INTRODUCTION:The ACHieve study assessed growth velocity, body proportionality, and clinical events in children with achondroplasia not receiving growth-promoting therapy. METHODS:ACHieve was a global, longitudinal, prospective, observational study. Children ≤8 years old with achondroplasia were enrolled and evaluated every 6 months for anthropometric parameters and clinical events. RESULTS:ACHieve enrolled 259 children in 15 countries, including 83 from China. Median follow-up was 21 months; median age of diagnosis was approximately 52 weeks in China and 2 weeks elsewhere. Growth parameters were similar regardless of region. Mean annualized growth velocity was 9.3 cm/year for males and 10.4 cm/year for females at age 1 and decreased to 4.1 cm/year and 4.6 cm/year, respectively, at age 4. Upper-to-lower-body segment ratio was generally consistent across regions. Overall, 77.2% of participants experienced clinical events, 34.0% of which were considered related to achondroplasia. Two deaths occurred (one accident and one cardiac arrest of unknown origin). CONCLUSION:ACHieve was one of the largest longitudinal natural history studies of achondroplasia to date and included the largest prospective Chinese achondroplasia cohort. The results demonstrated common trajectories in growth parameters regardless of region, indicating the generalizability of findings.

Achondroplasia is a skeletal dysplasia associated with multisystem complications including genu varum, which causes pain and limits mobility. Vosoritide, a targeted treatment for achondroplasia, improves growth in children and has an established safety profile, but its effect on genu varum is unclear. Data were collected from 183 participants from randomized, double-blind, placebo-controlled phase 2 (CANOPY ACH-2I [111-206; NCT03583697]) and phase 3 (CANOPY ACH-3 [111-301; NCT03197766]) studies evaluating vosoritide (weight-based dose of 15 or 30 µg/kg/day) in children aged 0-5 and >5 years, respectively. Anterior/posterior lower limb radiographs were taken at baseline and 1 year to measure parameters associated with genu varum. Differences in least-squares mean (LSM) change from baseline were calculated for vosoritide vs placebo using an analysis of covariance model. In both studies, age at treatment initiation and sex distribution were generally balanced between vosoritide and placebo (except 58% males received vosoritide in CANOPY ACH-2I). After 1 year of vosoritide treatment vs placebo, tibial bowing decreased in children who initiated treatment aged <5 years (n = 40) and remained stable in those ≥5 years (n = 57). Vosoritide-treated participants with evidence of abnormal fibular growth at baseline had reduced overall and distal fibular overgrowth vs placebo. Children aged ≥5 years improved in ankle joint to distal fibula physis distance (difference in LSM change from baseline, -0.07, P = .010) and fibula/tibia ratio (-0.025, P < .0001), and children aged 2-5 years had improved fibula/tibia ratio (-0.033, P = .0032). Preliminary results suggest vosoritide may improve or limit genu varum in children with achondroplasia.

Achondroplasia is a skeletal dysplasia condition caused by reduced endochondral ossification resulting in disproportionate short stature and skeletal deformities, including thoracolumbar kyphosis (TLK) and spinal stenosis. Vosoritide, the first and only approved targeted therapy for achondroplasia, increases bone growth, but its impact on spinal morphology has not been assessed. The randomized, double-blind, placebo-controlled phase 2 CANOPY ACH-2I study (111-206; NCT03583697) evaluated the safety and efficacy of vosoritide in 75 children aged 0 to <5 years. Interpedicular distance (IPD), sagittal width of the lumbar spinal canal, and TLK angle were measured on spinal radiographs taken at baseline and 1 year after vosoritide or placebo treatment. Differences in least-squares mean (LSM) change from baseline (95% CI) between treatment groups were determined with an analysis of covariance model. Measurable improvements in IPD and spinal canal width across L1 to L5 were observed with vosoritide compared with placebo after 1 year. L4 was the most impacted by vosoritide for IPD (LSM difference [95% CI], 0.509 [-0.034 to 1.052] mm, P = .066) and canal width (1.433 [0.547 to 2.320] mm, P = .002). Vosoritide treatment also reduced the natural increase in TLK angle in children 0 to <0.5 years and provided greater improvements in children ≥0.5 to <5 years. After 1 year, fewer children treated with vosoritide (33.3%) vs placebo (59.3%) had pathological (≥20°) TLK angles (P = .037). These preliminary results suggest that early vosoritide treatment may improve spinal morphology and reduce the risk of spinal stenosis in children with achondroplasia. Clinical Trial Information: NCT03583697.

