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Advances in Therapy Sep 2023Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment... (Review)
Review
BACKGROUND
Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research.
METHODS
Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines.
RESULTS
Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments.
CONCLUSIONS
This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies.
Topics: Humans; Quality of Life; Achondroplasia; Human Growth Hormone; Cost-Benefit Analysis
PubMed: 37382866
DOI: 10.1007/s12325-023-02549-3 -
European Journal of Medical Genetics Nov 2023The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical,...
The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.
Topics: Adolescent; Humans; Child; Adult; Quality of Life; Chronic Pain; Achondroplasia
PubMed: 37758167
DOI: 10.1016/j.ejmg.2023.104850 -
American Journal of Medical Genetics.... Oct 2020Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This... (Meta-Analysis)
Meta-Analysis
Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta-analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer-reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta-analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta-analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (Higgins I of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya-Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality.
Topics: Achondroplasia; Europe; Female; Humans; Male; Middle East
PubMed: 32803853
DOI: 10.1002/ajmg.a.61787 -
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 -
Orphanet Journal of Rare Diseases Jan 2022Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene. Recent advances in drug therapy for ACH have highlighted the importance of elucidating the natural history and socioeconomic burden of this condition. Recognition that there are many potential issues for the patient with ACH is the first step in planning cost-effective interventions in Latin America (LATAM), a vast geographic territory comprising countries with multicultural characteristics and wide socioeconomic differences. We conducted a systematic literature review to characterize the impact of ACH on affected individuals and on healthcare resources in LATAM countries.
METHODS
Searches of the global medical literature as well as regional and local medical literature up to August 2020. Observational studies on patients with ACH from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias.
RESULTS
Fifty-three unique studies (28 case series and cross-sectional studies and 25 case reports) including data on 1604 patients were eligible. Of these studies, 11 had data available for meta-analysis. Both premature mortality and all-cause mortality in the pooled studies was 15% [95% Confidence Interval (CI) 1.0E-3 to 0.47; I = 82.9%, p = 0.0029; three studies, n = 99 patients]. Frequency of cardio-respiratory-metabolic disorders was 17% [95% CI 0.04-0.37; I = 90.3%, p < 0.0001; four studies, n = 230 patients]; nervous system disorders was 18% [95% CI 0.07-0.33; I = 84.6%, p < 0.0001; six studies, n = 262 patients]; ear, nose, throat and speech disorders was 32% [95% CI 0.18-0.48; I = 73.4%, p = 0.0046; five studies, n = 183 patients]; and spinal issues including stenosis, compression and associated pain was 24% [95% CI 0.07-0.47; I = 91.3%, p < 0.0001; five studies, n = 235 patients].
CONCLUSIONS
There is currently evidence of high clinical burden in ACH patients in LATAM countries. Establishing the impact of ACH provides the necessary foundation for planning tailored and effective public health interventions.
Topics: Achondroplasia; Cross-Sectional Studies; Humans; Latin America
PubMed: 34983594
DOI: 10.1186/s13023-021-02142-3 -
Journal of Thoracic Disease Mar 2020Patients with achondroplasia and other causes of dwarfism suffer from increased rates of cardiovascular disease relative to the remainder of the population. Few studies... (Review)
Review
Patients with achondroplasia and other causes of dwarfism suffer from increased rates of cardiovascular disease relative to the remainder of the population. Few studies have examined these patients when undergoing cardiac surgery or percutaneous intervention. This systematic review examines the literature to determine outcomes following cardiac intervention in this unique population. An electronic search was performed in the English literature to identify all reports of achondroplasia, dwarfism, and cardiac intervention. Of the 5,274 articles identified, 14 articles with 14 cases met inclusion criteria. Patient-level data was extracted and analyzed. Median patient age was 55.5 [interquartile ranges (IQR), 43.8, 59.8] years, median height 102.0 [98.8, 112.5] cm, median BMI 32.1 [27.0, 45.9], and 57.1% (8/14) were male. Of these 14 patients, nine had the following documented skeletal abnormalities: 66.7% (6/9) had scoliosis, 66.7% (6/9) had kyphosis, 11.1% (1/9) had lordosis, 11.1% (1/9) pectus carinatum and 11.1% (1/9) spinal stenosis. Coronary artery disease was present in 53.8% (7/13), and 30.8% (4/13) patients previously suffered a myocardial infarction. Of the eight patients who underwent cardiac surgery, 37.5% (3/8) underwent multivessel coronary artery bypass grafting, 37.5% (3/8) underwent aortic valve replacement, 25.0% (2/8) underwent type A aortic dissection repair, and the remaining 12.5% (1/8) underwent pulmonary thromboendarterectomy. Six patients underwent percutaneous intervention. Median cardiopulmonary bypass time was 136.5 [110.0, 178.8] minutes. Median arterial cannula size was 20.0 [20.0, 24.0] Fr. Bicaval cannulation was performed in all cases describing cannulation strategy (5/5). Median superior vena cava cannula size was 28.0 [28.0, 28.0] Fr, and inferior vena cava cannula size was 28.0 [28.0, 28.0] Fr. No mortality was reported with a median follow up time of 6.0 [6.0, 10.5] months. In conclusion, Common cardiac procedures can be performed with reasonable safety in this patient population. Operative adjustments may need to be made with respect to equipment to accommodate patient-specific needs.
