Search

The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care.As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEVMARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

This is the accepted manuscript version of the work published in its final form as Carroll, R. S., Olney, R. C., Duker, A. L., Coghlan, R. F., Mackenzie, W. G., Ditro, C. P., Brown, C. J., O’Connell, D. A., Horton, W. A., Johnstone, B., Espiner, E. A., Prickett, T. C. R., & Bober, M. B. (2022). Collagen X Marker Levels are Decreased in Individuals with Achondroplasia.Calcified Tissue International. https://doi.org/10.1007/s00223-022-00966-0 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.

Neurosurgical patients with genetic syndromes often receive care from multidisciplinary teams. Successful models range from multiple providers in one clinic space seeing a patient together to specialists located at different institutions working together. Collaboration and bidirectional communication are key. Multidisciplinary care improves outcomes and patient satisfaction. Choosing the goal of the clinic, using ancillary staff, and obtaining institutional buy-in are important initial first steps to establishing a multidisciplinary team clinic. Multidisciplinary teams can leverage technology to expand care via telehealth in multidisciplinary clinics and more vitally communication between providers on the team.

This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control.In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing.A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward.This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Author(s): Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William R; Bacino, Carlos A; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B; Polgreen, Lynda E; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel; Ozono, Keiichi; Alanay, Yasemin; Arundel, Paul; Kotani, Yumiko; Yasui, Natsuo; White, Klane K; Saal, Howard M; Leiva-Gea, Antonio; Luna-Gonzalez, Felipe; Mochizuki, Hiroshi; Basel, Donald; Porco, Dania M; Jayaram, Kala; Fisheleva, Elena; Huntsman-Labed, Alice; Day, Jonathan RS | Abstract: PurposeAchondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.MethodsAfter completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.ResultsIn children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility. For the most fragile infants and young children with OI, intravenous (IV) bisphosphonate administration is essential, but IV access attempts often cause fractures. Port-a-caths help prevent these events, but some surgeons are hesitant to insert these devices in these infants due to lack of data on their safety. Retrospective study of pediatric patients with OI who underwent port-a-cath placement from 1999 to 2018; incidence of complications such as infection and thrombosis and need for reoperation or replacement are described. Port-a-caths were placed in 17 patients with OI (median age, 8 mos [5–23 mos]; median weight, 5.8 kg [3.96–9.08 kg]) and remained in place for a median of 53.5 mos (10–127 mos). One port-a-cath was replaced because of thrombosis. Two port-a-caths were removed because of malfunction, one for skin erosion, and one for infection. In these five cases, replacement was not needed because patients could safely tolerate IV access. Two patients have their port-a-cath in place and the remaining ten patients had theirs removed electively as it was no longer needed. Port-a-cath placement in pediatric patients with OI is safe and efficacious for durable central access, enabling reliable IV bisphosphonate delivery and reducing iatrogenic trauma.

OBJECTIVE The authors sought to determine the overall incidence of cervicomedullary decompression (CMD) in patients with achondroplasia and the characteristics associated with those surgeries across multiple institutions with experience caring for individuals with skeletal dysplasias. METHODS Data from CLARITY (Achondroplasia Natural History Study) for 1374 patients with achondroplasia from four skeletal dysplasia centers (A. I. duPont Hospital for Children, Johns Hopkins University, University of Texas Health, and University of Wisconsin School of Medicine and Public Health) followed from 1957 to 2017 were recorded in a Research Electronic Data Capture (REDCap) database. Data collected and analyzed included surgeries, indications, complications, ages at time of procedures, screening procedures, and medical diagnoses. RESULTS There were 314 CMD procedures in 281 patients (20.5% of the entire cohort). The median age of first CMD was 1.3 years in males and 1.1 years in females. Over time, there was a decrease in the median age of patients at first CMD. All patients born before 1980 who underwent CMD had the procedure after 5 years of age, whereas 98% of patients born after 2010 underwent CMD before 5 years of age. In addition, a greater proportion of patients born in more recent decades had documented neuroimaging and polysomnography (PSG) prior to CMD. Ventriculoperitoneal shunts (VPSs) were placed more frequently in patients undergoing CMD (23%) than in the entire cohort (8%). Patients who required either CMD or VPS were 7 times more likely to require both surgeries than patients who required neither surgery (OR 7.0, 95% CI 4.66–10.53; p < 0.0001). Overall, 10.3% of patients who underwent CMD required a subsequent CMD. CONCLUSIONS The prevalence of CMD in this large achondroplasia cohort was 20%, with more recently treated patients undergoing first CMD at younger ages than earlier patients. The use of neuroimaging and PSG screening modalities increased over time, suggesting that increased and better surveillance contributed to earlier identification and intervention in patients with cervicomedullary stenosis and its complications.

