RARE DISEASE
Achondroplasia
Achondroplasia
Achondroplasia
Drug discovery
12
drugs
With orphan designations
Overview
Achondroplasia is a genetic disorder caused by FGFR3 gene mutations, resulting in impaired endochondral ossification and disproportionate short stature (rhizomelic shortening). Key features include spinal stenosis, recurrent otitis media, sleep apnea, and orthopedic complications. Management involves multispecialty monitoring, surgical interventions for spinal/limb deformities, and emerging pharmacotherapies targeting FGFR3 pathways [1][6][8]. Most patients have normal intelligence and lifespan with proactive care [1][11].
Burden
Lifetime complications: 80% develop spinal stenosis by age 60; 20–50% experience neurological deficits [6][9][17].
Healthcare costs: Hospitalizations average $19,959/admission (35% above U.S. mean), driven by neonatal care and musculoskeletal surgeries [17].
Psychosocial impact: Reduced quality of life, emotional distress, and functional limitations due to chronic pain/disproportionate anatomy [4][5].
Therapies
Surgical: Limb lengthening (up to 30–40 cm total), spinal decompression, and guided growth procedures [3][8][17].
Pharmacologic: Vosoritide (FDA-approved CNP analog) improves growth velocity; investigational agents include TransCon CNP and FGFR3 inhibitors [4][5][13].
Supportive: Physical/occupational therapy, weight management, and polysomnography for sleep apnea [6][8].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
637 drug discovery papers about Achondroplasia, with 2 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
637 drug discovery papers about Achondroplasia, with 2 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-07-03 | Signatures of selection detected from whole-genome sequencing indicate that the small body size in dwarf rabbit breeds is caused by polygenic effects with a few major loci.
Early genetic studies have suggested that body size in rabbits can be considered a quantitative trait. Several rabbit breeds can be distinguished based on body size, including a few dwarf breeds differentiated by other morphological characteristics. While a large deletion in the HMGA2 gene is a major locus associated with dwarfism in Netherland Dwarf rabbits, it may not fully explain the reduced body size in this breed or other dwarf breeds. In this study, we compared the genomes of two dwarf rabbit breeds (Dwarf Lop and Netherland Dwarf) with those of non-dwarf rabbits by analysing whole-genome sequencing data obtained using a DNA-pool sequencing approach. We applied the fixation index (FST) and pooled heterozygosity (HP) statistics to identify signatures of selection related to small body size by contrasting dwarf with non-dwarf breeds and comparing dwarf breeds. We identified several genomic regions that contain genes previously linked to body dimensions in various species, including LCORL-NCAPG, COL2A1, GHRHR and CENPE. Functional enrichment analysis of genes within the top differentiated regions revealed biological terms related to skeletal development, further supporting the biological relevance of these loci. Additionally, the use of the latest version of the reference rabbit genome enabled the identification of a genomic region containing FGFR3, a gene linked to achondroplasia. Some genomic regions showed differentiation between the two dwarf breeds, suggesting that their small body size may, in part, arise through different genetic mechanisms. Overall, these findings support a polygenic architecture underlying small size in rabbits, influenced by a few major loci.
2025-01-16 | Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia.
Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (-29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3. Its CRISPR/Cas9-mediated deletion in otherwise WT mice reduced Fgfr3 expression in this domain by half without causing adverse phenotypes. Importantly, its deletion in mice harboring the ortholog of the most common human achondroplasia variant largely normalized long bone and vertebral body growth, markedly reduced spinal canal and foramen magnum stenosis, and improved craniofacial defects. Consequently, mouse achondroplasia is no longer lethal, and adults are overall healthy. These findings, together with high conservation of -29E in humans, open a path to develop genetic therapies for people with achondroplasia.
2023-08-08 | Hemiepiphysiodesis for Lower Extremity Coronal Plane Angular Correction in the Distal Femur and Proximal Tibia in Children With Achondroplasia.
Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee. The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle. Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment. Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum. Therapeutic level IV, Case series.
