age was 8 (0-90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.

Predictors of Rod Length Gain and Sagittal Alignment Change After Magnetically Controlled Growing Rod Lengthening.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: There are preoperative characteristics that predict rod lengthening of magnetically controlled growing rods (MCGR). The lengthening of MCGR will lead to increased kyphosis. SUMMARY OF BACKGROUND DATA: The amount of length gained by MCGR is variable, and predictors are lacking. Similarly, sagittal plane changes over the MCGR lengthening period have not been investigated. MATERIALS AND METHODS: Patients with MCGR and a minimum 2-year follow-up were identified and those with previous spine surgery were excluded. Preimplantation, postimplantation, and last follow-up postlengthening radiographs were examined. Multiple linear regression analyses were used for rod length gain predictors. RESULTS: Fifty-six patients with early-onset scoliosis met inclusion criteria: nine idiopathic, five congenital, 14 neuromuscular, 20 syndromic, and eight skeletal dysplasia patients. No difference was seen between subtypes of early-onset scoliosis for rod length gain ( P =0.62). Shorter preoperative T1-T12 height and higher curve correction rate after implantation were significant predictors for rod length gain ( P <0.001). Preoperative major curve magnitude and kyphosis were not significant predictors. Flattening of the spine around the actuator and compensative increase in T1-T5 kyphosis were seen secondarily after MCGR implantation. Maximum sagittal kyphosis, T1-T5 kyphosis, and T5-T12 kyphosis did not change during lengthening. Lumbar lordosis significantly decreased postimplantation (first erect) but then increased during lengthening. Pelvic incidence and sacral slope both increased during lengthening, but this may be age related. CONCLUSION: Patients who gained the most rod length with MCGR were those with an initially shorter T1-T12 height and better initial curve correction at implantation, likely representing that implants work best in small patients with flexible curves. Diagnosis, preoperative curve magnitude, and thoracic kyphosis were not related to rod length gain. Thoracic kyphosis did not deteriorate over the lengthening phase. LEVEL OF EVIDENCE: Level III-retrospective cohort study.

Hip Displacement in Spinal Muscular Atrophy: The Influences of Genetic Severity, Functional Level, and Disease-modifying Treatments.

PURPOSE: Hip displacement (HD) is common in spinal muscular atrophy (SMA), but neither genetic severity nor gross motor function level have been investigated as risk factors. Although disease-modifying agents (DMA) have improved function and overall health, their effects on the prevention of HD are unknown. The purpose of this study was to determine risk factors for HD development in SMA. METHODS: Retrospective cohort. Children with SMA presenting between January 2005 and August 2021, at least 1 hip radiograph, and a minimum 2-year follow-up were included. The primary outcome measure was the prevalence of HD (migration percentage ≥40%). Secondary outcomes included SMA type (I/II/III), survival motor neuron 2 copy number, Hammersmith Functional Motor Scale (HFMS, out of 66), ambulatory status (Functional Mobility Scale at 50 m), clinically relevant scoliosis (>40 degrees and/or surgery), and DMA treatment (>1-year duration, nusinersen/risdiplam/onasemnogene abeparvovec) as risk factors. Univariate and multivariate logistic regression analyses were performed. RESULTS: Eighty-two patients (52% female) with SMA type I (n=32, 39%), II (n=36, 44%), and III (n=14, 17%) met the inclusion criteria, with a final follow-up of 4.5 (SD: 2.7) years. Age at first hip radiograph was 3.4 (SD: 2.9) years. The prevalence of HD was 75.6%, with a mean age of onset of 4.6 (SD: 2.7) years. When stratified by SMA type, the prevalence/age of onset (mean, years) was 84%/3.1 (SD: 1.7), 80%/5.8 (SD: 2.3), and 36%/9.0 (SD: 4.3), respectively. HFMS score >23 was protective against HD by receiver operating characteristic analysis ( P =0.008). Significant risk factors by univariate analysis were SMA type I ( P =0.002) and II ( P =0.002), HFMS ≤23 ( P =0.01), nonambulatory status (Functional Mobility Scale at 50 m = 1, P =0.001), clinically relevant scoliosis ( P =0.01), and DMA treatment ( P =0.01). By multivariate analysis, only SMA type II ( P =0.04) and scoliosis ( P =0.04) were independent risk factors. CONCLUSIONS: The prevalence of HD in SMA is highly linked to disease severity. Identified risk factors can be used in the development of surveillance programs for early detection of HD in SMA, allowing for timely management. LEVEL OF EVIDENCE: Level III.