Mucopolysaccharidosis type IVA (MPS IVA) is characterized by progressive skeletal dysplasia and respiratory issues with difficult airway management during anesthesia. To characterize tracheal abnormalities in children and adults with MPS IVA including interplay of the trachea, vasculature, bones and thyroid at the thoracic inlet. 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. 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

Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. Children and adults with ACH have disproportionate short stature and are at risk for several significant co-morbidities, including obstructive sleep apnea, chronic otitis media with conductive hearing loss, and spinal stenosis. Obesity is a health problem in ACH and aggravates breathing difficulties (i.e. sleep apnea), back and joint pain, and reduced mobility. Individuals with ACH are predisposed to abdominal obesity, although the cause is not completely understood. The metabolic effect of visceral obesity does not suggest an association with the development of a diabetic profile. The objective of this study is to evaluate body mass index (BMI) and metabolic parameters in children with ACH participating in the PROPEL study, a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development for ACH. Methods Data were analyzed from 86 children (mean age 6.1±2.5 years; female n=52) enrolled in PROPEL. BMI was calculated at enrollment and compared with sex- and age-specific BMI curves for children with ACH in the United States. Cholesterol, triglycerides, and hemoglobin A1c were measured centrally in a subset of children. Results BMI (mean±SD) was 21.2±2.2 in females (range 16.8–26.2) and 20.5±1.6 in males (range 17.9–24.6), with 8/52 girls (15%) and 1/34 boys (2.9%) presenting BMI above the 95% of the sex- and age-specific BMI curves for ACH. The mean±SD for cholesterol and triglycerides measured in a subset of 43 children were 4.2±0.7 mmol/L (normal range [NR] 2.59–4.66) and 0.9±0.5 mmol/L (NR 0.56–1.36), respectively. Cholesterol was elevated in 9/43 children (20.9%), while triglycerides were high in 8/43 (18.7%). Hemoglobin A1c (HbA1c) was measured in 28 children and had a mean±SD of 0.052±0.002 (NR Hb fraction 0.04–0.06). Although all values were within normal ranges, 19/28 (68%) of children had values above the mean for laboratory reference values. Conclusion Results from this work illustrate the importance of using BMI tables developed for children with ACH when providing guidance on weight management. Furthermore, our findings suggest that, in this cohort, average cholesterol and HbA1c levels, although normal, are above the mean for the reference population; this highlights the importance of a healthy diet, weight management and regular physical activity starting at young age. Additional studies are needed to understand the relationship between BMI and body composition in individuals with short stature and to further investigate the clinical relevance of these findings given that no association between increased BMI and metabolic syndrome has been described in adults with ACH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Background Vosoritide increases annualized growth velocity (AGV) in children with achondroplasia aged 5 to 18 years. This global, phase 2, randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of vosoritide on growth in children with achondroplasia aged 3 months to Methods This study compared once-daily subcutaneous administration of vosoritide, at doses of 15 or 30 μg/kg of body weight, with placebo. Eligible patients had participated, for up to 6 months, in an observational growth study to calculate their baseline AGV. The primary objective was to evaluate the safety and tolerability of vosoritide in children with achondroplasia. The primary efficacy evaluation was the change from baseline in height Z-score versus placebo at week 52 using an ANCOVA model. Secondary efficacy analyses included change from baseline in AGV and upper-to-lower body segment ratio versus placebo at Week 52 using an ANCOVA model. Results A total of 75 patients were enrolled, with 11 sentinel subjects who received vosoritide to establish PK and safety. A further 32 were randomized to receive vosoritide and 32 to receive placebo. A total of 73 patients completed the 52-week trial. All patients reported at least one adverse event. Four serious adverse events occurred with vosoritide and 8 with placebo, none were treatment-related. Two participants discontinued, one on vosoritide with pre-existing respiratory morbidity who had a fatal respiratory arrest and one on placebo who withdrew consent. In the full analysis population, vosoritide (n=43) compared to placebo (n=32), increased height Z-score by 0.30 SD (95% CI 0. 07, 0.54); increased AGV by 0.92cm/year (95% CI 0.24, 1.59); and did not worsen upper-to-lower body segment ratio which changed by -0. 06 (95% CI -0.15, 0. 03). Conclusions Daily, subcutaneous administration of vosoritide to young children with achondroplasia was safe and resulted in increases in height Z-score and AGV. (Funded by BioMarin; ClinicalTrials.gov NCT03583697) Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Thanatophoric dysplasia (TD) is a rare skeletal dysplasia commonly thought to be lethal. In this case report, we discuss a nine-year-old male with TD and review his parents' decision making shortly after their son was born, the technology needed to sustain him, and his parents' perception of his quality of life. We also summarize the clinical course of published long-term survivors with TD. Pediatric Palliative Care teams, especially those conducting perinatal palliative care consultations, are often asked to support families in the face of prognostic uncertainty. Our case report and review of the literature adds to the uncertainty of prognosis in TD and suggests that pediatric palliative care providers should be wary of the label "lethal."

