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BACKGROUND: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. METHODS: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. RESULTS: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. CONCLUSIONS: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available.
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Current international consensus of the appropriate Beighton score cut-off to define if a child has generalised joint hypermobile or not is based upon expert opinion. Our aim was to determine the prevalence of Beighton scores of children worldwide to provide a recommendation for establishing the Beighton score cut-off to identify generalised joint hypermobility in children. We used AMED, OVID Medline, Embase and CINAHL to find published articles from inception to April 2024 describing Beighton scores of children up to and including 18 years from the general population. We extracted study demographics including country of publication, total number of participants, summary data about the age and sex of participant, Beighton scores and any cut-off used where authors deemed children hypermobile and how many children were rated at the corresponding Beighton scores. There were 37 articles reporting on the prevalence or incidence of hypermobility at cut-off scores from 28,868 participants. Using the cut-off of ≥ 6 resulted in a prevalence of 6% for studies reporting male data and 13% for studies reporting female data. Limited data reporting availability precluded further sub-analysis at a Beighton score of ≥ 7, age, pubertal status and ethnicity. Conclusion: The working threshold for identifying generalised joint hypermobility in children should be a Beighton score of 6 or more. Our analysis also suggests a Beighton score of 7 or greater may be appropriate in childhood, particularly for females. What is Known: ⢠The working threshold for identifying generalised joint hypermobility in children previously was set based on expert opinion. What is New: ⢠The threshold to identify hypermobility in children should be at a minimum of ≥ 6 on the Beighton score.
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Inestabilidad de la Articulación , Humanos , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/epidemiología , Niño , Adolescente , Femenino , Masculino , Prevalencia , PreescolarRESUMEN
BACKGROUND: Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years. METHODS: This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 µg/kg for infants aged 0-23 months; 15·0 µg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697. FINDINGS: Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53). INTERPRETATION: Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline. FUNDING: BioMarin Pharmaceutical.
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Acondroplasia , Gastroenteritis , Femenino , Humanos , Lactante , Masculino , Acondroplasia/tratamiento farmacológico , Método Doble Ciego , Péptido Natriurético Tipo-C/uso terapéutico , PreescolarRESUMEN
PURPOSE: Electrotherapies are commonly used to treat adult musculoskeletal pathologies. However, there is insufficient evidence supporting the use of electrotherapies for lower limb conditions in children. Currently, it is unknown how electrotherapies are used in paediatric clinical practice. This study aimed to investigate if practitioners use electrotherapy to treat children's lower limb conditions, frequency and why. MATERIALS AND METHODS: A custom-built online survey was disseminated via social media targeting international medical and healthcare practitioners who treat children with lower limb conditions using electrotherapy. Practitioners were asked if they did or did not use electrotherapies, and their reasons. Responses were described in frequencies and with thematic analysis. RESULTS: There were 445 practitioners who responded. From these, 301(68%) indicated they used electrotherapy, with the most frequently used being Transcutaneous Electrical Nerve Stimulation (n = 110). The most common reason cited for using electrotherapy was practitioner preference due to the alleged effectiveness of the chosen modality. The remaining 144 (32%) practitioners reported not using electrotherapy, the most common reason being lack of evidence. CONCLUSIONS: We found that a majority of practitioners used electrotherapies on children. The reasons for using or not using electrotherapy were practitioner centred.
Electrotherapy modalities are commonly used to treat musculoskeletal injuries in adultsThe management of children differs from adults due to physiological and psychological differences.The use of electrotherapy to treat musculoskeletal lower limb pathologies children is currently not supported by evidence, and the frequency of use of these modalities in children is not known.This study found that despite that, a majority of medical and health practitioners surveyed in this study routinely use electrotherapy to treat paediatric musculoskeletal injuries.