2021-08-28 | Targeted gene correction and functional recovery in achondroplasia patient-derived iPSCs
Abstract Background Achondroplasia (ACH) is the most common genetic form of dwarfism and belongs to dominant monogenic disorder caused by a gain-of-function point mutation in the transmembrane region of FGFR3 . There are no effective treatments for ACH. Stem cells and gene-editing technology provide us with effective methods and ideas for ACH research and treatment. Methods We generated non-integrated iPSCs from an ACH girl’s skin and an ACH boy’s urine by Sendai virus. The mutation of ACH iPSCs was precisely corrected by CRISPR-Cas9. Results Chondrogenic differentiation ability of ACH iPSCs was confined compared with that of healthy iPSCs. Chondrogenic differentiation ability of corrected ACH iPSCs could be restored. These corrected iPSCs displayed pluripotency, maintained normal karyotype, and demonstrated none of off-target indels. Conclusions This study may provide an important theoretical and experimental basis for the ACH research and treatment.
2018-11-29 | Optimizing CRISPR/Cas9 technology for precise correction of the Fgfr3-G374R mutation in achondroplasia in mice
CRISPR/Cas9 is a powerful technology widely used for genome editing, with the potential to be used for correcting a wide variety of deleterious disease-causing mutations. However, the technique tends to generate more indels (insertions and deletions) than precise modifications at the target sites, which might not resolve the mutation and could instead exacerbate the initial genetic disruption. We sought to develop an improved protocol for CRISPR/Cas9 that would correct mutations without unintended consequences. As a case study, we focused on achondroplasia, a common genetic form of dwarfism defined by missense mutation in the Fgfr3 gene that results in glycine to arginine substitution at position 374 in mice in fibroblast growth factor receptor 3 (Fgfr3-G374R), which corresponds to G380R in humans. First, we designed a GFP reporter system that can evaluate the cutting efficiency and specificity of single guide RNAs (sgRNAs). Using the sgRNA selected based on our GFP reporter system, we conducted targeted therapy of achondroplasia in mice. We found that we achieved higher frequency of precise correction of the Fgfr3-G374R mutation using Cas9 protein rather than Cas9 mRNA. We further demonstrated that targeting oligos of 100 and 200 nucleotides precisely corrected the mutation at equal efficiency. We showed that our strategy completely suppressed phenotypes of achondroplasia and whole genome sequencing detected no off-target effects. These data indicate that improved protocols can enable the precise CRISPR/Cas9-mediated correction of individual mutations with high fidelity. CRISPR/Cas9 is a powerful technology widely used for genome editing, with the potential to be used for correcting a wide variety of deleterious disease-causing mutations. However, the technique tends to generate more indels (insertions and deletions) than precise modifications at the target sites, which might not resolve the mutation and could instead exacerbate the initial genetic disruption. We sought to develop an improved protocol for CRISPR/Cas9 that would correct mutations without unintended consequences. As a case study, we focused on achondroplasia, a common genetic form of dwarfism defined by missense mutation in the Fgfr3 gene that results in glycine to arginine substitution at position 374 in mice in fibroblast growth factor receptor 3 (Fgfr3-G374R), which corresponds to G380R in humans. First, we designed a GFP reporter system that can evaluate the cutting efficiency and specificity of single guide RNAs (sgRNAs). Using the sgRNA selected based on our GFP reporter system, we conducted targeted therapy of achondroplasia in mice. We found that we achieved higher frequency of precise correction of the Fgfr3-G374R mutation using Cas9 protein rather than Cas9 mRNA. We further demonstrated that targeting oligos of 100 and 200 nucleotides precisely corrected the mutation at equal efficiency. We showed that our strategy completely suppressed phenotypes of achondroplasia and whole genome sequencing detected no off-target effects. These data indicate that improved protocols can enable the precise CRISPR/Cas9-mediated correction of individual mutations with high fidelity.
cell therapies
2026-01-28 | Spatiotemporal Regulation and Lineage Specification in Embryonic Endochondral Ossification.
Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9+/Fgfr3+ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1+ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5+ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a-Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh-PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint.
2025-02-03 | Early evaluation and treatment of thoracolumbar kyphosis in children with achondroplasia.