Purpose: Patient-reported outcome measures (PROMs) are increasingly recognized as valuable endpoints in clinical trials. Pediatric Outcomes Data Collection Instrument (PODCI) is a PROM utilized in children with musculoskeletal disorders. We evaluated the validity and reliability of PODCI in children with osteogenesis imperfecta (OI). Methods: Physical functioning and psychological well-being were assessed using PODCI in a large cohort of children enrolled in a multicenter study conducted by the Brittle Bone Disorders Consortium. Physical function scores were correlated with a validated, observer-rated scale, Brief Assessment of Motor Function (BAMF), and with psychological well-being scores. We calculated sample sizes required to detect clinically meaningful differences in physical function. Results: 459 children with OI types I, III, and IV were enrolled. Physical function scores in OI type III were significantly lower than those in OI types I and IV. There were no significant differences in psychological well-being. PODCI physical function scores showed moderate-to-strong correlation with BAMF. The Global Functioning Scale, a composite of physical function, did not consistently correlate with psychological well-being. Conclusion: PODCI can be a reliable measure of physical functioning in children with OI and offers valuable information about patient-reported health status and new ways to examine the utility of interventions in this population.

Background: The mainstay of deformity correction and fracture prevention for patients with osteogenesis imperfecta (OI) includes osteotomies and intramedullary rodding. Guided growth, described in the setting of skeletal dysplasias, offers a less invasive means of deformity correction. We report a multicenter case series of guided growth procedures in the setting of OI. Methods: We retrospectively reviewed patients with OI at three institutions from April 2012 to April 2019: 18 patients underwent guided growth for angular deformity correction with minimum 1-year follow-up or full deformity correction and removal of guided growth hardware. Clinical characteristics, deformity measurements, and complications were collected. Distal femoral and proximal tibial hemiepiphysiodesis was performed using figure-of-eight plates and screws, and distal tibial medial hemiepiphysiodesis with cannulated screws. Preoperative and postoperative lateral distal femoral angle, medial proximal tibial angle, and lateral distal tibial angle were measured. Frequency and descriptive statistics were completed. Results: Eighteen patients with OI (five-I, four- III, six-IV, three-V) underwent 33 guided growth procedures with mean follow-up of 3.09 years ; all received routine bisphosphonate treatment. Preoperative and postoperative mean joint angles were measured. The location for hemiepiphysiodesis included 8 distal femoral medial, 2 distal femoral lateral, 8 proximal tibial medial, 3 proximal tibial lateral, and 12 distal tibial medial. Twelve of the 33 procedures were in patients who had an intramedullary rod ; 1 demonstrated backout of the epiphyseal and metaphyseal screws of a distal femoral medial figure-of-eight plate. It was revised to a larger plate with longer screws and removed upon completion of deformity correction. Conclusion: Guided growth may be used as an effective means of angular deformity correction with dysplastic OI bone. Having an intramedullary rod did not preclude the use of a guided growth technique. One procedure demonstrated screw backout. Given the short stature associated with OI, performing a guided growth procedure at an early enough age to allow time for correction should be considered.

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. Achondroplasia is the most common skeletal dysplasia and is characterized by various lifelong clinical, functional and psychosocial challenges for affected individuals. This first International Consensus Statement on the care of children and adults with achondroplasia aims to facilitate the global standardization and improvement of achondroplasia clinical care.

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.

