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Cureus May 2024Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene....
Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene. Vosoritide, a C-type natriuretic peptide analog, is an emerging treatment for achondroplasia that functions by promoting endochondral ossification. Vosoritide was approved for the treatment of achondroplasia in Europe and the United States in 2021, and in Japan, the following year. However, vosoritide is associated with a risk of hypotension and vomiting after subcutaneous injection due to its vasodilating effect. Herein, we present two cases of cardiovascular adverse events in infants following vosoritide injection. Case 1 involved a one-month-old female infant with achondroplasia who received the first subcutaneous injection of vosoritide 30 minutes after her last formula intake. Following injection, she developed transient symptomatic hypotension accompanied by vomiting. Although established guidelines recommend that injections be administered after approximately 30 minutes (Europe/Japan) or within one hour (USA) following the last feeding, an extended interval of 1.5 to two hours was required to prevent hypotension-associated vomiting. Case 2 involved a three-month-old female infant with achondroplasia. The first subcutaneous vosoritide injection was administered four hours after the last formula intake, and she subsequently developed prolonged compensated shock with marked tachycardia requiring intervention, including repetitive bolus saline injection. These cases indicate the need to monitor patients for cardiovascular adverse events following subcutaneous injection of vosoritide in early infancy.
PubMed: 38841012
DOI: 10.7759/cureus.59695 -
Journal of Biomedical Research May 2024Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common...
Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.
PubMed: 38832540
DOI: 10.7555/JBR.37.20230301 -
EClinicalMedicine May 2024Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in . It presents with disproportionate short stature with a wide range of...
BACKGROUND
Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in . It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia.
METHODS
We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 μg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007).
FINDINGS
Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity.
INTERPRETATION
Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia.
FUNDING
This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.
PubMed: 38813446
DOI: 10.1016/j.eclinm.2024.102591 -
Advances in Therapy Jul 2024Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a... (Review)
Review
Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.
Topics: Achondroplasia; Humans; Adult; Checklist; Spinal Stenosis; Europe; Transition to Adult Care; Sleep Apnea, Obstructive
PubMed: 38748332
DOI: 10.1007/s12325-024-02880-3 -
Journal of Medical Case Reports May 2024People with achondroplasia exhibit distinct physical characteristics, but their cognitive abilities remain within the normal range. The challenges encountered...
BACKGROUND
People with achondroplasia exhibit distinct physical characteristics, but their cognitive abilities remain within the normal range. The challenges encountered during surgical procedures and perioperative care for achondroplastic individuals, are underrepresented in the existing literature.
CASE PRESENTATION
In this report, the management of a 26-year-old North-African achondroplastic male is highlighted. The patient suffered a complete intra-articular distal femur fracture (AO/OTA 33-C1) and an ipsilateral patella fracture (AO/OTA 34-C1). The patient's unusual anatomical variations and the lack of suitable orthopedic implants posed significant surgical challenges, particularly in the context of a resource-limited developing country. Facial and spinal deformities, which are common in patients with achondroplasia, further complicated the anesthetic approach.
CONCLUSIONS
The limited information on operative management of fractures in achondroplastic patients necessitated independent decision-making and diverging from the convenient approach where clear guidance is available in the literature.
Topics: Humans; Adult; Male; Achondroplasia; Femoral Fractures; Patella; Intra-Articular Fractures; Fracture Fixation, Internal
PubMed: 38730409
DOI: 10.1186/s13256-024-04566-4 -
Neurology India Mar 2024Achondroplasia is an autosomal dominant disorder with defect in the ossification of the cartilage of long bones. Many bony abnormalities constitute its clinical...
Achondroplasia is an autosomal dominant disorder with defect in the ossification of the cartilage of long bones. Many bony abnormalities constitute its clinical features, with craniovertebral junction (CVJ) anomalies being one of most common issues which need to be addressed at the earliest. CVJ anomalies in individuals may cause neurovascular compression, which may warrant an early surgery to prevent catastrophic complications. Posterior circulation strokes secondary to CVJ anomalies are well known. We hereby present an unusual case of posterior circulation stroke in an achondroplastic dwarf who presented to our tertiary care centre. Prospective case study. The present case adds to the existing literature about one of the preventable causes of fatal posterior circulation strokes in the young. A high index of suspicion for neurovascular compression at the foramen magnum and early initiation of treatment in achondroplastic young individuals may have gratifying results.