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The purpose of this study was to evaluate the effect of custom-made orthotics on pain, health-related quality of life (HRQoL), function and fatigue in children and adolescents with generalised joint hypermobility (GJH) and lower limb pain. Fifty-three children aged 5-18 years were fitted with custom-made polypropylene orthotics. Visual analogue scale (VAS) assessed lower limb pain severity, Paediatric Quality of Life Inventory assessed HRQoL and fatigue and six-minute walk test (6 MWT) measured functional endurance at baseline, at 1 month and 3 months post-intervention. A mixed model including a random intercept for participant and a fixed effect for time was used to assess differences in outcomes over time. Fifty-two children completed the study (mean age 10.6-years). Children reported significantly reduced pain (mean VAS reduction -27/100, 95%CI: -33, -21), improved HRQoL (mean total improvement 11/100, 95%CI: 7, -15), functional capacity (mean 6MWT improvement 27 m, 95%CI: 18, -36) and fatigue (mean total improvement 13/100, 95%CI: 9, -17) after 1 month of wearing the custom-made orthotics. From 1 month to 3 months there was further statistically but not clinically significant reduction in pain while benefit on other outcomes was maintained. In this study, children with GJH reported reduced lower limb pain, improved HRQoL, functional endurance and fatigue after a month post-fitting of custom-made orthotics which was maintained over a 3 month period. Orthotics were well-tolerated with no serious adverse events reported.
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Inestabilidad de la Articulación , Medicina , Humanos , Adolescente , Niño , Calidad de Vida , Fatiga , DolorRESUMEN
BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.
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Enfermedades del Tejido Conjuntivo , Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Adulto , Adolescente , Humanos , Niño , Inestabilidad de la Articulación/diagnóstico , Síndrome de Ehlers-Danlos/diagnóstico , PielRESUMEN
Achondroplasia is the most common form of skeletal dysplasia. In addition to altered growth, children and young people with achondroplasia may experience medical complications, develop and function differently to others and require psychosocial support. International, European and American consensus guidelines have been developed for the management of achondroplasia. The Australian focused guidelines presented here are designed to complement those existing guidelines. They aim to provide core care recommendations for families and clinicians, consolidate key resources for the management of children with achondroplasia, facilitate communication between specialist, local teams and families and support delivery of high-quality care regardless of setting and geographical location. The guidelines include a series of consensus statements, developed using a modified Delphi process. These statements are supported by the best available evidence assessed using the National Health and Medicine Research Council's criteria for Level of Evidence and their Grading of Recommendations Assessment, Development and Evaluation (GRADE). Additionally, age specific guides are presented that focus on the key domains of growth, medical, development, psychosocial and community. The guidelines are intended for use by health professionals and children and young people with achondroplasia and their families living in Australia.
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Acondroplasia , Humanos , Niño , Adolescente , Australia , Acondroplasia/terapia , Acondroplasia/psicología , Consenso , Calidad de la Atención de Salud , ComunicaciónRESUMEN
BACKGROUND: Rapid advances in mobile apps for clinical data collection for pain evaluation have resulted in more efficient data handling and analysis than traditional paper-based approaches. As paper-based visual analogue scale (p-VAS) scores are commonly used to assess pain levels, new emerging apps need to be validated prior to clinical application with symptomatic children and adolescents. OBJECTIVE: This study aimed to assess the validity and reliability of an electronic visual analogue scale (e-VAS) method via a mobile health (mHealth) App in children and adolescents diagnosed with hypermobility spectrum disorder/hypermobile Ehlers-Danlos syndrome (HSD/HEDS) in comparison with the traditional p-VAS. METHODS: Children diagnosed with HSD/HEDS aged 5-18 years were recruited from a sports medicine center in Sydney (New South Wales, Australia). Consenting participants assigned in random order to the e-VAS and p-VAS platforms were asked to indicate their current lower limb pain level and completed pain assessment e-VAS or p-VAS at one time point. Instrument agreement between the 2 methods was determined from the intraclass correlation coefficient (ICC) and through Bland-Altman analysis. RESULTS: In total, 43 children with HSD/HEDS aged 11 (SD 3.8) years were recruited and completed this study. The difference between the 2 VAS platforms of median values was 0.20. Bland-Altman analysis revealed a difference of 0.19 (SD 0.95) with limits of agreement ranging -1.67 to 2.04. An ICC of 0.87 (95% CI 0.78-0.93) indicated good reliability. CONCLUSIONS: These findings suggest that the e-VAS mHealth App is a validated tool and a feasible method of collecting pain recording scores when compared with the traditional paper format in children and adolescents with HSD/HEDS. The e-VAS App can be reliably used for pediatric pain evaluation, and it could potentially be introduced into daily clinical practice to improve real-time symptom monitoring. Further research is warranted to investigate the usage of the app for remote support in real clinical settings.