Tracheal Narrowing and Its Impact on Anesthesia Care in Patients With Morquio A (Mucopolysaccharidosis Type IVA): An Observational Study.

BACKGROUND: Recently, tracheal narrowing has been recognized as a significant comorbid condition in patients with Morquio A, also known as mucopolysaccharidosis IVA. We studied a large cohort of patients with Morquio A to describe the extent of their tracheal narrowing and its relationship to airway management during anesthesia care. METHODS: This is an observational study, collecting data retrospectively, of a cohort of patients with Morquio A. Ninety-two patients with Morquio A syndrome were enrolled, among whom 44 patients had their airway evaluated by computed tomography angiography and had undergone an anesthetic within a year of the evaluation. Our hypothesis was that the tracheal narrowing as evaluated by computed tomography angiography increases with age in patients with Morquio A. The primary aim of the study was to examine the degree of tracheal narrowing in patients with Morquio A and describe the difficulties encountered during airway management, thus increasing awareness of both the tracheal narrowing and airway management difficulties in this patient population. In addition, the degree of tracheal narrowing was evaluated for its association with age or spirometry parameters using Spearman's rank correlation. Analysis of variance followed by the Bonferroni test was used to further examine the age-based differences in tracheal narrowing for the 3 age groups: 1 to 10 years, 11 to 20 years, and >21 years. RESULTS: Patient age showed a positive correlation with tracheal narrowing ( rs= 0.415; 95% confidence interval [95% CI], 0.138-0.691; P = .005) with older patients having greater narrowing of the trachea. Among spirometry parameters, FEF25%-75% showed an inverse correlation with tracheal narrowing as follows: FEF25%-75% versus tracheal narrowing: ( rs = -0.467; 95% CI, -0.877 to -0.057; P = .007). During anesthetic care, significant airway management difficulties were encountered, including cancelation of surgical procedures, awake intubation using flexible bronchoscope, and failed video laryngoscopy attempts. CONCLUSIONS: Clinically significant tracheal narrowing was present in patients with Morquio A, and the degree of such narrowing likely contributed to the difficulty with airway management during their anesthetic care. Tracheal narrowing worsens with age, but the progression appears to slow down after 20 years of age. In addition to tracheal narrowing, spirometry values of FEF25%-75% may be helpful in the overall evaluation of the airway in patients with Morquio A.

Walking status and spinopelvic parameters in young children with achondroplasia: 10-year follow-up.

PURPOSE: Thoracolumbar kyphosis (TLK) is common in children with achondroplasia and resolves in 90% by 10 years of age. Our purpose was to describe the natural progression of TLK in a cohort of pre-walking children with achondroplasia. METHODS: A single-center, retrospective review identified 62 children (32 male, 30 female) with achondroplasia. Clinical information and sagittal spinopelvic parameters were collected. The children were divided into positive pelvic tilt (PT) and negative PT. All parents were routinely counseled about unsupported sitting. RESULTS: Spontaneous resolution rate was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% at 10 years of age. None of the children required posterior spinal decompression and fusion for progressive deformity or symptomatic spinal stenosis. At 1-year post-walking, the negative PT group had a higher sacral slope (p = 0.006), higher lumbar lordosis (p < 0.001), and lower pelvic incidence (p < 0.001). This relationship remained constant up to 10 years of age, and there was no association with TLK. CONCLUSION: In this largest series to date, spontaneous resolution of TLK in children with achondroplasia was 64.5% at 1-year post-walking, 74.2% at 5 years of age, and 88.7% in children followed to 10 years of age. With early identification and regular follow-up with patient education, no patient in this series required treatment or developed symptomatic spinal stenosis. While not predictive of resolution of TLK, the dichotomous presentation of PT in young children with achondroplasia persists at 5 and 10 years of age and reliably predicts the spinopelvic parameters. LEVEL OF EVIDENCE: III-retrospective comparative study.

Achondroplasia natural history study (CLARITY): 60-year experience in orthopedic surgery from four skeletal dysplasia centers.

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery.

Posterior cervical spinal fusion in the pediatric population using modern adult instrumentation - clinical outcome and safety.