Thoracolumbar kyphosis (TLK) is frequently reported in children with achondroplasia. The combination of TLK and the narrow spinal canal in achondroplasia increases the risk of developing symptomatic spinal stenosis. However, there is no consensus on the optimal management of TLK. This retrospective cohort study evaluated children under four years old with achondroplasia, monitoring TLK every six months. Pathologic TLK was defined as a Cobb angle of 20 degrees or more between T10 and L2. Management involved either a wait-and-see policy, which prohibited unsupported sitting, or bracing. Surgery was reserved for severe progressive TLK or spinal stenosis cases. TLK was evaluated over time. A receiver operating characteristic curve determined the baseline threshold where wait-and-see management failed to resolve TLK below 20 degrees. Multiple linear regression compared bracing versus wait-and-see management for cases exceeding 40 degrees. Sixty-two patients were included, with a median age of 10 months and a median follow-up of 31 months. TLK prevalence decreased from 85% at baseline to 42% at final follow-up. The mean Cobb angle decreased from 31 ± 11 degrees to 22 ± 16 degrees (p < 0.001). The threshold for ineffective wait-and-see management was identified as 33 degrees. Bracing resulted in significantly more TLK reduction than wait-and-see management for cases exceeding 40 degrees (15 degree difference, 95% CI 2-28, p = 0.023). Three patients required surgery. TLK is highly prevalent in achondroplasia, necessitating careful monitoring. A wait-and-see policy with restrictions on unsupported sitting is recommended initially, but early bracing should be considered for more severe cases.
2024-12-23 | Resolving the design principles that control postnatal vascular growth and scaling.
After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.
2023-12-04 | Achondroplasia Natural History Study (CLARITY): 60-year experience with hydrocephalus in achondroplasia from four skeletal dysplasia centers.
The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers. The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information. A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of hydrocephalus at a median age of 14.4 months. There was considerable variation in the percentage of patients treated for hydrocephalus by center and decade of birth, ranging from 0% to 28%, although in the most recent decade, all centers treated less than 6% of their patients, with an average of 2.9% across all centers. Undergoing a cervicomedullary decompression (CMD) was a strong predictor for treatment of hydrocephalus (OR 5.8, 95% CI 3.9-8.4), although that association has disappeared in those born since 2010 (OR 1.1, 95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) has become more common; it was used as the first line of treatment in 38% of patients in the most recent decade. Kaplan-Meier analysis suggests that a single ETV will treat hydrocephalus in roughly half of these patients. While many children with achondroplasia have features of hydrocephalus with enlarged intracranial CSF spaces and relative macrocephaly, treatment of hydrocephalus in achondroplasia patients has become relatively uncommon in the last 20 years. Historically, there was a significant association between symptomatic foramen magnum stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor with the recognition that CMD alone will treat hydrocephalus in some patients. Despite good experimental data demonstrating that hydrocephalus in achondroplasia is best understood as communicating in nature, ETV appears to be reasonably successful in certain patients and should be considered an option in selected patients.
2023-03-25 | Humeral lengthening: Systematic Review and Meta Analysis
Background: The humerus lengthening was mostly regarded an aesthetic procedure.Recent study indicates, however, that the objectives of bilateral humeral lengthening in achondroplasia are not just cosmetic, but also to restore proportions between the upper and lower limbs, extend reach, and enhance the capacity to perform perineal personal hygiene.This study's objective was to conduct a comprehensive evaluation and analysis of the outcomes of humeral lengthening.Methods: During this systematic review and meta-analysis preparation, we adhered to the PRISMA statement criteria and followed the Cochrane handbook for systematic reviews of interventions.Results: We identified eight studies discussing humeral lengthening including a total number of 158 humeri in 129 patients.The age range of patients across the studies ranged between 6.5 and 20 years.The male gender was common and ranging from 33% to 78%.The humeral lengthening was conducted among 158 humeri among them 34 in the right side.The mean length achieved was 7.7 cm among the included eight145 studies ranging from 5.1 cm to 9 cm.Pooled analysis of the involved trials showed significant association between length pre and post humeral lengthening (OR = -6.08;95% CI: [-6.79, -5.38]; P = <0.00001).The pooled studies were not heterogenous (I2 = 0%, P < 0.46).Conclusions: The lengthening of the humerus was regarded mostly as a cosmetic procedure.Using a variety of external fixators and intramedullary (IM) nails, the humerus was extended by distraction osteogenesis.There is a statistically significant link between length before and after humeral lengthening, although neither range of motion nor functional score are affected.