OBJECTIVES/HYPOTHESIS To quantify otolaryngologic surgery utilization in patients with achondroplasia, and to identify any changes in utilization over the past four decades. STUDY DESIGN Retrospective cohort study. METHODS A retrospective cohort study of 1,374 patients with achondroplasia enrolled in the CLARITY retrospective cohort study at four centers of multi-specialty care for patients with achondroplasia. Otolaryngologic surgeries are presented by birth cohort decade. The main outcomes were number of primary and additional otolaryngologic procedures; age at surgery; likelihood of repeated surgery; temporal trends in surgical utilization. RESULTS In this cohort of 1,374 patients with achondroplasia, 620 (45.1%) had pharyngeal surgery at least once, 150 (10.9%) had pharyngeal surgery on more than one occasion, and patients who had adenoidectomy first were 2.68 times more likely to require a second pharyngeal surgery than those who had adenotonsillectomy. Seven hundred and seventy-nine (56.7%) had tympanostomy tubes placed at least once, and 447 (32.5%) had tympanostomy tubes placed more than one time. Age at first pharyngeal surgery decreased by 1.2 years per birth cohort decade, and age at tympanostomy tube placement decreased by 1.1 years per decade. CONCLUSIONS Patients with achondroplasia often require otolaryngologic surgery, particularly adenoidectomy and/or tonsillectomy as well as tympanostomy tube placement. Such surgery is performed now more frequently and at younger ages than in earlier decades. While otolaryngologic disease associated with achondroplasia is now recognized earlier and treated more frequently, long-term outcome studies are needed. LEVEL OF EVIDENCE 3 Laryngoscope, 2021.

Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study. Methods Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms. Results A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference. Conclusions The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.

Background Achondroplasia (ACH), the most common non-lethal form of skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Infigratinib, a selective, orally bioavailable FGFR1–3 tyrosine kinase inhibitor, has been shown to reverse established growth arrest in chondrocytes and improve foramen magnum and long bone length in Fgfr3Y367C/+ mice. Infigratinib is being investigated for the treatment of ACH in the PROPEL program of three clinical trials: 1) PROPEL, designed to collect information on the natural history of ACH; 2) PROPEL2, designed to obtain preliminary evidence of efficacy and safety and to identify the dose of infigratinib to investigate further; 3) PROPEL OLE, which is designed to evaluate the long-term efficacy and safety of infigratinib in children with ACH. Methods PROPEL (NCT04035811) is a non-interventional clinical assessment study designed to characterize the natural history of up to 200 children aged 2.5–10 years with ACH over a 6−24-month period. The primary objective is to collect baseline height velocity measurements in children who may participate in an interventional study with infigratinib. The primary endpoint is the annualized growth velocity (AGV). Further objectives are to collect other baseline growth measurements, evaluate exploratory biomarker indicators of growth, and assess ACH-related medical events reported as medical history, or non-treatment adverse events (AEs). PROPEL2 (NCT04265651) is a phase 2, open-label study of infigratinib in children aged 3−11 years with ACH who completed ≥6 months observation in PROPEL. PROPEL2 includes dose-escalation with an extended dose-finding treatment phase (n≈40), a pharmacokinetics sub-study (n≈18), followed by a dose-expansion phase (n≈20) in which children receive infigratinib for 12 months to confirm the selected dose and provide evidence of efficacy. Primary endpoints are treatment-emergent AEs, change from baseline in AGV, and infigratinib pharmacokinetics. Secondary endpoints include safety/tolerability of infigratinib and changes from baseline in anthropometric parameters, including body proportions. Exploratory outcomes include changes in QoL and other parameters of disease burden. PROPEL OLE (NCT05145010) is a phase 2, open-label extension study in up to 230 children who completed an interventional study with infigratinib and, potentially, in ≤50 who are infigratinib-naive. The primary objectives are to evaluate safety, tolerability, and efficacy of long-term daily doses of infigratinib. Secondary objectives include evaluation of changes in other indicators of growth and development, and evaluation of QoL and disease burden. Children will receive infigratinib until they reach final/near final height. Summary PROPEL, PROPEL2, and PROPEL OLE are currently ongoing. Together, these studies are intended to provide key evidence on the safety and efficacy of oral infigratinib in children with ACH and will inform the design of future studies in this setting. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Osteogenesis imperfecta (OI) is a genetic disorder that causes skeletal fragility. For the most fragile infants and young children with OI, intravenous (IV) bisphosphonate administration is essential, but IV access attempts often cause fractures. Port-a-caths help prevent these events, but some surgeons are hesitant to insert these devices in these infants due to lack of data on their safety.Retrospective study of pediatric patients with OI who underwent port-a-cath placement from 1999 to 2018; incidence of complications such as infection and thrombosis and need for reoperation or replacement are described.Port-a-caths were placed in 17 patients with OI (median age, 8 mos [5-23 mos]; median weight, 5.8 kg [3.96-9.08 kg]) and remained in place for a median of 53.5 mos (10-127 mos). One port-a-cath was replaced because of thrombosis. Two port-a-caths were removed because of malfunction, one for skin erosion, and one for infection. In these five cases, replacement was not needed because patients could safely tolerate IV access. Two patients have their port-a-cath in place and the remaining ten patients had theirs removed electively as it was no longer needed.Port-a-cath placement in pediatric patients with OI is safe and efficacious for durable central access, enabling reliable IV bisphosphonate delivery and reducing iatrogenic trauma.