PubMed: 32274169
DOI: 10.21037/jtd.2020.02.05 -
Clinical Genetics Jan 2020This article provides an overview of the current knowledge on medical complications, health characteristics, and psychosocial issues in adults with achondroplasia. We... (Review)
Review
This article provides an overview of the current knowledge on medical complications, health characteristics, and psychosocial issues in adults with achondroplasia. We have used a scoping review methodology particularly recommended for mapping and summarizing existing research evidence, and to identify knowledge gaps. The review process was conducted in accordance with the PRISMA-ScR guidelines (Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews). The selection of studies was based on criteria predefined in a review protocol. Twenty-nine publications were included; 2 reviews, and 27 primary studies. Key information such as reference details, study characteristics, topics of interest, main findings and the study author's conclusion are presented in text and tables. Over the past decades, there has only been a slight increase in publications on adults with achondroplasia. The reported morbidity rates and prevalence of medical complications are often based on a few studies where the methodology and representativeness can be questioned. Studies on sleep-related disorders and pregnancy-related complications were lacking. Multicenter natural history studies have recently been initiated. Future studies should report in accordance to methodological reference standards, to strengthen the reliability and generalizability of the findings, and to increase the relevance for implementing in clinical practice.
Topics: Achondroplasia; Adult; Bone Diseases; Female; Female Urogenital Diseases; Humans; Obesity; Otorhinolaryngologic Diseases; Pain; Pregnancy; Quality of Life; Reproducibility of Results; Respiration Disorders; Sleep Wake Disorders; Spinal Stenosis
PubMed: 30916780
DOI: 10.1111/cge.13542 -
BioMed Research International 2014A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders... (Review)
Review
A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.
Topics: Bone Diseases; Bone and Bones; Humans; Osteogenesis; Rare Diseases
PubMed: 25530967
DOI: 10.1155/2014/670842 -
Journal of Children's Orthopaedics Mar 2012Thoracolumbar kyphosis (TLK) is described as a common presentation in children with achondroplasia. However, the prevalence and development of TLK are ill-defined, as...
PURPOSE
Thoracolumbar kyphosis (TLK) is described as a common presentation in children with achondroplasia. However, the prevalence and development of TLK are ill-defined, as well as its clinical implications. The goal of this study was to assess the existing evidence on the prevalence and development of TLK from the literature.
METHODS
A systematic literature review was performed in PubMed, EMBASE, and Thomson Reuters (ISI) Web of Knowledge. Articles were selected and evaluated with the Newcastle-Ottawa Scale in duplicate. Articles were included when the included patients were diagnosed with achondroplasia and the prevalence of TLK in this population was reported.
RESULTS
Seven studies were included. The prevalence of TLK varied between 50 and 100%, but the populations differed significantly. Also, the measurement method and definition of TLK was not given in any of the included studies. Two studies reported TLK in different age categories, but the development of TLK through age could not be inferred. Overall, the methodological quality was low.
CONCLUSIONS
The prevalence rates of TLK in achondroplasia could not be assessed from the literature because the populations differed and the definition of TLK in the studies was not described. In future studies, this definition needs to be given and patients need to be assessed over a longer period of time, with repeated assessments.
PubMed: 22442656
DOI: 10.1007/s11832-011-0378-7 -
Orphanet Journal of Rare Diseases Aug 2012Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically... (Review)
Review
Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically reviewed GSDs as defined in "Nosology and Classification of genetic skeletal disorders (2010 version)" using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% (12,312 cases) of the total cases. Five groups (group 8, 12, 14, 18, 21) defined by "Nosology and Classification of genetic skeletal disorders" have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%). In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.
Topics: Bone Diseases; China; Genetic Diseases, Inborn; Humans; Publishing
PubMed: 22913777
DOI: 10.1186/1750-1172-7-55