PURPOSE: Traditionally, less rigid fixation techniques have been applied to the pediatric cervical spine. There is a lack of long-term outcome data for rigid fixation techniques. The purpose of this study was to define the clinical outcome and safety of posterior instrumented fusion in the pediatric population using adult posterior instrumentation. METHODS: A multicenter, retrospective review of pediatric patients who underwent posterior cervical fusion using a 3.5 mm posterior cervical system for any indication was performed. Outcome parameters included complications, revision and fusion rates, operative time (OR), blood loss, and postoperative neurologic status. Outcomes were compared between patient groups (posterior only versus anterior/posterior approach, short versus intermediate versus long fusion, and between different etiologies) using Mann-Whitney and chi-square test. RESULTS: Seventy-nine patients with a mean age of 9.9 years and mean follow-up of 2.8 years were included. At baseline 44 (56%) had an abnormal neurologic exam. Congenital deformities and basilar invagination were the most common indications for surgery. Posterior-only surgery was performed in 71 (90%) cases; mean number of levels fused was 4 (range 1-15). Overall, 4 (5%) operative complications and 4 (5%) revisions were reported at an average postoperative time of 2.6 years. Neurologic status remained unchanged in 74%, improved in 23%, and worsened in 3%. When comparing outcome measures between the various groups, 2 significant differences were found: OR was longer in the anterior/posterior approach group and decline of neuro status was more frequent in the long fusion group. CONCLUSION: Posterior cervical fusion with an adult 3.5 mm posterior cervical system was safe in this cohort of 79 pediatric patients irrespective of surgical technique, fusion length, and etiology, resulting in a high fusion and low complication/revision rate.

Growth Modulation by Tension Band Plate in Achondroplasia With Varus Knee Deformity: Comparison of Gait Analysis Measurements.

BACKGROUND: Limited evidence exists concerning growth modulation by tension band plate (TBP) to correct varus deformity in patients with achondroplasia with limited growth due to FGFR3 gene mutation. We evaluated the efficacy of TBP in children with achondroplasia with genu varum and reported the static radiographic and dynamic motion data to determine parameters that impact the rate of deformity correction. METHODS: Patients with achondroplasia with genu varum who underwent TBP surgery for growth modulation were studied. Those with at least 1 year of follow-up with TBP were included. Radiographic parameters were measured. Growth velocity of femoral/tibial length was calculated separately. Patients were deemed successful or unsuccessful. Spearman correlation analysis and Student t test were used to describe statistical results. RESULTS: Twenty-two patients (41 limbs; 12 girls) fulfilled our criteria. Mean age at TBP surgery was 7.6±2.4 years. Thirty-six femoral TBP and 41 tibial TBP were in place for 24.5±9.7 months. Mean mechanical axis deviation, mechanical lateral distal femoral angle, and medial proximal tibial angle preoperatively were 30.1±7.6 mm, 97.2±6.4, and 80.3±4.3 degrees, and 11±15.6 mm, 87.4±5.9, and 84.7±5.3 degrees at last follow-up ( P <0.001). Fifteen limbs were successfully straightened; 4 limbs were in more varus than the initial deformity. Twenty-four limbs with TBP were still undergoing correction. In successful limbs, mean age at surgery was 6.5±1.7 years and duration of TBP was 29.9±7.8 months. In 4 unsuccessful limbs, mean age at surgery was 11.7±1.2 years. Analysis in the gait laboratory included physical examination with the measurement of knee varus and kinematic varus based on a posterior view static standing photograph. Photographic measurement of varus was higher than the radiographic measurement. CONCLUSIONS: Growth modulation by TBP surgery is a reliable and simple technique to correct genu varum in achondroplasia. An early age at TBP implementation (mean: 6.5 y) is crucial to successfully correct the varus knee deformity. Furthermore, we recommend early and regular surveillance of achondroplasia for progressive varus knee deformity. LEVEL OF EVIDENCE: Level IV-cohort study.

No difference in postoperative complication rates or cardiopulmonary function for early versus late scoliosis correction in Duchenne muscular dystrophy.

