The gut microbiota-derived metabolites regulate bone extracellular matrix homeostasis: Mechanisms and therapeutic implications.

Achondroplasia (ACH), the most common skeletal dysplasia, arises from gain-of-function variants in the fibroblast growth factor receptor 3 gene. Children with ACH experience lifelong medical, functional and psychosocial challenges requiring coordinated and anticipatory care. Although international guidance exists, the UK lacks national clinical care recommendations specific to its healthcare systems. To develop UK-specific, multidisciplinary clinical recommendations for the care of children and young people (CYP) with ACH. The UK Achondroplasia Network developed guidance in stages: stakeholder mapping of the care pathway, integration of contemporary literature with clinical expertise to draft age-specific guidance and Delphi statements, and a modified Delphi process with 25 multidisciplinary experts. The Delphi process involved two voting rounds and an in-person meeting, with consensus defined as ≥80% agreement. In the first Delphi round, all 20 statements achieved consensus; nine achieved 100% agreement. To strengthen consensus, after meeting in person, 17 statements were refined (four were divided into two statements), one created and one removed, resulting in 24 statements for Round 2; all achieved consensus, with 21 reaching 100% agreement. The guidance outlines age-specific monitoring and referral from infancy to adolescence. Recommendations address medical management of complications, psychosocial support, educational planning and transfer to adult care. These are the first UK-specific multidisciplinary recommendations for the care of CYP with ACH. Aligned with international best practices and tailored to UK healthcare systems, they support anticipatory care, promote independence and enhance health and psychosocial outcomes. The guidelines offer a foundation for service planning, standardisation and equitable care.

Meclizine has been shown to promote bone growth by inhibiting a key signaling pathway involved in achondroplasia (ACH). Earlier studies demonstrated its safety in children with ACH after short-term use. The purpose of this study is to assess the safety and efficacy of meclizine treatment over 26weeks in children with ACH. This open-label, single-arm, Phase 2 study was conducted at four sites in Japan. Nine children with ACH, aged 5-10years old, received daily meclizine (12.5mg/day for those < 20kg; 25mg/day for those ≥ 20kg). This was co-administered with growth hormone therapy for 26weeks. Safety was monitored through adverse events (AEs), while treatment efficacy was measured by changes in height velocity (cm/year). Secondary measures included the proportion of children achieving a height velocity of ≥ 6cm/year and changes in arm span growth. Arm span velocity and the proportion of participants reaching ≥ 6cm/year were evaluated through ad hoc analyses. No serious AEs were reported. Height velocity increased slightly from 4.35 ± 1.36cm/year pre-treatment to 4.46 ± 1.54cm/year post-treatment. One participant achieved a height velocity of ≥ 6cm/year. Mean height increased from 107.48 ± 9.04 to 109.77 ± 8.69cm over the study period. By contrast, arm span velocity was higher at 6.93 ± 2.50cm/year, with six children reaching ≥ 6cm/year. An additive effect of meclizine and growth hormone on promoting height was not observed; however, meclizine may enhance arm span growth in children with ACH.Trial registration number jRCT2041230001.

Introduction. Skeletal dysplasias are rare genetic disorders that affect bone and cartilage development, with a prevalence of 3.2 cases per 10,000 newborns in South America. Neonatal auxologic evaluation enables the early detection of these conditions, serving as a cost-effective and accessible tool for early intervention. This study aims to determine the prevalence of low birth weight, short body length, and body disproportion at birth in patients with a molecular diagnosis of achondroplasia (ACH), hypochondroplasia (HCH), SHOX gene alterations (SHOX), and familial hypophosphatemic rickets (FHR). Population and methods. Retrospective descriptive study based on medical records of patients evaluated between 2002 and 2023 in a high-complexity pediatric hospital. Patients with skeletal dysplasia and complete anthropometric data at birth were included in the study. Weight, body length, and head circumference were analyzed, with the calculation of Z-scores according to the INTERGROWTH-21st standards and the head circumference/body length index using Argentine references. Results. Of the 581 patients, 453 were included (ACH 62%, HCH 12%, SHOX 8%, FHR 18%); 31% of the neonates with ACH and 12% with HCH had body length < ̵2 SD. True macrocephaly (>2 SD) was observed in 47% (ACH) and 32% (HCH), and relative macrocephaly in 57% and 28%, respectively. Conclusion. Low body length at birth was more frequent in achondroplasia and hypochondroplasia. Relative macrocephaly, also prevalent in these groups, highlights the value of the head circumference/body length index as a neonatal screening tool.