We sought to examine the prevalence of depression and anxiety in adults with skeletal dysplasias, and to assess any correlations with pain. Participation was via an anonymous REDCap survey, which consisted of sociodemographic questions followed by the brief pain inventory-short form (BPI-SF), patient health questionnaire-8 (PHQ-8), and generalized anxiety disorder-7 (GAD-7) questionnaires. These assessed pain, depression, and anxiety respectively. Of the 336 usable responses, 16.1% scored 10 or greater on the PHQ-8 consistent with current depression while 17.3% scored 10 or greater on the GAD-7 consistent with current anxiety. The majority of participants (76.2%) experienced pain, which was significantly associated with prior mental health diagnoses (p

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.

Osteogenesis imperfecta (OI) is a genetic disorder causing skeletal fragility, multiple fractures, and other extraskeletal manifestations. Most cases are caused by mutations in COL1A1 or COL1A2. Recent investigations have discovered several other autosomal recessive genes responsible for OI. Among these genes is LEPRE1, which is involved in post-translational modifications of collagen. To date, more than 40 LEPRE1 mutations have been described. One of these mutations is carried by 1.5% of West Africans and 0.4% of African Americans, and is associated with OI Type VIII. We describe the case of a five year old male with a moderate form of OI and compound heterozygous LEPRE1 mutations (c.1080 + 1G > T; c.1646 T > G, p.Met549Arg). He was diagnosed shortly after birth following a skeletal survey demonstrating multiple healing fractures as well as lower extremity deformity suggestive of remote fractures. He was then without a fracture until a calvarial fracture at 18 months of age, a femur fracture at 4 years and seven months and a second femur fracture at 5 years and 4 months. He walked at age 14 months and has been an active boy. Pamidronate infusions began at seven weeks of age and were discontinued at three years of age due to increased bone mineral density and absence of fractures. Type VIII OI typically causes a severe to lethal phenotype presenting at birth with severe osteopenia, congenital fractures and other clinical manifestations. Only a few individuals have survived to childhood. This case description serves to expand the clinical phenotyping of this recessive form of OI into the more moderate spectrum. Keywords: Osteogenesis imperfecta, Non-collagen I osteogenesis imperfecta, LEPRE1, Recessive osteogenesis imperfecta

Background Skeletal dysplasia comprises a heterogeneous and collectively common group of inherited disorders of development, growth, and maintenance of the human skeleton. There is potential for increased perinatal morbidity and mortality in pregnant women who themselves have skeletal dysplasia, and for affected fetuses where skeletal dysplasia is suspected in utero. Objective We sought to establish guidelines for perinatal health care professionals who should be aware of these risks, to optimize maternal and child health pregnancy outcomes through best prenatal and delivery management practices. Study Design A panel of 13 multidisciplinary international experts participated in a Delphi process, which comprised consideration of thorough literature review and a list of 54 possible care recommendations subject to 2 rounds of anonymous voting and a face-to-face meeting. Those recommendations with >80% agreement were considered as consensual. Results During the first round, consensus was reached to support 30 out of the 54 statements. After the panel discussion, the group reached consensus on 40 statements. These statements include guidelines for the evaluation and treatment of pregnant women with skeletal dysplasia and for the unborn child with or suspected to have skeletal dysplasia. Conclusion Consensus-based best practice guidelines are provided as a minimum of standard care to minimize associated health risks, and improve clinical outcomes for patients with skeletal dysplasia.