Topics: Humans; Achondroplasia; Foramen Magnum; Risk Factors; Spinal Cord Compression; Stroke
PubMed: 38691484
DOI: 10.4103/ni.ni_537_21 -
CPT: Pharmacometrics & Systems... Apr 2024While randomized, placebo-controlled, double-blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in...
While randomized, placebo-controlled, double-blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in children with achondroplasia should be limited because it provides no clinical benefit while exhausting study participants' treatment window. Recifercept is an investigational drug for treating children with achondroplasia aged 2-10 years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi-variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post-recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12 months post-recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug.
PubMed: 38685585
DOI: 10.1002/psp4.13143 -
Clinical Pharmacokinetics May 2024Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and...
BACKGROUND AND OBJECTIVE
Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen.
METHODS
A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95-15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen.
RESULTS
A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population.
CONCLUSIONS
The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers.
CLINICAL TRIAL REGISTRATION
NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697.
Topics: Humans; Achondroplasia; Child; Adolescent; Models, Biological; Female; Child, Preschool; Male; Body Weight; Infant; Natriuretic Peptide, C-Type; Dose-Response Relationship, Drug
PubMed: 38649657
DOI: 10.1007/s40262-024-01371-6 -
Cureus Mar 2024Sleep-disordered breathing (SDB) is a frequently recognized comorbidity in infants and children with achondroplasia due to alterations in craniofacial and upper airway...
Sleep-disordered breathing (SDB) is a frequently recognized comorbidity in infants and children with achondroplasia due to alterations in craniofacial and upper airway anatomy. Foramen magnum stenosis and cervicomedullary compression can be associated with SDB in this population, requiring prompt evaluation by multidisciplinary teams. Untreated SDB is associated with adverse cardiovascular, metabolic, and behavioral effects in children, necessitating early screening and treatment of underlying causes. Cervicomedullary compression is also associated with increased mortality and sudden infant death in infants with achondroplasia. Management of SDB in children with achondroplasia may involve a combination of neurosurgical intervention, adenotonsillectomy, and/or continuous positive airway pressure (CPAP). We recognize a need for increased physician awareness of the recommended screening guidelines to optimize health outcomes for children with achondroplasia. In this report, we describe a case of a five-month-old infant with achondroplasia and severe SDB diagnosed by polysomnography and was found to have moderate-to-severe foramen magnum stenosis identified by MRI. Subsequently, this infant underwent foramen magnum decompression, which improved the severe SDB and was followed up for five years. Our case illustrates the importance of early screening in infants with achondroplasia for SDB to prevent further sequelae.
PubMed: 38623108
DOI: 10.7759/cureus.56291 -
Journal of Clinical Medicine Apr 2024Achondroplasia is a rare genetic disease, yet the most common form of dwarfism, characterized by limb shortening and disproportionate short stature along with...
Achondroplasia is a rare genetic disease, yet the most common form of dwarfism, characterized by limb shortening and disproportionate short stature along with musculoskeletal changes, such as postural deviations. Although postural changes in the spine in children with achondroplasia have been well investigated, little is known about the association of achondroplasia with spinal movements/mobility. This preliminary study aims to explore the association of achondroplasia with spinal mobility in children with achondroplasia compared to age- and sex-matched healthy individuals. Spinal posture and mobility were assessed using a radiation-free back scan, the Idiag M360 (Idiag, Fehraltorf, Switzerland). Between-group differences were determined using a two-way analysis of variance. Children with achondroplasia had smaller thoracic lateral flexion [difference between groups (Δ) = 20.4°, 95% CI 0.1°-40.6°, = 0.04], lumbar flexion (Δ = 17.4°, 95% CI 5.5°-29.4°, = 0.006), lumbar extension (Δ = 14.2°, 95% CI 5.7°-22.8°, = 0.002) and lumbar lateral flexion (Δ = 19.6°, 95% CI 10.7°-28.4°, < 0.001) than age- and sex-matched healthy individuals, except for thoracic extension (Δ = 16.5°, 95% CI 4.4°-28.7°, = 0.009) which was greater in children with achondroplasia. No differences were observed in global spinal postures between the two groups. Spinal mobility appears to be more influenced by achondroplasia than global spinal postures in childhood. These results also highlight the importance of considering the musculoskeletal assessment of segmental spinal postures and rehabilitative interventions aimed at promoting spinal flexibility in children with achondroplasia.
PubMed: 38610900
DOI: 10.3390/jcm13072135