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PURPOSE: 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. METHODS: 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. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 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 participants <1 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 aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: 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.
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Acondroplasia , Niño , Masculino , Femenino , Humanos , Preescolar , Estudios Prospectivos , Acondroplasia/epidemiología , Acondroplasia/genética , Acondroplasia/diagnóstico , EstaturaRESUMEN
BACKGROUND: Managing children and adolescents with syndromic hypermobility and their parents is challenging in the context of a standard consultation. The multi-organ involvement of the syndromes, the evolving classification criteria and their highly heterogeneous presentation complicate both diagnosis and management. OBJECTIVE: The purpose of this article is to provide an overview of the diagnosis, management and support of children with hypermobility syndromes, including the role of the multidisciplinary team and common associated features. DISCUSSION: Optimising the quality of life of people with syndromic hypermobility begins with the early identification of their signs and symptoms. Diagnosis, ideally by adolescence, provides affected children and their parents with validation and directs their focus to management aimed at mitigating the socioeconomic, educational and health-related quality of life impact of these conditions.
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Inestabilidad de la Articulación , Calidad de Vida , Adolescente , Niño , Humanos , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/terapia , SíndromeRESUMEN
AIM: To determine the rates of medical investigations, complications, interventions, and outcomes in children with achondroplasia. METHOD: Children and adolescents with achondroplasia born between 2000 and 2019, aged between 0 and 18 years of age, and seen at The Children's Hospital at Westmead skeletal dysplasia clinic were included. Data were collected retrospectively from clinical records. Standard descriptive statistics were used for analysis. RESULTS: The study included 108 participants, 58 males and 50 females. Ninety-nine participants (91.7%) entered the study at birth. The other nine (8.3%) participants entered the study after birth (mean age = 2 years 4 months, SD = 1 year 8 months). The median age of exit from the study was 8 years 8 months (IQR = 8 years 9 months) with a median follow-up of 8 years 8 months (IQR = 8 years 9 months). Fifty-two (48%) participants presented with craniocervical stenosis, 15 (13.9%) with hydrocephalus, 66 (61.1%) with hearing impairment, 44 (40.7%) with sleep-disordered breathing, 46 (42.6%) with lower-limb malalignment, 24 (22.2%) with thoracolumbar kyphosis, 10 (9.3%) with symptomatic spinal stenosis, 12 (11.1%) with obesity, and 16 (14.8%) who had at least one admission for respiratory illness. Two children died during the study period. INTERPRETATION: We report contemporary rates of medical complications in an Australian population of children with achondroplasia. Recommendations for surveillance in clinical practice are discussed. This information will help guide clinicians with their expectant management of achondroplasia and provide prognostic information to the families of children with achondroplasia.
