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Drugs of Today (Barcelona, Spain : 1998) Sep 2022Achondroplasia is the commonest form of dwarfism and results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. The mutation...
Achondroplasia is the commonest form of dwarfism and results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. The mutation is at nucleotide 1138 resulting in a G-to-A transition (134934.0001). This condition is characterized by full penetration meaning that everyone with this genetic mutation will exhibit the phenotypic characteristics of achondroplasia. It is a gain-of function mutation that causes increased inhibition of cartilage formation. C-type natriuretic peptide (CNP) acts on the growth plate through the natriuretic peptide receptor-B (NPR-B) causing the transformation of guanosine 5'-triphosphate into cyclic guanosine monophosphate. However, CNP cannot be used in the treatment of achondroplasia because it is rapidly degraded by neutral endopeptidase. Vosoritide is a modified recombinant human CNP and has a half-life 10 times that of CNP. Clinical trials have demonstrated that vosoritide is effective in significantly increasing the annualized growth velocity in children with achondroplasia before the fusion of the epiphyses.
Topics: Achondroplasia; Child; Humans; Mutation; Natriuretic Peptide, C-Type; Neprilysin
PubMed: 36102905
DOI: 10.1358/dot.2022.58.9.3422313 -
Orphanet Journal of Rare Diseases Aug 2022Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of...
BACKGROUND
Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of achondroplasia in adults has, until recently, been relatively lacking, and little is known about the care they receive or how they access it. The European Achondroplasia Forum undertook two exploratory surveys, one for healthcare professionals (HCPs) and one for patient advocacy group (PAG) representatives, to gain an understanding of current practices of the transition process of individuals with achondroplasia from paediatric to adult services and how adults perceive their care.
RESULTS
Most HCP respondents followed up more children than adults, and 8/15 responded that individuals did not transition to an adult multidisciplinary team (MDT) after paediatric care. Of 10 PAG respondents, none considered the experience of transition to adult services as good or very good and 50% considered it to be poor or very poor. A total of 64% (7/11) described the coordination of transition to adult services as "Not satisfactory" or "Poor". HCPs and PAG representatives largely agreed on the core specialists involved in adult care (orthopaedic surgeons, physiotherapists, rehabilitation specialists, rheumatologists, clinical geneticists). However, there was a discrepancy in the understanding of healthcare needs outside of this, with PAG representatives selecting neurosurgeons and genetic counsellors, while HCPs selected pulmonologists and obstetricians/gynaecologists. There was agreement between HCP and PAG respondents on the key barriers to effective care of adults with achondroplasia, with lack of an adult MDT, lack of interest from individuals in accessing care, and less experience in adult than paediatric MDTs ranking highly.
CONCLUSIONS
This study indicates that the care and follow up of adults with achondroplasia is challenging. Individuals are often lost to, or decline, follow up as they leave paediatric care, and it is largely unknown how, where, and why adults with achondroplasia access care later in life. Lifelong, multidisciplinary specialist care led by an identified physician should be accessible to all individuals with achondroplasia. It is important to ensure barriers to optimal care are addressed to enable access to appropriate care for all individuals with achondroplasia.
Topics: Achondroplasia; Adult; Child; Delivery of Health Care; Follow-Up Studies; Humans; Surveys and Questionnaires
PubMed: 35987833
DOI: 10.1186/s13023-022-02479-3 -
Pediatric Clinics of North America Oct 2023Achondroplasia is the most common form of disproportionate severe short stature. Management of achondroplasia requires a multidisciplinary approach and has been largely... (Review)
Review
Achondroplasia is the most common form of disproportionate severe short stature. Management of achondroplasia requires a multidisciplinary approach and has been largely symptomatic for medical complications and psychosocial implications. Increased understanding of genetic and molecular mechanisms of achondroplasia has led to the development of novel disease-modifying drugs. The current drugs under investigation target the growth plate to stimulate chondrocyte growth and development. These include analogs of C-type natriuretic peptide (CNP), FGFR3-selective tyrosine kinase inhibitors, anti-FGFR3 antibodies, aptamers against FGF2, and soluble forms of FGFR3. Long-term data on the effects of these therapies on medical comorbidities are pending at this time.