Real-world safety and age-dependent effectiveness of vosoritide in achondroplasia: A single-center retrospective analysis of transition from growth hormone to vosoritide.

Disclosure: C. McDonnell: Ascendis Pharma, BioMarin, Pfizer, Inc. H. Hove: Ascendis Pharma, Pfizer, Inc.. J.M. Legare: None. P.M. Campeau: Ascendis Pharma, BioMarin, Ipsen, Pfizer, Inc., Takeda. P.L. Hofman: Eli Lilly & Company, Novo Nordisk. D.G. Hoernschemeyer: BioMarin, Orthopediatrics, Zimvie. J.M. de Bergua Domingo: None. M.J. Abuzzahab: Ascendis Pharma, Endo, Inhale, Lumos, Medtronic, Novo Nordisk, Pfizer, Inc., Rhythm, Soleno. M. Mao: Ascendis Pharma. I. Ballance: Ascendis Pharma. L.C. Freiberg: Ascendis Pharma. L.W. Dalby: Ascendis Pharma. A.D. Shu: Ascendis Pharma. C.A. Bacino: Ascendis Pharma, BioMarin, Ionis Pharmaceuticals Inc., Roche. R. Savarirayan: Ascendis Pharma, BioMarin, BridgeBio.Background: Safety and tolerability are key considerations in assessing the value of emerging therapies that aim to address clinical manifestations and potentially life-threatening complications of achondroplasia (ACH). Navepegritide is an investigational prodrug of C-type natriuretic peptide (CNP), administered SC once weekly and designed to provide a low Cmax through sustained release of active CNP. Continuous exposure to the released CNP stimulates natriuretic peptide receptor B (NPR-B) to counteract the constitutively active fibroblast growth factor receptor 3 (FGFR3) characteristic of ACH. We report safety and tolerability data from ApproaCH, a pivotal, randomized, double-blind, placebo-controlled trial in which children with ACH were treated with navepegritide or placebo for 52 weeks. Based on the reported experience with an available daily CNP analogue, symptomatic hypotension and injection site reactions (ISRs) were defined as adverse events of special interest in the ApproaCH trial. Methods: Participants (N=84, aged 2-11 years) were stratified by age and sex and randomized 2:1 to receive navepegritide (100 μg/kg/week) or placebo. The primary endpoint was annualized growth velocity (AGV) at week 52. Safety and tolerability were assessed via treatment-emergent adverse events (TEAEs), laboratory values, vital signs, physical and skeletal examination, electrocardiogram, Tanner staging, bone age, and bone-related safety events. Results: Navepegritide demonstrated AGV superiority over placebo with an LS mean AGV of 5.89 cm/year vs. 4.41 cm/year in the placebo group (LS mean difference 1.49 cm/year, p<0.0001). Navepegritide was well tolerated, with ∼99% of reported AEs being mild (Grade 1) or moderate (Grade 2). No AEs led to trial withdrawal or treatment discontinuation. Incidence of treatment-related AEs was similar between groups (21.1% with navepegritide vs 25.9% with placebo). There was a low incidence of ISRs in both groups (19.3% or 0.41 events per person year of exposure to navepegritide vs 14.8% or 0.15 with placebo). All ISRs were mild (Grade 1). AEs of asymptomatic hypotension were documented in two participants in each the navepegritide group (3.5%) and the placebo group (7.4%); none were considered treatment-related. Conclusion: In the pivotal ApproaCH trial, navepegritide significantly improved linear growth in children with ACH while maintaining a safety profile comparable to placebo. The treatment was well-tolerated and most TEAEs were mild or moderate. Weekly administration of navepegritide was associated with a low incidence of ISRs and no evidence of treatment-related hypotensive effects. These results suggest that the design of once-weekly navepegritide as a prodrug with a low CNP Cmax contributes to a favorable safety and tolerability profile, and may address limitations of existing ACH therapies and support improved treatment adherence.Presentation: Monday, July 14, 2025