BACKGROUND:Achondroplasia is a genetic skeletal condition caused by FGFR3 pathogenic variants. Infigratinib, an oral FGFR1-3 tyrosine kinase inhibitor, down-regulates key pathways in the pathogenesis of achondroplasia. METHODS:In this phase 3, multicenter, double-blind, placebo-controlled trial, we randomly assigned children with achondroplasia (3 to 17 years of age) in a 2:1 ratio to receive infigratinib (at a dose of 0.25 mg per kilogram of body weight) or placebo once daily for 52 weeks. The primary end point was the change from baseline in the annualized height velocity in the infigratinib group as compared with the placebo group at week 52. Key secondary end points were the change from baseline in the height z score and in the upper-to-lower body segment ratio at week 52. The primary analysis evaluated the treatment effect at week 52 in the full analysis population, with missing data handled with a prespecified imputation approach. RESULTS:In all, 114 patients underwent randomization: 75 patients to receive infigratinib (with 1 withdrawal before treatment) and 39 patients to receive placebo. The difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 was 1.74 cm per year (95% confidence interval [CI], 1.31 to 2.17; P<0.001) for the annualized height velocity, 0.32 (96% CI, 0.23 to 0.41; P<0.001) for the height z score, and -0.02 (96% CI, -0.06 to 0.01) for the upper-to-lower body segment ratio. Adverse events occurred in 71 of 74 patients (96%) in the infigratinib group and in 37 of 39 patients (95%) in the placebo group; serious adverse events occurred in 4 of 74 patients (5%) and 1 of 39 patients (3%), respectively. No serious adverse events or adverse events leading to treatment discontinuation were considered by the investigator to be related to infigratinib or placebo. CONCLUSIONS:In children with achondroplasia, treatment with once-daily oral infigratinib for 52 weeks resulted in a significantly greater increase from baseline in the annualized height velocity than placebo. (Funded by BridgeBio Pharma; PROPEL 3 ClinicalTrials.gov number, NCT06164951; EudraCT number, 2023-506130-67.).

Cleidocranial dysplasia is a rare genetic condition negatively impacting skeletal development. Clinical guidelines for patients, their family members, and clinicians on the diagnosis, treatment, and management of this disease are lacking. The aim of this study was to align expert opinion on standard of care (SoC) medical recommendations for patients with cleidocranial dysplasia, primarily for adults and children (≥2 yrs of age). A modified Delphi panel comprised of a 3-round survey was used to determine consensus among a multidisciplinary team of 13 experts with experience treating patients with cleidocranial dysplasia. Statements for Round 1 were generated from a targeted literature review and received input from a steering committee of 2 experts within the panel. Expert discussion held after Round 2 helped refine statements for Round 3; the steering committee also reviewed statements before dissemination in each round. The consensus threshold was pre-defined as ≥70% agreement or disagreement for Likert-scale statements or ≥70% of experts selecting the same response for a multiple-choice option. For statements wherein consensus was measured, 79% (n/N = 26/33), 91% (n/N = 21/23), and 100% (n/N = 12/12) of statements reached consensus, respectively, in Round 1, Round 2, and Round 3. Overall, consensus was reached on 37 SoC recommendations for patients with cleidocranial dysplasia: 9 regarding diagnosis, 24 regarding treatment and management, consisting of 7 dental/orthodontic and 17 other medical (non-dental/orthodontic), and 4 regarding care providers. The expert consensus reached in this panel informs the first comprehensive best practice guidelines for patients, their family members, and healthcare providers to diagnose, treat, and manage the dental/orthodontic and other medical complications of cleidocranial dysplasia.

