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Endocrine Journal Apr 2024Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the...
Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.
PubMed: 38569854
DOI: 10.1507/endocrj.EJ24-0109 -
Journal of Children's Orthopaedics Apr 2024Literature regarding total hip arthroplasty for pediatric hip diseases is scarce. This review aims to portray the various orthopedic conditions of childhood that can... (Review)
Review
PURPOSE
Literature regarding total hip arthroplasty for pediatric hip diseases is scarce. This review aims to portray the various orthopedic conditions of childhood that can lead to significant impairment of the hip joint and, ultimately, to total hip arthroplasty in adolescence and adulthood.
METHODS
In total, 61 out of 3666 articles were selected according to (1) the diagnosis of one of the 12 pediatric hip pathologies (Legg-Perthes-Calvé disease, developmental dysplasia of the hip, slipped capital femoral epiphysis, neuromuscular hip dysplasia, post-traumatic avascular necrosis of the proximal femur, juvenile rheumatoid arthritis, achondroplasia, spondyloepiphyseal dysplasia, mucopolysaccharidosis, mucolipidosis, hip infections, and tumors) that required total hip arthroplasty; (2) minimum follow-up of 16 months; (3) assessed outcome with a clinical or radiologic score; (4) Methodological Items for Non-Randomized Studies quality score of 9 or higher. The following information for each pathology was retrieved: mean age at total hip arthroplasty, reason for total hip arthroplasty, type of total hip arthroplasty, surgical technique, mean follow-up, and outcomes.
RESULTS
Overall, the mean age at total hip arthroplasty for pediatric hip disease is in the sixth and seventh decade, except for tumors and skeletal dysplasias. The reason for performing total hip arthroplasty is often osteoarthrosis and abnormal anatomy. Prosthesis types change based on patient's conditions and technological advances; custom-made implants are used for tumors, juvenile rheumatoid arthritis, and skeletal dysplasias; for other diseases, the most frequent are modular cementless implants. Outcomes are generally good, and all studies portray functional and pain improvements.
CONCLUSION
Total hip arthroplasty is performed more frequently than in the past in patients with pediatric hip pathologies; it enhances patients' quality of life by reducing pain and improving function. However, revision rate in these patients is not negligible.
PubMed: 38567046
DOI: 10.1177/18632521241229608 -
JBMR Plus Apr 2024Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor...
Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH ( mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in mice. Meclozine (2 mg/kg/d) was orally administered to mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.
PubMed: 38544920
DOI: 10.1093/jbmrpl/ziae018 -
Journal of Functional Morphology and... Feb 2024Achondroplasia is a rare genetic skeletal condition characterized by disproportionate short stature. There is limited evidence on postural control in adults with...
BACKGROUND
Achondroplasia is a rare genetic skeletal condition characterized by disproportionate short stature. There is limited evidence on postural control in adults with achondroplasia and how lower limb lengthening (intervention) interacts with body dynamics. This study investigated sway variability during quiet standing in adults with achondroplasia with natural growth (N) and with lower limb lengthening (LL).
METHODS
Sixteen adults performed bilateral/unilateral standing tasks. Linear (total excursion, amplitude, and ellipse area) and nonlinear (sample entropy and correlation dimension) center of pressure sway metrics were analyzed in the anteroposterior/mediolateral directions. Relationships between posture metrics, strength, and physical activity were explored. Between-groups statistics were calculated.
RESULTS
The LL group exhibited amplified linear sway, indicating larger postural deviations, and reduced sample entropy and correlation dimension, indicative of more rigid and repeated corrections. The N group exhibited more unpredictable and adaptive movement corrections. Numerous correlations emerged between strength and posture measures, with relationships altered by intervention.
CONCLUSIONS
Adults with achondroplasia display distinct balance strategies influenced by intervention. The results indicate that LL is associated with altered variability and adaptability compared to natural development. Relationships with muscle strength spotlight a key role of muscle capacity in postural control modulation after growth alterations in this population.