Objectives: Vosoritide is a potent stimulator of endochondral bone growth and is in development for the treatment of achondroplasia, the most common form of disproportionate short stature. We previously reported on a 52-week, phase 3, pivotal study that demonstrated a highly statistically significant improvement in annualized growth velocity (AGV) when vosoritide was compared to placebo in children with achondroplasia aged 5-18 years (Savarirayan et al, Lancet, 2020). This is an analysis of data after an additional 52 weeks of treatment in the ongoing phase 3 extension study. Methods: After completion of the phase 3 placebo-controlled study, 119 children were enrolled into the extension study, where they all receive open label 15 μg/kg/day vosoritide. AGV, height Z-score and body proportion ratio were analyzed to assess efficacy of vosoritide in children who were treated with vosoritide for up to 2 years. Fifty-eight continued treatment with vosoritide and 61 switched from placebo to vosoritide. Two participants on continuous vosoritide treatment discontinued before the Week 52 timepoint. Four participants on continuous vosoritide treatment and 7 participants who switched from placebo to vosoritide missed the Week 52 assessment due to Covid-19. Results: In children randomized to receive daily vosoritide, baseline mean (SD) AGV was 4.26 (1.53) cm/year. After the first 52 weeks of treatment, mean (SD) AGV was 5.67 (0.98) cm/year. Mean (SD) AGV over the second year was 5.57 (1.10) cm/year. Mean (SD) change from baseline in height Z-score improved by +0.24 (0.31) at Week 52 in the pivotal study and +0.45 (0.56) at Week 52 in the extension study. Mean (SD) upper-to-lower body segment ratio improved with a change from baseline of -0.03 (0.11) at Week 52 in the pivotal study and -0.09 (0.11) at Week 52 in the extension study. In children who switched from placebo to vosoritide after 52 weeks, baseline AGV was 4.06 (1.20) cm/year and 3.94 (1.07) cm/year after 52 weeks on placebo. In the second year, after receiving 52 weeks of vosoritide, mean AGV was 5.65 (1.47) cm/year, the mean (SD) change in height Z-score was +0.24 (0.34), and the change in upper-to-lower body segment ratio was -0.03 (0.08). No new adverse events associated with vosoritide treatment were detected with up to 2 years of continuous daily, subcutaneous treatment. Most adverse events were mild and no serious adverse events were attributed to vosoritide. The most common adverse event remains mild and transient injection site reactions. Conclusions: The effect of vosoritide administration on growth as measured through AGV and height Z-score was maintained for up to 2-years in children with achondroplasia aged 5 to 18 years, with an improvement of body proportions.

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.

Background Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is the most common form of primordial dwarfism, caused by bialleic mutations in the pericentrin gene (PCNT). Aside from its classic features, there are multiple associated medical complications, including a well-documented risk of neurovascular disease. Over the past several years, it has become apparent that additional vascular issues, as well as systemic hypertension and kidney disease may also be related to MOPDII. However, the frequency and extent of the vasculopathy was unclear. To help address this question, a vascular substudy was initiated within our Primordial Dwarfism Registry. Results Medical records from 47 individuals, living and deceased, ranging in age from 3 to 41 years of age were interrogated for this purpose. Of the total group, 64% were diagnosed with moyamoya, intracranial aneurysms, or both. In general, the age at diagnosis for moyamoya was younger than aneurysms, but the risk for neurovascular disease was throughout the shortened lifespan. In addition to neurovascular disease, renal, coronary and external carotid artery involvement are documented. 43% of the total group was diagnosed with hypertension, and 17% had myocardial infarctions. A total of 32% of the entire cohort had some form of chronic kidney disease, with 4% of the total group necessitating a kidney transplant. In addition, 38% had diabetes/insulin resistance. Ages of diagnoses, treatment modalities employed, and location of vasculopathies were notated as available and applicable, as well as frequencies of other comorbidities. Conclusions It is now clear that vascular disease in MOPDII is global and screening of the cardiac and renal vessels is warranted along with close monitoring of blood pressure. We recommend a blood pressure of 110/70 mmHg as a starting point for an upper limit, especially if the individual has a history of neurovascular disease, chronic kidney disease and/or diabetes. Additionally, providers need to be at high alert for the possibility of myocardial infarctions in young adults with MOPDII, so that appropriate treatment can be initiated promptly in an acute situation.