This article arises from conversations over the past two decades between the lead author and many other orthopaedic leaders, especially pediatric orthopaedic division chiefs, about the best model for compensating pediatric orthopaedic surgeons. These discussions covered compensation, incentives, and the work of pediatric orthopaedic leaders in developing programs that aim for excellence—primarily in both operative and nonoperative care of children but also in research to advance our field and educational initiatives that pass along knowledge and skills to the next generation of surgeons. We hope these future surgeons will drive innovations and improvements. Two of the coauthors are experienced chiefs with years of hiring, evaluating, and compensating surgeons, while two are more recently appointed chiefs beginning to build excellent programs. Over the past decade, the five authors have overseen the compensation of approximately 100 pediatric orthopaedic surgeons each year. The essential foundation for a top-tier pediatric orthopaedic surgical program is to hire, develop, retain, and promote outstanding surgeons. This article discusses the role of compensation in achieving that goal.

OBJECTIVE:Respiratory failure secondary to multilevel airway compromise may present complex airway challenges in patients with specific skeletal dysplasia diagnoses. This study sought to identify and characterize subgroups of skeletal dysplasia diagnoses that more frequently undergo operative airway evaluations and tracheostomy placement. METHODS:Retrospective electronic medical record review of pediatric patients with an ICD-10 associated skeletal dysplasia diagnosis and CPT-specified airway intervention at a tertiary pediatric hospital from 1990 to 2022. Patients without a defined skeletal dysplasia diagnosis, subjects with craniosynostosis syndromes, and those with limited clinical data were excluded. Collected variables included demographics, age at diagnosis, comorbidities, operative procedures, and airway interventions. Descriptive statistical analysis was utilized to evaluate data distribution. RESULTS:From the initial population of 313 patients, 41 subjects were confirmed to have clinical features and/or genetic testing consistent with a skeletal dysplasia diagnosis. A tracheostomy was placed in 19/41 subjects and these patients' records were further analyzed. Skeletal dysplasia groups with more frequent tracheostomy placement included Filamins and related disorders, Sulfation disorders, and Chondrodysplasia punctata. In the patients with a tracheostomy, skeletal dysplasia was diagnosed at a median age of 0.3 years (IQR 4.8 years), and tracheostomy was initiated at a median age of 1.8 years (IQR 2.2 years). Only four of these patients were successfully decannulated, and two subjects are deceased. CONCLUSION:Over 32 years, nearly half of the skeletal dysplasia patients who underwent airway interventions eventually had a tracheostomy placed. Respiratory insufficiency and complex airway management challenges are common manifestations of skeletal dysplasia.

INTRODUCTION:Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS:Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS:A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION:The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.

Development dysplasia of the hip represents a spectrum of disease. Selective screening by physical examination and imaging is recommended. Most cases of congenital muscular torticollis resolve spontaneously. Physical therapy and surgery are reserved for recalcitrant cases. A variety of foot deformities are common and can be encountered in the neonate. Stretching, casting, or surgery may be required for resolution. Torsional and angular deformities of the lower extremities must be differentiated from physiologic variants. Asymmetry and rapid progression are the hallmarks of pathologic variants. Congenital vertebral anomalies result from failures of formation or segmentation of spinal elements. Spinal deformities such as scoliosis or kyphosis may ensue.

Aims The aim of this study was to compare outcomes after growth- friendly treatment for earlyonset scoliosis (EOS) between patients with skeletal dysplasias versus those with other syndromes. Methods We retrospectively identified 20 patients with skeletal dysplasias and 292 with other syndromes (control group) who had completed surgical growth- friendly EOS treatment between 1 January 2000 and 31 December 2018. We compared radiological parameters, complications, and health- related quality of life (HRQoL) at mean follow - up of 8.6 years (SD 3.3) in the dysplasia group and 6.6 years (SD 2.6) in the control group. Results Mean major curve correction per patient did not differ significantly between the dysplasia group (43%) and the control group (28%; p = 0.087). Mean annual spinal height increase was less in the dysplasia group (9.3 mm (SD 5.1) than in the control group (16 mm (SD 9.2); p < 0.001). Mean annual spinal growth adjusted to patient preoperative standing height during the distraction period was 11% in the dysplasia group and 14% in the control group (p = 0.070). The complication rate was 1.6 times higher (95% confidence interval (CI) 1.3 to 2.0) in the dysplasia group. The following complications were more frequent in the dysplasia group: neurological injury (rate ratio (RR) 5.1 (95% CI 2.3 to 11)), deep surgical site infection (RR 2.2 (95% CI 1.2 to 4.1)), implant- related complications (RR 2.0 (95% CI 1.5 to 2.7)), and unplanned revision (RR 1.8 (95% CI 1.3 to 2.5)). Final fusion did not provide additional spinal height compared with watchful waiting (p = 0.054). There were no significant differences in HRQoL scores between the groups. Conclusion After growth- friendly EOS treatment, patients with skeletal dysplasias experienced a higher incidence of complications compared to those with other syndromes. Surgical growth- friendly treatment for skeletal dysplasia- associated EOS should be reserved for patients with severe, progressive deformities that are refractory to nonoperative treatment.