BACKGROUND: Given reduced rates of both pulmonary function decline and scoliosis progression with steroid treatment in Duchenne muscular dystrophy (DMD), the role of early scoliosis surgery has been questioned. The purpose of this study was to compare the postoperative complication rates of early versus late scoliosis correction in DMD. METHODS: This study was a retrospective cohort, conducted at an academic tertiary level children's hospital. Patients with DMD who underwent posterior scoliosis correction, with preoperative pulmonary function testing [forced vital capacity (FVC)] were included and divided into two groups by preoperative curve angles: ≤ 45° and > 45°. The primary outcome variable was postoperative complications by Clavien-Dindo classification grading. Secondary outcome variables included postoperative complications occurring after the first 90 days, age at surgery, duration of wheelchair dependency preoperatively, pulmonary function, steroid utilization, shortening fraction by echocardiogram, surgery duration, intensive care unit/hospital length of stay, days intubated, infection, and percent curve correction. Two-tailed t-test and Chi-square testing were used for analysis of patient factors and Clavien-Dindo complication grade, respectively. RESULTS: Thirty-one patients were included with a total follow-up of 8.3 ± 3.2 years, 4.8 ± 2.2 years post-spinal fusion. Steroid treatment (prednisone, deflazacort) was utilized for 21 (67.7%) patients. Primary curve correction was not different between groups (65.0% vs 71.4% [p = 0.37]). There were no significant differences in Clavien-Dindo classification grades between groups (p > 0.05). For the entire cohort, the overall complication rate was higher for patients with steroid treatment (61.9% vs 10.0% [p = 0.008]). Neither forced vital capacity nor fractional shortening on echocardiogram was different between groups at final follow-up (p = 0.6 and p = 0.4, respectively). CONCLUSION: The comparable risk of perioperative complications for early and late scoliosis correction supports a "watchful waiting" approach, whereby curves less than 45° can be carefully followed while cardiopulmonary function is maintained. Patients undergoing steroid treatment should be counseled regarding the higher risk of postoperative blood transfusion and deep wound infection. LEVEL OF EVIDENCE: III Retrospective cohort.

Improved distribution of leg forces after fibular resection and synostosis.

PURPOSE: Genu varum- a common symptom in achondroplasia- may lead to ankle valgus in children. Ankle valgus may be mitigated by tibiofibular synostosis, but this is not always the case. The mechanical environment around the growth plates plays an important role in ankle valgus. The purpose of this project is 1) to determine the strain through the distal fibular growth plate before and after tibiofibular synostosis, and 2) postulate whether the change in strain affects ankle valgus. This project measured the distal fibular strain in a porcine hind leg model. METHODS: The lower legs of seven pigs were removed, instrumented with strain gauges, and loaded compressively in a material testing machine. Loads were applied at three phases: 1) the intact leg, 2) leg with fibula resected, and 3) leg with fibula resected and tibiofibular synostosis. Mean strains were compared between phases using a mixed affect model. The significance level was adjusted for multiple comparisons using the Bonferroni method. RESULTS: Phase 1, intact leg, had the highest strain value at 1247.9µÉ›. In phase 2, the mean strain was 106.2µÉ›. In phase 3, the compressive mean strain dropped to 477.4µÉ›, which is 38% of the strain in phase 1. Standard error was 86.8µÉ›; p < 0.001. CONCLUSION: Results indicate that more of the force through the leg is transmitted through the tibia after fibular resection and tibiofibular synostosis, which improves the balance of forces through the leg.

Collagen X Marker Levels are Decreased in Individuals with Achondroplasia.

Collagen X marker (CXM) is a degradation fragment of collagen type X. It is a real-time biomarker of height velocity with established norms. Plasma C-type natriuretic peptide (CNP) and NTproCNP levels have also been found to correlate with growth velocity in the general population and are elevated in individuals with achondroplasia compared with age- and sex-matched controls. Collagen X marker levels in people with fibroblast growth factor receptor 3 (FGFR3)-opathies have never been systematically measured. The objective of this study was to measure CXM in a population of dwarfism caused by FGFR3-opathies. Using the same cohort in which CNP and NTproCNP levels were previously measured, archived serum aliquots from 63 children with achondroplasia, six with hypochondroplasia, and two with thanatophoric dysplasia had CXM concentrations measured. Results were plotted against age- and sex-specific norms, and standard deviation scores were plotted for comparison between clinical diagnoses. CXM levels were significantly decreased (p < 0.0001) in children with achondroplasia compared with age- and sex-matched controls. Temporal patterns of change in CXM levels were sex-dependent. As the FGFR3 pathway was more constitutively active, CXM levels decreased. New tools are emerging to study impact of skeletal dysplasia on growth plate regulation and function.