small molecules
2026-08-11 | Computational Evaluation of Dabogratinib and C-Type Natriuretic Peptide Analogue Co-treatment in Achondroplasia
Achondroplasia is usually caused by an overactive form of FGFR3, a receptor that normally slows bone growth. Dabogratinib (TYRA-300) blocks FGFR3, while C-type natriuretic peptide (CNP) analogues act further down the same signalling network. This computer study asked whether combining these two approaches could restore growth-plate signalling better than either approach alone. Four ordinary differential equations represented active FGFR3, CNP-driven cGMP/PKG signalling, MAPK/ERK and STAT1. Two further outputs represented cell proliferation and matrix/differentiation. A 21 × 21 grid tested 441 pairs of normalised treatment intensities. Combination effects were measured with Bliss independence and highest-single-agent (HSA) scores. The untreated disease state lowered the proliferation index from 1.000 to 0.563. The strongest qualifying pair was T = 0.20 for dabogratinib and C = 0.30 for the CNP analogue. Its Bliss score was 0.216 and its HSA score was 0.457. Eighty-one pairs met the study's synergy rule, 360 were approximately additive and none were antagonistic. In 3,000 tests with varied parameter values, 97.2% of samples still met the synergy rule. At high intensities, the result became additive because the output had already reached its upper limit. These findings support an intermediate-intensity synergy hypothesis within the model. They do not prove that the drug combination is safe or effective in people. Laboratory data are needed to test and improve the model.
2026-08-09 | Longitudinal growth pattern of Hungarian children with achondroplasia: The evaluation of treatment-related growth changes
Background: Achondroplasia is characterized by a distinctive growth pattern involving disproportionate short stature, limb shortening, macrocephaly and altered growth velocities throughout childhood. Objective: The project aims to examine the impact of vosoritide (VOXZOGO®) treatment on growth patterns in children with achondroplasia and to assess the applicability of the European achondroplasia-specific growth references to a Hungarian achondroplasia cohort. Subjects and methods: The longitudinal study was initiated in October 2025. To date, 20 Hungarian children with achondroplasia, aged 2–13 years, have been enrolled at the Department of Paediatrics, Semmelweis University, Budapest, Hungary. Anthropometric assessments are conducted at baseline and repeated at 3‑month intervals throughout the follow-up period. Measurements include body weight, body height/length, sitting height, arm span, lengths of the upper and lower limb segments, trunk and limb circumferences and breadths, as well as head dimensions. The observed growth patterns are evaluated relative to the growth channels defined by the European achondroplasia-specific reference standards. Results: In this pilot study, analyses focused on body weight, body height/length, body mass index and head circumference. The preliminary findings demonstrate the applicability of the European achondroplasia-specific reference standards for monitoring individual growth trajectories. At this preliminary stage, the analyses focus on determining whether the observed growth patterns remained within or deviated from the growth channels of the achondroplasia-specific references. Conclusion: Our newly developed anthropometric protocol provides a standardized framework for the longitudinal assessment of growth in children with achondroplasia and includes an extensive set of body and head measurements that enable detailed monitoring of body proportions and cranial growth throughout childhood. Extended follow-up will be required to clarify the influence of vosoritide treatment on the overall growth patterns of children with achondroplasia.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-04-19 | Evaluating the impact of vosoritide on complications of achondroplasia.