There are some syndromes that present with unique manifestations pertaining to the spinal column. A good working understanding of these common syndromes is useful for the spinal deformity surgeons and related healthcare providers. This review attempts to encompass these unique features and discuss them in three broad groups: hypermobility syndromes, muscle pathology-related syndromes, and syndromes related to poor bone quality. This review explores the features of these syndromes underpinning the aspects of surgical and medical management. This review represents the proceedings of the Paediatric Half-Day Course at the 57th Annual Meeting of the Scoliosis Research Society.

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.

Patients with early onset scoliosis are at high risk of sleep disordered breathing, sleep disruption, and adverse consequences of poor sleep. In this study, we aim to assess the prevalence of periodic limb movements of sleep in a cohort of children with early onset scoliosis and identify factors that correlate with the presence of periodic limb movements. This is a retrospective chart review of 40 patients with EOS (ages 1–17 years) who underwent a PSG from 2003 through 2019. Data collected included age, sex, and polysomnography parameters. Descriptive statistics were used: independent T test and Pearson correlation. The average age was 9.6 years (SD 5.2); 22 were female. Eleven patients (27.5

Background: Magnetic controlled growth rods (MCGR) are the most common type of implant used for operative treatment of patients with early-onset scoliosis (EOS). Rods can have either a 7-cm actuator, allowing 2.8 cm of potential expansion, or a 9-cm actuator which allows 4.8 cm potential expansion. We hypothesized that the rate of unplanned return to the operating room (UPROR) will be increased when the 9-cm actuator is implanted in smaller patients. In addition, we aimed to identify a cutoff for spine length between planned upper and lower instrumented MCGR levels that best differentiated between patients having a high versus low risk of UPROR. Methods: We identified 167 patients from a prospectively collected registry of EOS patients who began MCGR treatment at 9 years of age or younger, with greater than 1 year of follow-up, and had adequate radiographs. Demographic, clinical, and surgical characteristics were analyzed for 7-cm and 9-cm actuator patients. Chi-square tests and Student t tests were used to test for differences between the 2 actuator rod groups. A predictive model for UPROR within 2 years was developed based on variables significantly predictive of UPROR. Results: The average follow-up was 2.6 years (range, 1 to 5 y) in both the 7 cm (n=74) and 9 cm (n=93) groups. Twenty-five complications in 14 patients led to UPROR within 2 years of MCGR insertion, 8% incidence (95% CI, 4%-13%). Device-related complications (n=15) were the most common reason for UPROR, followed by wound complications (n=4), pain-related complications (n=3), junctional kyphosis (n=2), and incarcerated umbilical hernia (n=1). After adjusting for age, spine height, number of spine anchors, sex, and diagnosis, there was no significant difference in UPROR rates between groups. Fewer proximal anchors, smaller T1-S1 height, and more caudal mid-point of primary coronal curvature were significantly associated with UPROR in the predictive model. Conclusion: MCGR actuator size is not a significant factor in predicted UPROR. Smaller height, fewer anchors, and caudal apex increased UPROR risk. Level of Evidence: This is a retrospective, multicenter comparative cohort study (Level III therapeutic).

CASE:We describe treatment of severe multilevel congenital thoracic fusion in a 3-year-old girl with Apert Syndrome by posterior element excision, posterior column osteotomies, and gradual distraction with magnetically controlled growing rods (MCGR) with 3-year follow-up. We also describe short-term follow-up with similar management in an 8-year-old patient with a congenitally fused thoracic spine from Jarcho-Levin syndrome. CONCLUSION:Posterior element resection and targeted posterior column osteotomies combined with gradual distraction with MCGR offers a promising treatment course for children with severe thoracic insufficiency syndrome derived from congenital fusions.