To study genotype-phenotype correlations in children with FGFR3 variants and to improve clinical recognition of related disorders. Clinical data of 95 patients aged 0-18 years harboring FGFR3 variants, confirmed by whole‑exome sequencing at Shanghai Children's Medical Center from January 2012 to December 2023, were retrospectively reviewed. Detailed phenotypic characterization was performed for 22 patients with achondroplasia (ACH) and 10 with hypochondroplasia (HCH). Among the 95 patients, 52 (55%) had ACH, 24 (25%) had HCH, 9 (9%) had thanatophoric dysplasia, 3 (3%) had syndromic skeletal dysplasia, 2 (2%) had severe achondroplasia with developmental delay and acanthosis nigricans, and 5 (5%) remained unclassified. A previously unreported FGFR3 variant, c.1663G>T, was identified. All 22 ACH patients presented with disproportionate short stature accompanied by limb dysplasia, commonly with macrocephaly, a depressed nasal bridge, bowed legs, and frontal bossing; complications were present in 17 (77%). The 10 HCH patients predominantly exhibited disproportionate short stature with limb dysplasia and depressed nasal bridge. ACH is the most frequent phenotype associated with FGFR3 variants, and missense variants constitute the predominant variant type. The degree of FGFR3 activation appears to correlate with the clinical severity of skeletal dysplasia.

Achondroplasia (ACH) is the most common skeletal dysplasia and the leading genetic cause of dwarfism. It is characterized by disproportionate short stature and lifelong medical complications, with an estimated incidence of 1 in 25,000–30,000 live births. The condition results from a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, causing receptor overactivation and impaired bone growth at the growth plates. This review provides an overview of achondroplasia, including its pathophysiology, clinical features, diagnostic methods, and novel therapeutic options, with emphasis on vosoritide. Historically, management has focused on symptomatic treatment and surgical interventions to address complications such as foramen magnum stenosis, hydrocephalus, and postural deformities. Vosoritide (Voxzogo) marks a breakthrough as the first disease-modifying therapy targeting the underlying pathophysiology. It is a C-type natriuretic peptide (CNP) analog that inhibits the overactive MAPK pathway, thereby promoting chondrocyte proliferation and differentiation in growth plates and enabling endochondral bone growth. Phase 3 clinical trials demonstrated that vosoritide significantly increases annual growth velocity (by approximately 1.57 cm) and improves body proportions, with a favorable safety profile. Reported adverse effects were generally mild, including transient hypotension and injection site reactions. Despite these advances, vosoritide therapy does not eliminate the need for coordinated multidisciplinary care and psychological support. Patients require ongoing monitoring and management of associated complications, including neurological, orthopedic, respiratory, and developmental issues. In summary, achondroplasia remains the most frequent genetic form of dwarfism, traditionally managed through supportive care and surgery. The introduction of vosoritide represents a paradigm shift, offering the first targeted therapy that directly modifies disease progression and opens new perspectives for improving patients’ quality of life.

Genetic skeletal disorders (GSDs) comprise a diverse group of disorders that affect bone development and homeostasis. In some areas of Iran, GSD occurs more frequently than in other places for still unknown reasons. The aim of this study was to characterize the genetic landscape of GSDs in a cohort from southwestern Iran using Exome sequencing (ES), with a focus on identifying pathogenic and likely pathogenic variants. Osteogenesis Imperfecta (OI) was the most prevalent disorder, with an unexpectedly high frequency of autosomal recessive subtypes, likely due to a high consanguinity rate (61.3%) in the cohort. Achondroplasia (ACH) was the second most common disease and, comparable to another population, the NM_000142.5:c.1138G>A, p.(Gly380Arg), was the most common variant in FGFR3. ES identified twenty novel and fifteen previously reported pathogenic variants in several genes associated with GSDs. We provide the first comprehensive ES-based molecular diagnosis of GSDs in an Iranian population and uncover novel pathogenic variants that expand the known spectrum of variants. The results underscore the importance of genetic testing in the diagnosis of rare skeletal diseases and highlight the need for targeted genetic counseling in populations with high consanguinity.