Impaired endochondral bone growth in people with achondroplasia causes complications that impair function, cause pain, require surgery, and contribute to mortality. Rates of complications in participants with achondroplasia enrolled in clinical trials of vosoritide, a targeted treatment, were analyzed and compared with published natural history (NH) rates. Prevalence (medical history + new events post-treatment initiation) and incidence (new/worsening events posttreatment initiation) were calculated for complications across 6 clinical trials (2.5-30 μg/kg/day vosoritide) in children with achondroplasia, stratified by age at treatment initiation (<5 years/≥5 years). Complication-related procedures and mortality rates were examined. By August 2024, 230 participants received vosoritide (68 aged <5 years at treatment initiation [exposure, 289.1 person-years]; 162 aged ≥5 years at treatment initiation [exposure, 834.5 person-years]). Prevalence for most complications was consistent with or lower than NH rates. Incidence of leg malalignment; foramen magnum stenosis; spinal stenosis; kyphosis; lordosis; hydrocephalus; ear, nose, and throat complications; and pain was generally lower than NH rates. Foramen magnum decompression frequency was 3.0% overall (5.9% in participants who initiated treatment aged <2 years). Crude mortality was lower than NH rates. Vosoritide was not associated with worsening of complications in children with achondroplasia and may reduce their frequency.
2026-04-09 | Dkk1 inhibition restores mandibular growth in an achondroplasia mouse model.
Meckel's and condylar cartilages are key to mandible development, with Meckel's cartilage acting as a template and condylar cartilage as a growth center. In achondroplasia, the most common form of genetic dwarfism, abnormalities of these cartilages lead to micrognathia, with significant functional repercussions for affected individuals. How FGFR3 overactivation in achondroplasia disrupts Meckel's and condylar cartilages is largely unknown. Our aim was to identify the pathways driving these disruptions by analyzing the genes expressed in these cartilages in a mouse model mimicking achondroplasia. Using cartilage laser-microdissection and RNA-sequencing analyses, we first compared the transcriptome of Meckel's and condylar cartilages from E16.5 embryos of control and Fgfr3Y367C/+ mice. Over 900 genes were differentially expressed, including the Dkk1 gene, which encodes an inhibitor of β-catenin-dependent Wnt signaling and was significantly overexpressed in chondrocytes of Fgfr3 mutants in both Meckel's and condylar cartilages. Immunostaining of sections of the cartilages confirmed the high expression at the protein level. Primary cultures of Meckel's cartilage chondrocytes showed that, in Fgfr3Y367C/+ mutants, activation of the canonical Wnt pathway with Wnt3a was reduced, while a Dkk1 antagonist increased Wnt activity, suggesting that Dkk1 overexpression was responsible for decreased canonical Wnt activity in mutants. In a mandible organ culture model, inhibition of Dkk1 also significantly increased the mandible size, due to an increased elongation of the condylar cartilage of mutants, as seen after tissue clearing and Sox9 immunolabeling. In this cartilage, increased proliferation and defective differentiation into hypertrophic chondrocytes was partially corrected by Dkk1 inhibition. Our data suggest that dysregulation of Wnt/β-catenin activity due to Fgfr3 gain-of function mutation constitutes an important underlying mechanism in craniofacial defects observed in achondroplasia.
proteins
2026-09-17 | Consensus statement on the management of Achondroplasia in the Middle East
Achondroplasia is the most common skeletal dysplasia and presents as a lifelong, multi-system condition characterized by disproportionate short stature, rhizomelic limb shortening, macrocephaly with frontal bossing, and a spectrum of neurological, respiratory, orthopedic, and psychosocial complications. Effective management requires anticipatory surveillance, coordinated multidisciplinary care, and early recognition of life-threatening complications. Therapeutic options have expanded in recent years with the introduction of vosoritide, a C-type natriuretic peptide analog that targets the underlying pathophysiology and has demonstrated significant improvements in linear growth and body proportionality in eligible children. However, global advances have not been uniformly translated into clinical practice across the Middle East, where challenges such as delayed diagnosis, inconsistent access to genetic testing, limited multidisciplinary infrastructure, and inequities in treatment availability continue to impact patient outcomes. In this document, a panel of pediatric endocrinologists and clinical geneticists from the Middle East convened to develop a set of regionally relevant, evidence-informed consensus statements on the diagnosis and management of achondroplasia in light of novel advances in the management of this condition. Using a modified Delphi process, the panel achieved consensus on 25 statements covering diagnosis, surveillance, multidisciplinary management, psychosocial support, pharmacologic interventions, transition to adult care, and research priorities. This consensus, endorsed by the Arab Society for Pediatric Endocrinology and Diabetes (ASPED) and the MENA Medical Genetics Association, aims to standardize and enhance the quality of care for individuals with achondroplasia across the region by integrating international best practices with local healthcare realities. The author panel believes that the implementation of these recommendations has the potential to improve early detection, optimize long-term outcomes, strengthen family support, and expand equitable access to emerging therapies.
