X-linked hypophosphataemia is a rare, genetic, lifelong disorder caused by phosphate-regulating endopeptidase homologue X-linked pathogenic variants and, if left untreated, is associated with a progressive accumulation of musculoskeletal manifestations. Burosumab is a fully human monoclonal antibody that targets circulating fibroblast growth factor 23 and directly inhibits its activity, thereby correcting the abnormal phosphate homoeostasis in people with X-linked hypophosphataemia (XLH). The efficacy and safety of burosumab has been demonstrated in a programme of clinical trials in children and adults. Few data describe the experience of adolescents with XLH receiving burosumab treatment before and after skeletal growth ends. This prospective, multicentre, mixed-methods study described the lived experience of adolescents with XLH treated with burosumab at the end of skeletal growth (NCT05181839). Using patient-reported outcomes, wearable devices, and interviews, we found low median symptom severity scores for pain (0.00), stiffness (0.00), and fatigue (1.75) on a 0-10 scale. Symptoms were usually triggered by physical activity but rarely interfered with daily life. Some adolescents reported emotional concerns related to XLH and treatment transition. These insights can inform patient support during transition to adult care.

BACKGROUND:Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis. CASE PRESENTATION:A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition). CONCLUSION:This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. J. De Bergua: None. P. Arundel: None. J. Salles: None. V. Saraff: None. B. Delgado: None. A. Leiva-Gea: None. H. McDevitt: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. M. Salcedo: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. M. Skae: None. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M.B. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C.P. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. S. Raj: None. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by impaired endochondral ossification resulting from gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone growth. People with ACH are at risk for several significant co-morbidities, including compression of the brainstem due to foramen magnum stenosis, sleep-disordered breathing, chronic otitis media with conductive hearing loss, and symptomatic spinal stenosis. Infigratinib is an oral, selective FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of children with ACH in a phase 2 interventional study (PROPEL 2). Methods: PROPEL 2 (NCT04265651) is a phase 2 dose-finding, open-label study of infigratinib in children 3−11 years of age with ACH who participated for ≥6 months in PROPEL (NCT04035811), a non-interventional clinical assessment study. The PROPEL 2 dose-escalation (DE) phase comprises 5 ascending dose cohorts ranging from 0.016 mg/kg/day to 0.25 mg/kg/day. The primary endpoints are safety; change from baseline (BL) in annualized height velocity (AHV); and infigratinib pharmacokinetics in this population. Secondary endpoints include changes from BL in body proportions, and changes in quality of life. Other parameters of disease burden are evaluated as exploratory endpoints. Summary: Children enrolled in the PROPEL 2 DE phase completed ≥6 months of treatment at the assigned cohort dose. Cohorts 1-3 (n=37; doses 0.016, 0.032, and 0.064 mg/kg/day) did not show a significant increase in AHV and these doses were assessed as non-efficacious. Treatment at the cohort 4 dose (0.128 mg/kg/day) resulted in an increase in AHV from BL of 1.52 cm/year in children ≥5 years old (n=11; p=0.02). Infigratinib at the cohort 5 dose (n=10 with month 6 data, 0.25 mg/kg/day) resulted in a significant mean increase from BL of 3.03 cm/year (p=0.0022). In children considered responders (Δ in AHV ≥25% from BL, n=8/10), the mean change in AHV at the cohort 5 dose was +3.81±1.8 cm/year, with a median of +4.14 cm/year. Infigratinib was well tolerated with no serious AEs or AEs that led to study discontinuation, with most AEs mild or moderate in severity. At the cohort 5 dose level, no grade 3 AEs or treatment-related AEs were reported. Conclusion: Oral infigratinib in children with ACH, up to a dose of 0.25 mg/kg/day, was well tolerated and showed dose-dependent increases in AHV, with a significant mean change from BL of +3.03cm/year at the cohort 5 dose. The safety and efficacy of this oral, once-daily dose of infigratinib at 0.25 mg/kg/day will be further explored in a phase 3 randomized controlled study. If these phase 2 data are confirmed, infigratinib could potentially offer children with ACH the first safe and effective oral therapy to improve growth, enhance functionality and decrease medical complications. Presentation: Saturday, June 17, 2023