Background TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.Methods ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 mu g CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).Findings Forty-two participants received TransCon CNP at doses of 6 mu g (n = 10; 7 female), 20 mu g (n = 11; 3 female), 50 mu g (n = 10; 3 female), or 100 mu g (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 mu g CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0 & sdot;41] vs -0 & sdot;08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 mu g CNP/kg/week.Interpretation This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 mu g CNP/kg/week in the ongoing pivotal trial.

Abstract Disclosure: R. Savarirayan: Advisory Board Member; Self; Biomarin, Ascendis. Consulting Fee; Self; BridgeBio. C. McDonnell: Advisory Board Member; Self; Pfizer. Research Investigator; Self; Ascendis, KyowaKirin. Other; Self; Honoraria: Biomarin, Pfizer; Travel, Accommodations, and Expenses: Pfizer. D.G. Hoernschemeyer: Consulting Fee; Self; Orthopediatrics. Grant Recipient; Self; Zimvie. Research Investigator; Self; Zimvie, Biomarin. Speaker; Self; Zimvie. Stock Owner; Self; Orthopediatrics. Other; Self; Travel, Accommodations, Expenses: Orthopediatrics; Honoraria: Biomarin; Patents, Royalties, Other IP: Orthopediatrics; Other relationship: Orthopediatrics, Zimvie. H.B. Hove: Advisory Board Member; Self; Pfizer. Consulting Fee; Self; Pfizer, Ascendis Pharma. Y.A. Zarate: None. M.B. Bober: Advisory Board Member; Self; Biomarin, Ultragenyx. Consulting Fee; Self; Biomarin, QED, Ascendis. Grant Recipient; Self; Biomarin. Research Investigator; Self; Biomarin, Pfizer/Therachon, QED, Ascendis, Takeda, Ultragenyx, MedLife, Sobi. Speaker; Self; Alexion. Other; Self; Honoraria: Novo Nordisk. C.A. Bacino: Consulting Fee; Self; Best Doctors, Inc (Teladoc). Grant Recipient; Self; Ascendis, Roche, Ionis, BioMarin. Other; Self; Patents, Royalties, Other IP: UpToDate. J.M. Legare: Grant Recipient; Self; BioMarin. Research Investigator; Self; BioMarin. Speaker; Self; BioMarin. Other; Self; Honoraria (Self): BioMarin. W. Högler: Advisory Board Member; Self; Biomarin, Alexion. Consulting Fee; Self; Alexion, Pfizer. Grant Recipient; Self; Novo Nordisk. Research Investigator; Self; Alexion, Kyowa Kirin, Amgen. Other; Self; Honorara (Self): Alexion; Travel, Accommodations, Expenses: Alexion, Kyowa Kirin. T. Quattrin: Consulting Fee; Self; ProventionBio, Ascendis, Merck, Janssen. Research Investigator; Self; Ascendis, Janssen, Merck, Pfizer, ProventionBio. M. Abuzzahab: Advisory Board Member; Self; Pfizer, NovoNordisk, Ascendis, Rhythm. Consulting Fee; Self; Ascendis, Rhythm. Research Investigator; Self; Ascendis, NovoNordisk, Rhythm, Lumos, Soleno, Saniona, Levo, Affreza, Medtronic. P.L. Hofman: Other; Self; Honoraria (Self): Novo Nordisk and Eli-Lilly. K.K. White: Research Investigator; Self; Biomarin, Ascendis, Pfizer, Ultragenyx. Other; Self; Honorara (Self): Biomarin; Patents, Royalties, Other IP: UpToDate.com. N. Ma: Research Investigator; Self; Ascendis Pharma (site-PI), Ultragenyx (Sub-I), Amgen (site-PI). Other; Self; Patents, Royalties, Other IP (Self): UpToDate peer reviewer royalties, Co-Editor of Pediatrics section of Current Osteoporosis Reports. D. Schnabel: Advisory Board Member; Self; Biomarin, Novo Nordisk, Sandoz, Kyowa Kirin. Consulting Fee; Self; Kyowa Kirin. Other; Self; Honoraria: Kyowa Kirin, Sandoz; Travel, Accommodations, Expenses: Kyowa Kirin. S.B. Sousa: Advisory Board Member; Self; Biomarin, Ascendis. Other; Self; Honoraria (Self): Biomarin, Ascendis, Kiowa