Achondroplasia (ACH), the most prevalent form of human dwarfism, is caused by the G380R mutation in FGFR3 in approximately 99% of cases. Through structural hybridization of Tyra-300 and LY2874455, we developed compound 23, a new dual-target FGFR2/3 inhibitor demonstrating potent activity against both wild-type and mutant FGFR3. In preclinical ACH mouse models, compound 23 showed a dose-dependent improvement in growth rate, with significantly enhanced efficacy versus infigratinib at equivalent doses. This work presents a new structural scaffold for developing FGFR3 kinase inhibitors to target pathogenic FGFR3 mutations and treat ACH.

Introduction. Macrocephaly is a phenotypic feature of achondroplasia (ACH), the most common form of disproportionate short stature. In 2011, we published head circumference (HC) references for this population, but due to the scarcity of data about older ages, the centiles were estimated only up to 6 years of age. Objective. To estimated centiles of the HC between birth and 21 years of age for ACH. Population and methods. Data from children with ACH assisted between 1992 an 2024 at a thirdlevel hospital in Argentina were used for its estimation. The growth curves were adjusted using the LMS method. To evaluate the magnitude of the differences between the Argentine references of ACH and those of the general population, the 3, 50, and 97 centiles at different ages were plotted comparatively. Results. The HC of ACH was more significant at all ages than the general population's references. During the first year of life, males and females reach 84% and 86% of adult size, respectively, completing growth after 20 years of age. Conclusions. Due to the difference in cephalic size between the general population and ACH, it is essential to have specific references for this population. This will allow us to detect growth trajectories not attributed to ACH and to suspect deviations that require a rapid interdisciplinary approach.

Achondroplasia (ACH) is the most common skeletal dysplasia and is characterized by a short-limbed short stature, sagittal spinal malalignment, and genu varum. Vosoritide promotes longitudinal bone growth in children with ACH; however, its effects on various disease-specific complications, other than short stature, are unknown. This study aimed to investigate the therapeutic effects of vosoritide on spinal and lower limb malalignment in children with ACH. This single-center, open-label, prospective study included patients with ACH aged younger than or equal to 15 years who received vosoritide treatment and had a minimum follow-up period of 1 year. To evaluate alignment after vosoritide treatment, radiologic parameters were measured from sagittal radiographs of the spine and anteroposterior radiographs of the bilateral lower limbs before the administration of vosoritide and 12 months after treatment. Paired t tests were used to compare parameters before and after vosoritide treatment. Seventeen patients (mean age, 7.6±2.7y) were included. After 1-year treatment of vosoritide, the mean height increased by 5.4±1.3cm. Changes in spinal alignment after 1 year of vosoritide treatment were 1.5 degrees for cervical lordosis, -1.3 degrees for thoracic kyphosis, -2.8 degrees for thoracolumbar kyphosis, -5.2 degrees for lumbar lordosis (LL), -2.2 degrees for pelvic tilt, -2.6 degrees for pelvic incidence, -0.4 degrees for sacral slope, and 2.6 mm for C7 sagittal vertical axis. Alignment changes in the lower limbs were -3.4 degrees for mechanical axis angle (MAA), 1.7 degrees for mechanical lateral proximal femoral angle (mLPFA), -2.8 degrees for mechanical lateral distal femoral angle (mLDFA), -0.2 degrees for medial proximal tibial angle, and -0.5 degrees for lateral distal tibial angle. The LL, MAA, mLPFA, and mLDFA levels showed statistically significant changes towards the normal range after treatment. One-year treatment of vosoritide decreased the exaggerated LL and improved genu varum deformity in children with ACH. Vosoritide therapy may not only increase longitudinal bone growth but also improve spinal and lower limb malalignment in children with ACH. Level II: prospective comparative study.