Abstract Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. J. De Bergua: None. P. Arundel: None. H. McDevitt: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. V. Saraff: None. M. Skae: None. B. Delgado: None. A. Leiva-Gea: None. M. Salcedo: None. J. Salles: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips III: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED Therapeutics, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed 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 is a selective, orally bioavailable FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of ACH in the observational and 2 interventional studies, as detailed below. Methods: PROPEL (NCT04035811) is a non-interventional clinical assessment study designed to characterize the natural history of ∼250 children 2.5 to <17 years of age with ACH over a 6−24-month period. Primary objective: collect baseline height velocity measurements in children who may participate in an interventional study with infigratinib. Primary endpoint: annualized growth velocity (AGV). Further objectives: collect other baseline growth measurements; evaluate exploratory biomarker indicators of growth; assess ACH-related medical events reported as medical history, or non-treatment adverse events (AEs), health-related quality of life, body pain, functional abilities and cognitive functions in children with ACH. PROPEL 2 (NCT04265651) is a phase 2, open-label study of infigratinib in children 3−11 years of age with ACH who completed ≥6 months of observation in PROPEL. This study includes dose-escalation (extended dose-finding treatment phase, n≥40), a pharmacokinetics sub-study (n≥18), and a dose-expansion phase (n≈20) to confirm the selected dose and provide evidence of efficacy. Primary endpoints: AEs; change from baseline in AGV; and infigratinib pharmacokinetics. Secondary endpoints: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters. Exploratory outcomes: changes in quality of life (QoL) and other parameters of disease burden. PROPEL OLE (NCT05145010) is a phase 2, open-label extension study in ∼230 children who completed an interventional study with infigratinib and, potentially, in ≤50 infigratinib-naïve children. Primary objectives: safety, tolerability; and efficacy of long-term daily doses of infigratinib. Secondary objectives: changes in other indicators of growth/development, skeletal abnormalities, QoL/disease burden, and cognitive functions. Children may receive infigratinib until they reach final height. Summary: The PROPEL, PROPEL 2, and PROPEL OLE studies are ongoing. Together, they are intended to contribute to the understanding of the natural history of ACH, provide key evidence on the safety and efficacy of oral infigratinib, including QoL and skeletal changes in children with ACH, and inform the design of future studies in this setting. Presentation: Thursday, June 15, 2023

X-linked acrogigantism (X-LAG) is characterized by extreme tall stature from early childhood resulting from duplication of the GPR101 gene, in turn resulting in GH excess. Most cases present with pituitary tumors secreting GH and prolactin. Diffuse pituitary hyperplasia is uncommon and normal prolactin is rare. We present a girl with tall stature from 3 years of age; her height was +4.25 SD score at 5 years, with no signs of syndromic disease. She had significant GH excess, serum IGF-1 4 times the upper limit of normal and normal circulating GHRH, with normal pituitary magnetic resonance imaging over 13 years. No abnormalities were found in either the AIP or MEN1 genes. Treatment with somatostatin analogues and dopamine agonists showed minimal therapeutic benefit, but significant side effects. She tested positive for duplication of GPR101 6 years after the initial diagnosis. She was then initiated on pegvisomant aged 12 years, achieving prompt IGF-1 normalization and growth cessation. Aged 16.5 years, she showed escape from IGF-1 control, and height velocity increased, but this responded well to a dose increase in pegvisomant, with reassuring long-term pediatric safety over 7 years. Her final height is +2.9 SD score. Currently, life-long pegvisomant treatment is planned with genetic counselling regarding future offspring.

Abstract Objectives Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality. Diagnosis is often challenging. We describe three cases of ROHHAD with heterogeneous presentations but some consistent clinical features, including hyperprolactinaemia at diagnosis. We highlight when the diagnosis of ROHHAD should be considered at an early stage. Case presentation All three patients presented between 4 and 6 years old with rapid-onset obesity. They all have central hypoventilation requiring nocturnal BiPAP, varying degrees of hypothalamic dysfunction with hyperprolactinaemia being a consistent feature, and autonomic dysfunction. One patient has a neuro-endocrine tumour (NET) and two have glucose dysregulation. Conclusions High prolactin was a consistent early feature. Central hypoventilation and NET may present later and therefore regular sleep studies and screening for NETs are required. A high suspicion of ROHHAD is warranted in patients with rapid, early-onset obesity and hyperprolactinaemia without structural pituitary abnormality.

BackgroundResearch on the effects of the COVID-19 pandemic on people with rare diseases is limited. Few studies compare healthcare throughout the progression of the ongoing pandemic. AimsTo assess the impact of the pandemic on individuals with osteogenesis imperfecta across two consecutive years, understand what challenges were encountered, and analyse the experience of remote consultation. MethodsAn initial survey was distributed following the first lockdown in August 2020, and a second survey in April 2021. The surveys explored four themes- effects on therapy, alternatives to consultation, effect on mental health, and perceived risks of COVID-19. ResultsIn the 2020 survey, of the 110 respondents, 69 (63%) had at least one appointment delayed due to the lockdown, compared with 89 of the 124 respondents (72%) in 2021. Of the 110 respondents in 2020, 57 (52%) had a remote consultation, increasing to 92 of 124 (74%) in the follow-up survey. In the 2020 survey 63 of 91 respondents (69%) expressed anxiety due to lockdown, compared with 76 of 124 (61%) in 2021. The percentage of total respondents expressing a preference for remote consultation was 48% in 2020, increasing to 71% in 2021. ConclusionsThe pandemic has had widespread effects on the mental and physical health of those with OI. These effects, alongside appointment delays, have increased as the pandemic progresses. Encouragingly, the increasing preference for remote consultation may indicate that this could be a viable long-lasting alternative to face-to-face appointments, especially for patients who previously traveled vast distances for specialist care.

Abstract 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.

Objectives: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI. Methods: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging. Results: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients. Conclusion: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI.

Abstract 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.

Abstract 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/Objectives In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. Methods Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. Results One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). Conclusion Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.