2026-06-25 | Second drug approved for achondroplasia
Navepegritide (Yuviwel), a C-type natriuretic peptide analog, is the second drug to be approved for the treatment of achondroplasia. It is administered subcutaneously once weekly. The retail cost for navepegritide is expected to be almost half a million dollars annually.
2026-06-03 | Navepegritide: First Approval.
Navepegritide (YUVIWEL®) is a prodrug of C-type natriuretic peptide (CNP) developed by Ascendis Pharma for the treatment of achondroplasia and is being investigated for hypochondroplasia. Navepegritide is administered once weekly and designed to provide sustained release and continuous exposure of active CNP, which is needed to counteract the overactive fibroblast growth factor receptor 3 signaling in achondroplasia, resulting in improved growth velocity. Navepegritide recently received accelerated approval in the USA for increasing linear growth in paediatric patients aged ≥ 2 years with achondroplasia with open epiphyses. This article summarizes the milestones in the development of navepegritide leading to this first approval for achondroplasia.
2026-05-26 | Co-Occurrence of Achondroplasia and 16p11.2 Deletion Syndrome in a Child With Group 4 Medulloblastoma: Expanding the Spectrum of Dual Genetic Diagnoses.
Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G > A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 signaling and impairs endochondral ossification. The 16p11.2 microdeletion (OMIM #611913) is a recurrent ~600 kb copy-number variant associated with developmental delay, autism spectrum disorder, epilepsy, and obesity, encompassing dosage-sensitive genes including MAPK3, KCTD13, and PRRT2. Recent genome-wide analyses have linked 16p11.2 deletion to a 13.9-fold increased risk of neuroblastoma, though no association with medulloblastoma has been documented. Medulloblastoma, the most common malignant pediatric brain tumor, is classified into molecularly defined subgroups-WNT-activated, SHH-activated, Group 3, and Group 4-each with distinct genetic drivers and clinical outcomes. We describe a 13-year-old male with achondroplasia confirmed by the pathogenic FGFR3 c.1138G > A variant and a de novo 16p11.2 microdeletion who developed metastatic non-WNT/non-SHH (Group 4) medulloblastoma with leptomeningeal dissemination (M3) at age 12. Despite multimodal therapy including resection, craniospinal irradiation, and combination chemotherapy, the tumor recurred and progressed. The patient died at age 13. To our knowledge, this is the first report of co-occurring achondroplasia and 16p11.2 deletion complicated by medulloblastoma. Although neither condition independently confers established risk for this tumor, both perturb MAPK/ERK signaling-a pathway implicated in Group 4 medulloblastoma biology. This case underscores the importance of recognizing multilocus pathogenic variation and supports further investigation of potential interactions between developmental and oncogenic signaling networks.
2026-05-25 | Navepegritide: First Approval
DeclarationsAuthorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Connie Kang is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability Not applicable.
Additional information about this Adis Drug Review can be found here.
Abstract
Navepegritide (YUVIWEL®) is a prodrug of C-type natriuretic peptide (CNP) developed by Ascendis Pharma for the treatment of achondroplasia and is being investigated for hypochondroplasia. Navepegritide is administered once weekly and designed to provide sustained release and continuous exposure of active CNP, which is needed to counteract the overactive fibroblast growth factor receptor 3 signaling in achondroplasia, resulting in improved growth velocity. Navepegritide recently received accelerated approval in the USA for increasing linear growth in paediatric patients aged ≥ 2 years with achondroplasia with open epiphyses. This article summarizes the milestones in the development of navepegritide leading to this first approval for achondroplasia.