Topics: Humans; Achondroplasia; Growth Disorders
PubMed: 37704353
DOI: 10.1016/j.pcl.2023.05.008 -
American Journal of Medical Genetics.... Dec 2020Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive... (Review)
Review
Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.
Topics: Argentina; Bone and Bones; Humans; Latin America; Osteochondrodysplasias; Prevalence
PubMed: 33219737
DOI: 10.1002/ajmg.c.31861 -
Children (Basel, Switzerland) Jun 2021Extensive limb lengthening (ELL) was completed in 75 patients: 66 achondroplasia and 9 hypochondroplasia. The average lengthening was 27 cm for achondroplasia (12-40 cm)... (Review)
Review
Extensive limb lengthening (ELL) was completed in 75 patients: 66 achondroplasia and 9 hypochondroplasia. The average lengthening was 27 cm for achondroplasia (12-40 cm) and 17 cm for hypochondroplasia (range 10-25 cm). There were 48 females and 27 males. Lengthening was done either by 2-segment (14 patients; both tibias and/or both femurs) or by 4-segment lengthenings (64 patients; both femurs and tibias at the same time). Most patients also had bilateral humeral lengthening. Patients had 2 or 3 lower limb lengthenings and one humeral lengthening. Lengthenings were either juvenile-onset (31), adolescent-onset (38) or adult-onset (6). The average age at final follow-up was 26 years old (range 17-43 years). There were few permanent sequelae of complications. The most serious was one paraparesis. All patients returned to activities of normal living and only one was made worse by the surgery (paraparesis). This is the first study to show that ELL can lead to an increase of height into the normal height range. Previous studies showed mean increases of height of up to 20 cm, while this study consistently showed an average increase of 30 cm (range 15-40 cm) for juvenile-onset and mean increase of 26 cm (range 15-30 cm) for adolescent-onset. This results in low normal height at skeletal maturity for males and females. The adult-onset had a mean increase of 16.8 (range 12-22 cm). This long-term follow-up study shows that ELL can be done safely even with large lengthenings and that 4-segment lengthening may offer advantages over 2-segment lengthening. While all but the more recent cases were performed using external fixation, implantable limb lengthening promises to be an excellent alternative and perhaps an improvement.
PubMed: 34202538
DOI: 10.3390/children8070540 -
Developmental Medicine and Child... Aug 2022To determine the rates of medical investigations, complications, interventions, and outcomes in children with achondroplasia.
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.
Topics: Achondroplasia; Adolescent; Australia; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Kyphosis; Male; Retrospective Studies; Spinal Stenosis
PubMed: 35238031
DOI: 10.1111/dmcn.15194 -
Journal of Bone and Mineral Metabolism Mar 2022Achondroplasia (ACH) is the most common skeletal dysplasia and characterized by a disproportionate short stature, macrocephaly with frontal bossing, exaggerated lumbar... (Review)
Review
Achondroplasia (ACH) is the most common skeletal dysplasia and characterized by a disproportionate short stature, macrocephaly with frontal bossing, exaggerated lumbar lordosis, and trident hands. It is induced by activated mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In addition to short stature, patients with ACH have a high prevalence of medical complications, including upper airway obstructive apnea, increased mortality, foramen magnum stenosis, hydrocephalus, developmental delay, recurrent ear infections, genu varum, obesity, and spinal canal stenosis, throughout their whole life. Several investigational drugs that modulate abnormal FGFR3 signaling have recently emerged, vosoritide being the most developed. This review presents the different disease-specific complications of ACH occurring in neonates, infants, childhood, adolescent, and adults and reports the current multidisciplinary interventions for these various complications. Moreover, we propose treatment strategies for children with ACH from the perspective of quality of life in adulthood.