Achondroplasia (ACH) and hypochondroplasia (HCH), the two most common types of dwarfism, are each caused by FGFR3 gain-of-function mutations that result in increased FGFR3 signaling, which disrupts chondrogenesis and osteogenesis, resulting in disproportionately shortened long bones. In this study, TYRA-300, a potent and selective FGFR3 inhibitor, was evaluated in 3 genetic contexts: wild-type mice, the Fgfr3Y367C/+ mouse model of ACH, and the Fgfr3N534K/+ mouse model of HCH. In each model, TYRA-300 treatment increased nasoanal length and tibia and femur length. In the two FGFR3-altered models, TYRA-300–induced growth partially restored the disproportionality of long bones. Histologic analysis of the growth plate in Fgfr3Y367C/+ mice revealed that TYRA-300 mechanistically increased both proliferation and differentiation of chondrocytes. Importantly, children with ACH can experience medical complications due to foramen magnum stenosis, and TYRA-300 significantly improved the size and shape of the skull and foramen magnum in Fgfr3Y367C/+ mice. Spinal stenosis is also a frequent complication, and TYRA-300 increased the lumbar vertebrae length and improved the shape of the intervertebral discs in both models. Taken together, these studies demonstrate that the selective FGFR3 inhibitor TYRA-300 led to a significant increase in bone growth in two independent FGFR3-driven preclinical models as well as in wild-type mice.

Achondroplasia (ACH) is a common skeletal dysplasia in children, primarily caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. These mutations disrupt the process of endochondral ossification in different types of bones, including long bones of the limbs and vertebrae. Children with ACH typically present with short stature and may experience severe multi-system complications. The diagnosis of ACH is based on typical clinical manifestations, imaging features, and genetic testing results. Treatment options mainly include pharmacological interventions and surgical procedures aimed at improving height, as well as symptomatic management for associated complications. This article discusses both prenatal and clinical diagnostic approaches for ACH, as well as treatment strategies focused on enhancing height, aiming to deepen the understanding of this condition.

Vosoritide is the first approved targeted therapy for achondroplasia (ACH) based on increased annualized growth velocity in clinical trials. The aim of our project was an assessment of the real-world setting and treatment with vosoritide. This was a 12-month, retrospective observational study on an inception cohort of 34 patients with ACH treated with vosoritide. Thirty-four patients with ACH (22 males; aged 2.8 to 15.3 years at treatment initiation) who received vosoritide treatment for at least 12 months at a specialized clinic for skeletal dysplasia in childhood were included in the analysis. Auxological measurements at baseline and after 12 months of therapy were converted into disease-specific (ACH) and general population [Centers for Disease Control and Prevention (CDC)] z-scores. Physical function assessed by a 6-minute walk test was converted into z-scores and compared to an unaffected reference cohort. After 12 months of treatment, both ACH and CDC height z-scores showed significant increases, with mean changes (mean ± SD) of 0.52 ± 0.35 and 0.38 ± 0.44, respectively (both P < .0001). The annualized growth velocity exceeded reference values for untreated children with ACH. No significant changes were observed in body mass index, upper to lower body segment ratio (sitting height/height), or head circumference. The 6-minute walking distance improved, with z-scores increasing from -2.00 ± 1.12 to -1.39 ± 1.23 (P = .0215). In a real-world setting, children with ACH showed significant improvements in growth and physical function after 12 months of treatment with vosoritide.

CDK8 inhibitor KY-065 rescues skeletal abnormalities in achondroplasia model mice.

Bipedal static postural stability in children with achondroplasia compared to typically developed children in the age range of 9-12 years - A pilot study.