Addressing the need for patient-friendly medical communications: adaptation of the 2019 recommendations for the management of MPS VI and MPS IVA.

BACKGROUND: Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases that affects multiple organs and parts of the body. Independent guidelines on the treatment of these diseases were recently published, providing evidence- and expertise-driven recommendations to optimize patient management. However, while healthcare providers may have the training and knowledge to understand these guidelines, patients and their caregivers can find the technical content challenging. Hence, we aimed to develop plain language summaries (PLS) of the MPS VI and MPS IVA guidelines with patients as the primary audience. RESULTS: A review of the guidelines by an expert team identified six domains of information relevant to patients: The multidisciplinary team, regular tests and check-ups, disease-modifying and supportive treatments, general anesthetics, ear-nose-throat/respiratory care, and surgeries. This information was adapted into a series of infographics specific to either MPS VI or MPS IVA, designed to appeal to patients and clearly present information in a concise manner. CONCLUSIONS: The use of patient-friendly materials, like the infographics we have developed, has the potential to better inform patients and engage them in their care. We issue a "call to arms" to the medical community for the development of similar PLS materials in rare diseases intended to inform and empower patients.

Risk Factors for Rebound After Correction of Genu Valgum in Skeletal Dysplasia Patients Treated by Tension Band Plates.

BACKGROUND: Growth modulation using tension band plates (TBPs) is increasingly important for lower limb deformity correction in patients with skeletal dysplasia (SKD). Development of rebound deformity is a concern after TBP removal. Data regarding this complication are rare; therefore, we evaluated the prevalence and risk factors for rebound deformity in children with SKD undergoing correction of genu valgum using TBP. METHODS: All patients with SKD with genu valgum treated by TBP at the distal femur or/and proximal tibia at a single center were reviewed. Inclusion criteria were: (1) minimum 2-year follow-up after TBP removal or having revision surgery for rebound deformity and (2) implant removal age for girls 14 years and below and boys 16 years and below. Exclusion criteria were any femoral/tibial osteotomies during TBP treatment or follow-up. A change of ≥3 degrees of mechanical lateral distal femoral and/or medial proximal tibial angle was accepted as rebound deformity and analyzed statistically. RESULTS: Thirty-three patients (59 limbs; 52 femur and 29 tibia physes) met our criteria. Mean follow-up after implant removal was 43.7 months. Rebound deformities were seen in 43 limbs (39 femurs and 13 tibias). Boys had more rebound than girls; however, this was not influenced by body mass index. Femurs had more rebound than tibias. Patients in the rebound group were younger than the nonrebound group. Time from application to removal of TBP was shorter in the rebound versus nonrebound group. Overcorrected limbs had more rebound deformity than not overcorrected. The difference in growth velocity of lower limbs in the rebound versus nonrebound group was statistically significant. Patients with epiphyseal dysplasia had more rebound than metaphyseal dysplasia, but this was not statistically significant. CONCLUSION: Risk factors for developing a rebound deformity after correction of genu valgum using TBP in SKD included male sex, TBP surgery at a young age, short duration of TBP implantation, overcorrected extremity (mechanical axis deviation ≤1), and high percent growth velocity after TBP removal. LEVEL OF EVIDENCE: Level IV-retrospective study.

Elongation-Derotation-Flexion Casting Treatment of Early-Onset Progressive Scoliosis in Skeletal Dysplasia.