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Acondroplasia , Cifosis , Estenosis Espinal , Acondroplasia/complicaciones , Acondroplasia/epidemiología , Adolescente , Australia , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Cifosis/complicaciones , Masculino , Estudios RetrospectivosRESUMEN
Orthostatic intolerance (OI) is frequently reported in young women with generalized hypermobility spectrum disorder (G-HSD) and hypermobile EDS (hEDS). However, it remains currently unclear whether OI is a comorbidity or fundamental part of the pathophysiology of G-HSD or hEDS. This study investigated the prevalence and impact of OI in young women across the hypermobility spectrum. Forty-five women (14-30 years, 15 controls, 15 G-HSD, and 15 hEDS) undertook a head-up tilt (HUT) and active stand test. Postural Orthostatic Tachycardia Syndrome (POTS) and Orthostatic Hypotension (OH) were assessed using age-related criteria. Autonomic dysfunction and quality-of-life questionnaires were also completed. The prevalence of POTS was higher in women with G-HSD than hEDS and control groups during HUT (43% vs. 7% and 7%, respectively, p < 0.05), but similar between groups during the active stand (47%, 27%, and 13% for G-HSD, hEDS, and control, respectively). No participants had OH. hEDS and G-HSD participants reported more severe orthostatic symptoms and poorer quality of life than controls. Although POTS was observed in hypermobile participants, there is no conclusive evidence that its prevalence differed between groups due to differences between the HUT and active stand assessments. Nevertheless, OI and broader autonomic dysfunction impacted on their quality of life.
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Síndrome de Ehlers-Danlos , Inestabilidad de la Articulación , Intolerancia Ortostática , Síndrome de Taquicardia Postural Ortostática , Síndrome de Ehlers-Danlos/diagnóstico , Femenino , Humanos , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/epidemiología , Intolerancia Ortostática/epidemiología , Síndrome de Taquicardia Postural Ortostática/diagnóstico , Síndrome de Taquicardia Postural Ortostática/epidemiología , Prevalencia , Calidad de VidaRESUMEN
PURPOSE: Longitudinal fibular deficiency (LFD) is the most common congenital long bone deficiency. This study aimed to objectively assess the physical performance of children and adolescents with LFD compared with unaffected peers, and to examine trends over age for subgroups of the LFD population. METHODS: Differences between children with LFD and unaffected peers were examined with hand-held dynamometry for lower-limb muscle strength, Six-Minute Walk Test, Timed up and down stairs test, Star Excursion Balance Test, and Standing long jump. RESULTS: Thirty-nine children with LFD and 284 unaffected peers participated. Children with LFD performed at a lower level than their unaffected peers, on all measures of physical performance (mean 2.1 z-scores lower, all p < 0.01), except in long jump (p = 0.27). When comparing the performance of children with LFD to their unaffected peers across four age groups, there was a significant between-groups difference on all strength measures, and on the Six-Minute Walk distance, between children with and without LFD. These differences were smallest in young children (3-6 years) and largest in the older children (15-18 years) (all p < 0.01). Children with no lengthening surgery performed better on the Six-Minute Walk Test, covering a greater distance during the test, than those who had surgery (mean difference 83 metres, p < 0.01). There were no significant differences between children who had or had not undergone an amputation. CONCLUSIONS: Children with LFD performed at a significantly lower level than unaffected peers on all measures of physical performance other than jumping. The largest differences were in older children. This paper provides baseline functional data for future interventions in LFD. LEVEL OF EVIDENCE: Cross-sectional study.Implications for RehabilitationThis paper provides the first baseline functional data using validated objective measures on a consecutive cohort of children and adolescents with longitudinal fibular deficiency.Children with LFD performed significantly worse than their unaffected peers on all measures of physical performance other than jumping, with children falling further behind their peers as they age.Children who undergo an amputation typically have the most severe anatomical presentation and yet perform at an equivalent functional level.This paper identifies multiple modifiable impairments that represent potential opportunities for rehabilitation professionals to target with conservative treatment options to improve functional performance.