Children with achondroplasia (ACH) are at risk for sudden death in infancy due to sleep disordered breathing (SDB) and foramen magnum stenosis (FMS). Sleep studies and neuroimaging are performed in infants with ACH, but interpretation of infant studies is challenging. We sought to describe baseline data on polysomnography (PSG) indices in infants with achondroplasia as well as effects of age and surgery on these parameters. Retrospective data were abstracted from the multisite CLARITY ACH database from years 2008-2017. Both obstructive apnea hypopnea index (OAHI) and central apnea index (CAI) were extracted, and effects of age and surgical intervention (adenoidectomy [AD] or cervicomedullary decompression [CMD]) were analyzed. 172 PSGs from 86 infants were analyzed. In surgically naive children, OAHI decreased over the first year but then increased in the second year, while CAI was mostly stagnant over the first two years. There were no significant differences between age at first PSG or PSG indices for surgically naive infants versus those who underwent AD or CMD. OAHI decreased after AD and CAI decreased after CMD. Similar to average stature infants, our results demonstrate the need to interpret sleep study findings of children with ACH in the context of age, particularly for obstructive indices. Neither OAHI nor CAI differentiated those infants who subsequently underwent surgery, suggesting that there were other important clinical factors in the surgical decision-making process. Independent of age, AD resulted in improvement in OSA and CMD with improvement in central sleep apnea.

Background: Frontal knee malalignments are hallmarks of Achondroplasia (ACH), along with disproportional short stature. Typically, X-rays are used to assess them, but 3D gait analysis (3DGA) may additionally be used to evaluate dynamic knee function. The research questions were as follows: (1) What is the relationship between X-rays and 3DGA in ACH? (2) Do children with ACH have abnormal frontal knee kinematics and kinetics? (3) Are there aspects of 3DGA that relate to knee symptoms? Methods: A total of 62 knees of 31 children with ACH (age: 11.1 ± 4.3 years, 34 symptomatic knees) underwent 3DGA and X-ray as part of their standard clinical care. X-rays were analyzed for mechanical tibiofemoral angle (mTFA). Relationships between X-rays and 3DGA were determined. Sixty-two knees of 31 age-matched typically developing (TD) children served as references for 3DGA. Frontal knee kinematics (including thrust RoM) and adduction moments (KAMs) were compared. Multiple regression was performed for measurements associated with KAM, and ANOVA was used to compare TD and ACH knees with and without pain. Results: There was a high correlation between static frontal knee angles and mTFA (r = 0.93, p < 0.001, mean difference = -2.9°). ACH knees with a regular mTFA also showed significantly increased KAM. Multiple regression analysis showed that mTFA was the most relevant predictor of KAM (R2 = 0.41-0.75). Symptomatic knees (n = 34/62) experienced significantly more knee RoM in early stance than asymptomatic knees. Conclusions: Three-dimensional gait analysis may be an objective screening method for dynamic knee alignment and stability and may complement radiography in monitoring ACH. Symptoms may depend on knee thrust, while the impact of altered KAM needs further study.

Abstract The aim of this study was to describe sleep-disordered breathing (SDB) and treatment in children with achondroplasia (ACH). A retrospective longitudinal study was conducted at the Sleep Unit, Hospital de Pediatría Garrahan. Children with ACH, aged 0 to 18 years, referred for SDB due to clinical symptoms or foramen magnum stenosis (FMS) with at least one polysomnography (PSG) between 2002 and 2019 were included in the study. The primary outcomes included SDB typification and therapeutic interventions. We included 89 patients; 79.7% had one PSG, 13.4% had two PSGs, and 5.6% had three PSGs. The first PSG confirmed SDB in 65.16% patients. Obstructive sleep apnea (OSA) was present in 59.6% patients, central sleep apnea (CSA) in 1.72% patients, OSA + CSA in 4.49% patients, and normal PSG in 34.83% patients. OSA was mild in 32.07% patients, moderate in 18.86% patients, and severe in 49.05% patients. Clinical and airway evaluation, central imaging, evoked potentials, and PSG were considered before each therapeutic decision. After the first PSG, patients received one or more treatments as needed: watchful waiting; nasal steroids; ear, nose, and throat surgery; foramen magnum decompression; and noninvasive ventilation. A second PSG was available in 18 patients and 72.22% had SDB. A third PSG was available in 10 patients and 77.8% had SDB. We reconfirm an elevated frequency of SDB in ACH children and underline the need for a multidisciplinary and stepwise longitudinal approach.