Topics: Achondroplasia; Adolescent; Adult; Animals; Child; Humans; Infant; Infant, Newborn; Mutation; Quality of Life; Sleep Apnea, Obstructive; Spinal Stenosis
PubMed: 35028714
DOI: 10.1007/s00774-021-01298-z -
International Journal of Molecular... Nov 2022Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among... (Review)
Review
Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among people over 50 years old. We perform a systematic review of molecular and genetic mechanisms that cause SS. The five main mechanisms of SS were found to be ossification of the posterior longitudinal ligament (OPLL), hypertrophy and ossification of the ligamentum flavum (HLF/OLF), facet joint (FJ) osteoarthritis, herniation of the intervertebral disc (IVD), and achondroplasia. FJ osteoarthritis, OPLL, and HLF/OLFLF/OLF have all been associated with an over-abundance of transforming growth factor beta and genes related to this phenomenon. OPLL has also been associated with increased bone morphogenetic protein 2. FJ osteoarthritis is additionally associated with Wnt/β-catenin signaling and genes. IVD herniation is associated with collagen type I alpha 1 and 2 gene mutations and subsequent protein dysregulation. Finally, achondroplasia is associated with fibroblast growth factor receptor 3 gene mutations and fibroblast growth factor signaling. Although most publications lack data on a direct relationship between the mutation and SS formation, it is clear that genetics has a direct impact on the formation of any pathology, including SS. Further studies are necessary to understand the genetic and molecular changes associated with SS.
Topics: Humans; Middle Aged; Spinal Stenosis; Ossification of Posterior Longitudinal Ligament; Ligamentum Flavum; Achondroplasia; Osteoarthritis
PubMed: 36362274
DOI: 10.3390/ijms232113479 -
Osteoarthritis and Cartilage Apr 2022Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex... (Review)
Review
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3.
Topics: Achondroplasia; Humans; Mutation; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction
PubMed: 34864168
DOI: 10.1016/j.joca.2021.11.017 -
Hormone Research in Paediatrics 2023Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic... (Review)
Review
BACKGROUND
Several novel treatment options have recently become available in childhood bone diseases. The purpose of this article is to provide an update on some of the therapeutic agents used in the treatment of pediatric osteoporosis, X-linked hypophosphatemic rickets, and achondroplasia (ACH).
SUMMARY
Vitamin D3 and Ca supplementation remains the basis of childhood osteoporosis treatment. Bisphosphonate (BP) therapy is the main antiresorptive therapeutic option, while denosumab, a human monoclonal IgG2 antibody with high affinity and specificity for a primary regulator of bone resorption - RANKL, represents a possible alternative. Its potent inhibition of bone resorption and turnover process leads to continuous increase of bone mineral density throughout the treatment also in the pediatric population. With a half-life much shorter than BPs, its effects are rapidly reversible upon discontinuation. Safety and dosing concerns in children remain. Novel treatment options have recently become available in two rare bone diseases. Burosumab, a monoclonal antibody against FGF-23, has been approved for the treatment of children with X-linked hypophosphatemic rickets older than 1 year. It presents an effective, more etiology-based treatment for rickets compared to conventional therapy, without the need for multiple daily oral phosphate supplementation. Its long-term efficacy and safety are currently being investigated. After years of anticipation, a novel treatment option for ACH has become available. C-type natriuretic peptide analog vosoritide effectively increases proportional growth and has a reasonable safety profile in children >2 years. Its effect on other features of the disease and the final height is yet to be determined. Several other treatment options for ACH exploring different therapeutic approaches are currently being investigated.
KEY MESSAGES
Denosumab is effective in the treatment of childhood-onset osteoporosis; however, further studies are necessary to determine the optimal treatment protocol. Burosumab is more etiology-based and convenient in comparison to conventional treatment of X-linked hypophospha
-- temic rickets in children and adults. Vosoritide importantly changes the natural course of achondroplasia, at least in the short term.Topics: Adult; Humans; Child; Denosumab; Familial Hypophosphatemic Rickets; Antibodies, Monoclonal; Osteoporosis; Bone Density; Bone Resorption; Achondroplasia
PubMed: 35235937
DOI: 10.1159/000523868