BACKGROUND: Early-onset scoliosis in children with skeletal dysplasia is progressive, contributing to cardiopulmonary restrictive disease. Serial elongation-derotation-flexion (EDF) casting, used in other etiologies of scoliosis to delay curve progression, may be beneficial in maximizing spine growth. Our hypothesis is serial EDF casting can be safely used as a temporary alternative to surgery, delaying progression and preserving growth, to treat scoliosis in skeletal dysplasia. METHODS: All patients with skeletal dysplasia treated at a single institution with serial EDF casting for scoliosis were reviewed retrospectively. Radiographic parameters: Cobb angle of major and minor curves, curve location, thoracic height, thoracolumbar height, space available for lung, and rib vertebra angle difference were measured before casting (C1), in first casting (C2), in last casting (C3), and out of last casting (C4). Peak inspiratory pressure (PIP) values were monitored and recorded during the casting application. RESULTS: Eleven patients met the inclusion criteria (mean 9.7 castings). The mean duration of EDF serial casting was 35 months. The mean major Cobb angles were 54 degrees° (C1), 30 degrees (C2), 37 degrees (C3), and 49 degrees (C4) with no statistically significant differences. The mean minor Cobb angles were 35 degrees (C1), 25 degrees (C2), 33 degrees (C3), and 51 degrees (C4) with no statistically significant differences. The mean thoracic heights were 130 mm (C1), 155 mm (C2), 173 mm (C3), and 160 mm (C4). The 19-mm mean difference between C2 and C3 represents spinal growth. The PIP-1, PIP-2, and PIP-3 mean values were 15, 27, and 18 cmH2O, respectively. Changes in PIP-1 and PIP-2 and PIP-2 and PIP-3 were statistically significant. CONCLUSION: Serial EDF casting can delay surgical scoliosis correction in children younger than 7 years with a diagnosis of skeletal dysplasia. Our study showed that serial casting controls progression of the major curve and allows longitudinal growth of the spine with possible expansion of lung volume for nearly 3 years. During cast application, PIP increased with molding and traction, and improved until windowing and trimming of the cast. LEVEL OF EVIDENCE: Level IV-retrospective study.

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.

Evaluation of Gait Pattern and Lower Extremity Kinematics of Children with Morquio Syndrome (MPS IV).

Morquio syndrome (mucopolysaccharidosis IV/MPS IV) is a genetic disorder leading to skeletal abnormalities and gait deviations. Research on the gait patterns and lower extremity physical characteristics associated with skeletal dysplasia in children with MPS IV is currently limited. This research aimed to provide baseline gait patterns and lower limb skeletal alignment of children with MPS IV utilizing three-dimensional instrumented gait analysis. This Institutional Review Board-approved retrospective study evaluates the kinematics of the lower extremities of children with MPS IV during gait, comparing them with an age-matched group of typically developing children. Thirty-three children with MPS IV were included (8.6 ± 4.0 years old). Children with MPS IV walk with increased anterior pelvic tilt, knee valgus, knee flexion, external tibial torsion, and reduced walking speed and stride length (p < 0.001). Multiplanar abnormal alignment results in abnormal knee moments (p < 0.001). Limited correlations exist (r = 0.69-0.28) between dynamic three-dimensional measurements of knee varus/valgus and rotational alignment and traditional static two-dimensional measures (physical examination or radiographs) suggesting the possibility of knee instability during gait and the benefits of dynamic assessment.

Late Conditions Diagnosed 1-4 Months Following an Initial Coronavirus Disease 2019 (COVID-19) Encounter: A Matched-Cohort Study Using Inpatient and Outpatient Administrative Data-United States, 1 March-30 June 2020.

BACKGROUND: Late sequelae of COVID-19 have been reported; however, few studies have investigated the time course or incidence of late new COVID-19-related health conditions (post-COVID conditions) after COVID-19 diagnosis. Studies distinguishing post-COVID conditions from late conditions caused by other etiologies are lacking. Using data from a large administrative all-payer database, we assessed type, association, and timing of post-COVID conditions following COVID-19 diagnosis. METHODS: Using the Premier Healthcare Database Special COVID-19 Release (release date, 20 October 2020) data, during March-June 2020, 27 589 inpatients and 46 857 outpatients diagnosed with COVID-19 (case-patients) were 1:1 matched with patients without COVID-19 through the 4-month follow-up period (control-patients) by using propensity score matching. In this matched-cohort study, adjusted ORs were calculated to assess for late conditions that were more common in case-patients than control-patients. Incidence proportion was calculated for conditions that were more common in case-patients than control-patients during 31-120 days following a COVID-19 encounter. RESULTS: During 31-120 days after an initial COVID-19 inpatient hospitalization, 7.0% of adults experienced ≥1 of 5 post-COVID conditions. Among adult outpatients with COVID-19, 7.7% experienced ≥1 of 10 post-COVID conditions. During 31-60 days after an initial outpatient encounter, adults with COVID-19 were 2.8 times as likely to experience acute pulmonary embolism as outpatient control-patients and also more likely to experience a range of conditions affecting multiple body systems (eg, nonspecific chest pain, fatigue, headache, and respiratory, nervous, circulatory, and gastrointestinal symptoms) than outpatient control-patients. CONCLUSIONS: These findings add to the evidence of late health conditions possibly related to COVID-19 in adults following COVID-19 diagnosis and can inform healthcare practice and resource planning for follow-up COVID-19 care.