PubMed: 38535419
DOI: 10.3390/jfmk9010039 -
Diagnostics (Basel, Switzerland) Feb 2024The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates,...
The Balance Error Scoring System (BESS) is a commonly used method for clinically evaluating balance after traumatic brain injury. The utilization of force plates, characterized by their cost-effectiveness and portability, facilitates the integration of instrumentation into the BESS protocol. Despite the enhanced precision associated with instrumented measures, there remains a need to determine the clinical significance and feasibility of such measures within pediatric cohorts. To report a comprehensive set of posturographic measures obtained during instrumented BESS and to examine the concurrent validity, reliability, and feasibility of instrumented BESS in the pediatric point of care setting. Thirty-seven participants (18 female; aged 13.32 ± 3.31 years) performed BESS while standing on a force plate to simultaneously compute stabilometric measures (instrumented BESS). Ellipse area (EA), path length (PL), and sway velocity (VM) were obtained for each of the six BESS positions and compared with the respective BESS scores. Additionally, the effects of sex and age were explored. A second BESS repetition was performed to evaluate the test-retest reliability. Feedback questionnaires were handed out after testing to evaluate the feasibility of the proposed protocol. The BESS total score was 20.81 ± 6.28. While there was no statistically significant age or sex dependency in the BESS results, instrumented posturography demonstrated an age dependency in EA, VM, and PL. The one-leg stance on a soft surface resulted in the highest BESS score (8.38 ± 1.76), EA (218.78 cm ± 168.65), PL (4386.91 mm ± 1859.00), and VM (21.93 mm/s ± 9.29). The Spearman's coefficient displayed moderate to high correlations between the EA (rs = 0.429-0.770, = 0.001-0.009), PL (rs = 0.451-0.809, = 0.001-0.006), and VM (rs = 0.451-0.809, = 0.001-0.006) when compared with the BESS scores for all testing positions, except for the one-leg stance on a soft surface. The BESS total score significantly correlated during the first and second repetition (rs = 0.734, ≤ 0.001), as did errors during the different testing positions (rs = 0.489-0.799, ≤ 0.001-0.002), except during the two-legged stance on a soft surface. VM and PL correlated significantly in all testing positions (rs = 0.465-0.675, ≤ 0.001-0.004; (rs = 0.465-0.675, ≤ 0.001-0.004), as did EA for all positions except for the two-legged stance on a soft surface (rs = 0.392-0.581, ≤ 0.001-0.016). A total of 92% of participants stated that the instructions for the testing procedure were very well-explained, while 78% of participants enjoyed the balance testing, and 61% of participants could not decide whether the testing was easy or hard to perform. Instrumented posturography may complement clinical assessment in investigating postural control in children and adolescents. While the BESS score only allows for the consideration of a total score approximating postural control, instrumented posturography offers several parameters representing the responsiveness and magnitude of body sway as well as a more differentiated analysis of movement trajectory. Concise instrumented posturography protocols should be developed to augment neuropediatric assessments in cases where a deficiency in postural control is suspected, potentially stemming from disruptions in the processing of visual, proprioceptive, and/or vestibular information.
PubMed: 38472985
DOI: 10.3390/diagnostics14050513 -
European Journal of Medical Genetics Apr 2024Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis,...
Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.