Kirin; Travel, Accomodations, Expenses: Biomarin. X. Fan: Employee; Self; Ascendis Pharma Inc. M. Chakraborty: Employee; Self; Ascendis Pharma Inc. A. Giwa: Employee; Self; Ascendis Pharma Inc. S.E. Smith: Employee; Self; Ascendis Pharma Inc. B. Volck: Employee; Self; Ascendis Pharma A/S. A.D. Shu: Employee; Self; Ascendis Pharma, Inc. Background: Achondroplasia (ACH) is the most common form of hereditary disproportionate short stature and is associated with complications that can diminish functional capacity and quality of life. ACH is caused by a pathogenic variant in the FGFR3 gene resulting in fibroblast growth factor 3 pathway overactivation leading to impaired endochondral ossification. C-type natriuretic peptide (CNP) promotes chondrocyte development by inhibiting the FGFR3 pathway. TransCon CNP is an investigational prodrug of CNP, designed to provide sustained release of CNP supporting continuous CNP exposure and a once-weekly dosing regimen. The ACcomplisH trial assessed TransCon CNP for the treatment of children with ACH aged 2 to 10 years. Methods: ACcomplisH is a phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial of once-weekly TransCon CNP in prepubertal children aged 2-10 years with ACH. Participants were randomized to TransCon CNP dosed at 6, 20, 50 and 100 μg CNP/kg/week across 4 cohorts or placebo in a 3:1 ratio. The primary objectives were safety and annualized height velocity (AHV) at 52 weeks. Results: 57 participants were enrolled; 42 received TransCon CNP: 6 μg CNP/kg/week (n=10), 20 μg CNP/kg/week (n=11), 50 μg CNP/kg/week (n=10), or 100 μg CNP/kg/week (n=11 of which 55% female, 73% ≥5 years); or pooled placebo (n=15; 33% female, 47% ≥5 years). TransCon CNP was well tolerated with no treatment discontinuations. No serious treatment-emergent adverse events (TEAEs) were reported as related to TransCon CNP. Most TEAEs were mild (grade 1) with no grade 3 or 4 TEAEs reported. There was a low frequency of injection site reactions (ISRs). In >2,000 TransCon CNP injections, only 11 ISRs in 8 participants over 52 weeks were reported. There were no reports of symptomatic hypotension and no trends to suggest worsening of disproportionality. TransCon CNP 100 μg CNP/kg/week resulted in significantly higher AHV vs placebo at 52 weeks (least square [LS] mean 5.42 vs 4.35 cm/year; p=0.022) resulting in improved ACH-specific height SDS from baseline vs placebo (LS mean 0.22 vs -0.08; p=0.028). There was a dose-dependent treatment effect on AHV of 4.09 cm/year (6 μg CNP/kg/week) to 5.42 cm/year (100 μg CNP/kg/week; p=0.003). All participants completed blinded treatment and continued in the 2-year open-label extension (OLE), receiving 100 μg CNP/kg/week of TransCon CNP. Preliminary OLE data suggest sustained efficacy and safety. Conclusion: Once-weekly TransCon CNP dosed up to 100 μg CNP/kg/week was generally safe and well tolerated with mild TEAEs, few ISRs, and no discontinuations. TransCon CNP at 100 μg CNP/kg/week provided statistically significant improvement in AHV vs placebo. These results support continued investigation of TransCon CNP for children with ACH in the ongoing Phase 2b ApproaCH trial (NCT05598320) including treatment impact on ACH-related complications. Presentation: Thursday, June 15, 2023

The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 +/- 10 cm in MPS IH, 161 +/- 11 cm in MPS IA, 161 +/- 14 cm in MPS II, and 128 +/- 15 cm in MPS VI. Adult average BMI percentiles were high: 75 +/- 30%ile in MPS IH, 71 +/- 37%ile in MPS IA, 71 +/- 25%ile in MPS II, and 60 +/- 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.