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Ectromelia , Adolescente , Amputación Quirúrgica , Niño , Preescolar , Estudios Transversales , Ectromelia/cirugía , Peroné/anomalías , Peroné/cirugía , Humanos , Rendimiento Físico FuncionalRESUMEN
BACKGROUND: Generalised joint hypermobility (GJH) is highly prevalent among children and associated with symptoms in a fifth with the condition. This study aimed to synthesise outcome measures in interventional or prospective longitudinal studies of children with GJH and associated lower limb symptoms. METHODS: Electronic searches of Medline, CINAHL and Embase databases from inception to 16th March 2020 were performed for studies of children with GJH and symptoms between 5 and 18 years reporting repeated outcome measures collected at least 4 weeks apart. Methodological quality of eligible studies were described using the Downs and Black checklist. RESULTS: Six studies comprising of five interventional, and one prospective observational study (total of 388 children) met the inclusion criteria. Interventional study durations were between 2 and 3 months, with up to 10 months post-intervention follow-up, while the observational study spanned 3 years. Three main constructs of pain, function and quality of life were reported as primary outcome measures using 20 different instruments. All but one measure was validated in paediatric populations, but not specifically for children with GJH and symptoms. One study assessed fatigue, reporting disabling fatigue to be associated with higher pain intensity. CONCLUSIONS: There were no agreed sets of outcome measures used for children with GJH and symptoms. The standardisation of assessment tools across paediatric clinical trials is needed. Four constructs of pain, function, quality of life and fatigue are recommended to be included with agreed upon, validated, objective tools.
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Inestabilidad de la Articulación , Calidad de Vida , Niño , Humanos , Inestabilidad de la Articulación/diagnóstico , Estudios Observacionales como Asunto , Evaluación de Resultado en la Atención de Salud , Dimensión del Dolor , Estudios ProspectivosRESUMEN
PURPOSE: Achondroplasia 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. METHODS: After 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. RESULTS: In 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. CONCLUSION: Vosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.
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Acondroplasia , Péptido Natriurético Tipo-C , Acondroplasia/tratamiento farmacológico , Acondroplasia/genética , Niño , Método Doble Ciego , Humanos , Péptido Natriurético Tipo-C/análogos & derivados , Péptido Natriurético Tipo-C/uso terapéutico , Resultado del TratamientoRESUMEN
Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology, and interrelationships of achondroplasia-related comorbidities across the lifespan. When possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.
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Acondroplasia , Foramen Magno , Acondroplasia/genética , Adolescente , Adulto , Niño , Estudios Transversales , Humanos , Estudios LongitudinalesRESUMEN
The aim of this study was to estimate the childhood prevalence of achondroplasia, trends over time in birth prevalence, and age at diagnosis in Australia. Children born between 1990 and 2019 with a clinical and radiological and/or molecular diagnosis of achondroplasia were identified from a tertiary hospital servicing New South Wales (NSW) and the Australian Capital Territory (ACT) and compared with population data from the Australian Bureau of Statistics. Childhood prevalence of achondroplasia, based on children ≤19 years of age and resident in NSW/ACT on June 30, 2019 (n = 109), was 5.2 per 100,000. A total of 127 individuals with achondroplasia were born in 1990-2019 in NSW/ACT. Birth prevalence rates increased across birth decades, from 3.3 per 100,000 live births in 1990-1999 to 5.3 per 100,000 in 2010-2019 (p < 0.0001). Median age at diagnosis decreased to 17 days in 2010-2019 compared with 30 days in 1990-1999 (p = 0.035), although the overall decreasing trend across consecutive decades did not reach statistical significance. This is the first study to show a rising birth prevalence rate for achondroplasia in Australia with a concurrent decreasing age at diagnosis, both of which were statistically significant after 2 decades.