Topics: Male; Child; Child, Preschool; Female; Humans; Adult; Infant; Prevalence; Quality of Life; Joint Instability; Achondroplasia; Prospective Studies; Osteochondrodysplasias
PubMed: 38428804
DOI: 10.1016/j.ejmg.2024.104930 -
Biomolecules Jan 2024Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread... (Review)
Review
Natural products with health benefits, nutraceuticals, have shown considerable promise in many studies; however, this potential has yet to translate into widespread clinical use for any condition. Notably, many drugs currently on the market, including the first analgesic aspirin, are derived from plant extracts, emphasizing the historical significance of natural products in drug development. Curcumin and resveratrol, well-studied nutraceuticals, have excellent safety profiles with relatively mild side effects. Their long history of safe use and the natural origins of numerous drugs contrast with the unfavorable reputation associated with nutraceuticals. This review aims to explore the nutraceutical potential for treating pseudoachondroplasia, a rare dwarfing condition, by relating the mechanisms of action of curcumin and resveratrol to molecular pathology. Specifically, we will examine the curcumin and resveratrol mechanisms of action related to endoplasmic reticulum stress, inflammation, oxidative stress, cartilage health, and pain. Additionally, the barriers to the effective use of nutraceuticals will be discussed. These challenges include poor bioavailability, variations in content and purity that lead to inconsistent results in clinical trials, as well as prevailing perceptions among both the public and medical professionals. Addressing these hurdles is crucial to realizing the full therapeutic potential of nutraceuticals in the context of pseudoachondroplasia and other health conditions that might benefit.
Topics: Curcumin; Resveratrol; Dietary Supplements; Biological Products; Achondroplasia
PubMed: 38397390
DOI: 10.3390/biom14020154 -
Genes Feb 2024Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast...
Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 (), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an (NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.
Topics: Child; Adult; Humans; Osteochondrodysplasias; Achondroplasia; Mutation; Exons; Phenotype; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 38397214
DOI: 10.3390/genes15020225 -
Genes Jan 2024Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK)...
Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two variants-c.1138G>A (p.G380R) and c.1948A>G (p.K650E)-which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor's age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline.
Topics: Aged; Humans; Male; Achondroplasia; Mutation; Receptor Protein-Tyrosine Kinases; Receptor, Fibroblast Growth Factor, Type 3; Semen; Spermatozoa; Testis; Cellular Senescence
PubMed: 38397181
DOI: 10.3390/genes15020191 -
Pediatric Research May 2024Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this... (Meta-Analysis)
Meta-Analysis Review
Skeletal Class III (SCIII) is among the most challenging craniofacial dysmorphologies to treat. There is, however, a knowledge gap regarding which syndromes share this clinical phenotype. The aims of this study were to: (i) identify the syndromes affected by the SCIII phenotype; (ii) clarify the involvement of maxillary and/or mandibular structures; (iii) explore shared genetic/molecular mechanisms. A two-step strategy was designed: [Step#1] OMIM, MHDD, HPO, GeneReviews and MedGen databases were explored; [Step#2]: Syndromic conditions indexed in [Step#1] were explored in Medline, Pubmed, Scopus, Cochrane Library, WOS and OpenGrey. Eligibility criteria were defined. Individual studies were assessed for risk of bias using the New Ottawa Scale. For quantitative analysis, a meta-analysis was conducted. This scoping review is a hypothesis-generating research. Twenty-two studies met the eligibility criteria. Eight syndromes affected by the SCIII were targeted: Apert syndrome, Crouzon syndrome, achondroplasia, X-linked hypohidrotic ectodermal dysplasia (XLED), tricho-dento-osseous syndrome, cleidocranial dysplasia, Klinefelter and Down syndromes. Despite heterogeneity between studies [p < 0.05], overall effects showed that midface components were affected in Apert and Down Syndromes, lower face in Klinefelter Syndrome and midface and lower face components in XLED. Our review provides new evidence on the craniofacial characteristics of genetically confirmed syndromes exhibiting the SCIII phenotype. Four major regulatory pathways might have a modulatory effect on this phenotype. IMPACT: What does this review add to the existing literature? To date, there is no literature exploring which particular syndromes exhibit mandibular prognathism as a common trait. Through this research, it was possibly to identify the particular syndromes that share the skeletal Class III phenotype (mandibular prognathism) as a common trait highlighting the common genetic and molecular pathways between different syndromes acknowledging their impact in craniofacial development.
Topics: Humans; Craniofacial Abnormalities; Genotype; Malocclusion, Angle Class III; Phenotype; Syndrome
PubMed: 38347173
DOI: 10.1038/s41390-023-02907-5