The impact of scoliosis surgery on pulmonary function in spinal muscular atrophy: a systematic review.

Scoliosis often occurs coincident with pulmonary function deterioration in spinal muscular atrophy but a causal relationship has not yet been reliably established. A systematic literature review was performed, with pulmonary function testing being the primary outcome pre- and post-scoliosis surgery. Levels of evidence were determined and GRADE recommendations made. Ninety studies were identified with only 14 meeting inclusion criteria. Four studies were level III and the rest were level IV evidence. The average age at surgical intervention was 11.8 years (follow-up 6.1 years). Post-operative pulmonary function progressively declined for the majority of studies. Otherwise, pulmonary function: improved (two studies), were unchanged (two studies), had a decreased rate of decline (three studies), declined initially then returned to baseline (two studies). Respiratory and spine-based complications were common. Given the available evidence, the following GRADE C recommendations were made: (1) surgery is most often associated with decreases in pulmonary function; (2) the impact of surgery on pulmonary function is variable, but does not improve over pre-operative baseline; (3) surgery may result in a decreased rate of decline in pulmonary function post-operatively. Given this lack of evidence-based support, the risk-benefit balance should be taken into consideration when contemplating scoliosis surgery.

Use of bot and content flags to limit the spread of misinformation among social networks: a behavior and attitude survey.

The COVID-19 infodemic is driven partially by Twitter bots. Flagging bot accounts and the misinformation they share could provide one strategy for preventing the spread of false information online. This article reports on an experiment (N = 299) conducted with participants in the USA to see whether flagging tweets as coming from bot accounts and as containing misinformation can lower participants' self-reported engagement and attitudes about the tweets. This experiment also showed participants tweets that aligned with their previously held beliefs to determine how flags affect their overall opinions. Results showed that flagging tweets lowered participants' attitudes about them, though this effect was less pronounced in participants who frequently used social media or consumed more news, especially from Facebook or Fox News. Some participants also changed their opinions after seeing the flagged tweets. The results suggest that social media companies can flag suspicious or inaccurate content as a way to fight misinformation. Flagging could be built into future automated fact-checking systems and other misinformation abatement strategies of the social network analysis and mining community.

Tracheal narrowing in children and adults with mucopolysaccharidosis type IVA: evaluation with computed tomography angiography.

BACKGROUND: Mucopolysaccharidosis type IVA (MPS IVA) is characterized by progressive skeletal dysplasia and respiratory issues with difficult airway management during anesthesia. OBJECTIVE: To characterize tracheal abnormalities in children and adults with MPS IVA including interplay of the trachea, vasculature, bones and thyroid at the thoracic inlet. MATERIALS AND METHODS: Computed tomography (CT) angiograms of the chest were analyzed for trachea shape, narrowing and deviation at the thoracic inlet, course of vasculature, bone alignment and thyroid location. The tracheal cross-sectional area was measured at the cervical, thoracic inlet and intrathoracic levels. RESULTS: Thirty-seven patients (mean age: 18.1 years) were included. The mean tracheal cross-sectional area narrowing at the thoracic inlet was 63.9% (range: -2.1-96%), with a trend for increased tracheal narrowing in older children. The trachea was commonly deviated rightward posterior (22/37, 59%). T- or W-shaped tracheas had two times greater tracheal narrowing than D- or U-shaped tracheas (P<0.05). The brachiocephalic artery was tortuous in 35/37 (95%) with direct impingement on the trachea in 24/37 (65%). No correlation was observed between bony thoracic inlet diameter and tracheal narrowing. The thyroid was located in the thoracic inlet in 28/37 (76%) cases, significantly associated with tracheal narrowing (P=0.016). CONCLUSION: Narrowing, deviation and abnormal shape of the trachea at the thoracic inlet are common in children and adults with MPS IVA, with a trend toward increased narrowing with advancing age in children. A W- or T-shaped trachea is associated with focal tracheal narrowing. Crowding of the thoracic inlet, due to vascular tortuosity and thyroid position, appears to play a major role.