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Acondroplasia/diagnóstico , Acondroplasia/epidemiología , Prevalencia , Acondroplasia/genética , Acondroplasia/patología , Adolescente , Australia/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Nacimiento Vivo , Masculino , Nativos de Hawái y Otras Islas del Pacífico/genética , Nueva Gales del Sur/epidemiología , EmbarazoRESUMEN
BACKGROUND: Skeletal dysplasia are genetic disorders of cartilage and bone, characterized by impairments commonly resulting in short stature, altered movement biomechanics, pain, fatigue and reduced functional performance. While current tools quantify functional mobility performance, they have not been standardly used in this population group and do not capture patient-reported symptoms such as pain or fatigue. This study evaluated a new tool, the Screening Tool for Everyday Mobility and Symptoms (STEMS), designed to accurately and objectively assess functional mobility and associated symptomology for individuals with skeletal dysplasia. METHODS: Individuals aged 5-75 years with a skeletal dysplasia completed the STEMS, the Functional Mobility Scale (FMS) and Six Minute Walk Test (6MWT). The correlation among the STEMS, use of mobility aides, FMS and 6MWT normalised for leg length was calculated. One-way analysis of variance compared the STEMS symptomatology to normalised 6MWT distance. RESULTS: One hundred and fifty individuals with skeletal dysplasia (76 achondroplasia, 42 osteogenesis imperfecta, 32 other; 74 < 18 years, 76 ≥ 18 years) participated. Almost two thirds of the group reported pain and/or fatigue when mobilising at home, at work or school and within the community, but only twenty percent recorded use of a mobility device. The STEMS setting category demonstrated highly significant correlations with the corresponding FMS category (r = - 0.983 to - 0.0994, all p < 0.001), and a low significant correlation with the normalised 6MWT distance (r = - 0.323 to - 0.394, all p < 0.001). A decreased normalised 6MWT distance was recorded for individuals who reported symptoms of pain and/or fatigue when mobilising at home or at work/school (all p ≤ 0.004). Those who reported pain only when mobilising in the community had a normal 6MWT distance (p = 0.43-0.46). CONCLUSIONS: The Screening Tool for Everyday Mobility and Symptoms (STEMS) is a useful new tool to identify and record mobility aide use and associated self-reported symptoms across three environmental settings for adults and children with skeletal dysplasia. The STEMS may assist clinicians to monitor individuals for changes in functional mobility and symptoms over time, identify individuals who are functioning poorly compared to peers and need further assessment, and to measure effectiveness of treatment interventions in both clinical and research settings.
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Fatiga , Dolor , Adulto , Niño , Humanos , Tamizaje Masivo , Prueba de PasoRESUMEN
BACKGROUND: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings. METHODS: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 µg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11. FINDINGS: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred. INTERPRETATION: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be. FUNDING: BioMarin Pharmaceutical.
Asunto(s)
Acondroplasia/tratamiento farmacológico , Péptido Natriurético Tipo-C/análogos & derivados , Osteogénesis , Absorciometría de Fotón , Acondroplasia/sangre , Adolescente , Biomarcadores/sangre , Estatura , Densidad Ósea , Niño , Preescolar , Colágeno Tipo X/sangre , Método Doble Ciego , Femenino , Humanos , Reacción en el Punto de Inyección , Inyecciones Subcutáneas , Masculino , Péptido Natriurético Tipo-C/uso terapéuticoRESUMEN
Longitudinal fibular deficiency (LFD), or fibular hemimelia, is congenital partial or complete absence of the fibula. We aimed to compare the lower limb function of children and young people with LFD to that of unaffected peers. A cross-sectional study of Australian children and young people with LFD, and of unaffected peers, was undertaken. Twenty-three (12 males) children and young people with LFD (74% of those eligible) and 213 unaffected peers, all aged 7â»21 years were subject to the Knee Osteoarthritis Outcome Score (KOOS/KOOS-Child) and the Cumberland Ankle Instability Tool (CAIT/CAIT-Youth). Linear regression models compared affected children and young people to unaffected peers. Participants with LFD scored lower in both outcomes (adjusted p < 0.05). The difference between participants with LFD and unaffected peers was significantly greater among younger participants than older participants for KOOS activities and sports domain scores (adjusted p ≤ 0.01). Differences in the other KOOS domains (pain/symptoms/quality of life) and ankle function (CAIT scores) were not affected by age (adjusted p ≥ 0.08). Children and young people with LFD on average report reduced lower limb function compared to unaffected peers. Knee-related activities and sports domains appear to be worse in younger children with LFD, and scores in these domains become closer to those of unaffected peers as they become older.