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other
2026-02-21 | Foramen Magnum Stenosis in Achondroplasia: Imaging-Based Surgical Indications, Synchondrosis Fusion, and the Role of Ventriculomegaly.
Foramen magnum stenosis (FMS) and ventriculomegaly are frequent in achondroplasia due to cranial base hypoplasia. While FMS can cause spinal cord compression, the optimal treatment strategy remains debated. We reviewed our single-center experience and explored factors influencing surgical decisions. We retrospectively analyzed 18 children with achondroplasia evaluated between 2008 and 2024. MRI was used to assess FMS by anterior-posterior diameter and cerebrospinal fluid (CSF) area at the foramen magnum level. Ventriculomegaly was defined as an Evans Index ≥0.30. CT was used to evaluate foramen magnum morphology and synchondrosis fusion. Surgical indications were based on imaging findings of compression and intramedullary changes. The median age at initial imaging was 9.5 months. Thirteen patients underwent foramen magnum decompression (FMD) and 5 were managed conservatively. The surgical group showed significantly smaller craniocervical junction CSF spaces compared with nonsurgical cases (p < 0.05). Synchondrosis fusion occurred earlier in achondroplasia than in controls. Ventriculomegaly was present in 66%, but its severity did not correlate with FMD. All surgical cases achieved decompression without major complications. Of the 13 surgical patients, 9 were followed for more than 1 year (median follow-up: 122 months). Within this subgroup, 4 developed radiological bone regrowth with re-stenosis, but all remained asymptomatic and none required reoperation. FMS in achondroplasia poses major risks, yet its natural history and management remain unclear. Our findings support early imaging-based screening and timely intervention in cases with cord compression. While FMD effectively relieves compression, it does not address underlying ossification abnormalities, requiring continued surveillance. Premature synchondrosis fusion may play a key role, and future studies should consider combined surgical and medical approaches to improve outcomes.
2024-02-10 | Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report
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 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 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 FGFR3(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 FGFR3 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, FGFR3 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.
2021-08-31 | The Effect of Wnt Family Member 5a Gene Silencing on the Proliferation of Achondroplasia Using a DNAzymes-CoOOH Nanocomposite.
Achondroplasia is a kind of congenital dysplasia due to the defect of endochondral ossification. Achondroplasia is considered to be a protein folding disease leading to endoplasmic reticulum stress. Endoplasmic reticulum stress may lead to disease by affecting the function and survival state of chondrocytes, but the specific mechanism requires further study. In this study, bioinformatics methods, online database mining, screening of differentially expressed genes for pathway enrichment, and interaction analysis were conducted to detect the Wnt family member 5a (Wnt5a) gene. Additionally, we designed a novel DNAzymes-based nanocomposite that can simultaneously silence Wnt5a genes in chondrocytes. The nanocomposite was composed of amino-functionalized cobalt oxyhydroxide nanoflakes modified by DNAzymes that target the Wnt5a gene. Further, we conducted in vitro experiments to verify that Wnt5a can mediate the mitogen-activated protein kinase signaling pathway through the endoplasmic reticulum stress pathway to affect the proliferation of chondrocytes.
gene therapies
2025-07-03 | Signatures of selection detected from whole-genome sequencing indicate that the small body size in dwarf rabbit breeds is caused by polygenic effects with a few major loci.
Early genetic studies have suggested that body size in rabbits can be considered a quantitative trait. Several rabbit breeds can be distinguished based on body size, including a few dwarf breeds differentiated by other morphological characteristics. While a large deletion in the HMGA2 gene is a major locus associated with dwarfism in Netherland Dwarf rabbits, it may not fully explain the reduced body size in this breed or other dwarf breeds. In this study, we compared the genomes of two dwarf rabbit breeds (Dwarf Lop and Netherland Dwarf) with those of non-dwarf rabbits by analysing whole-genome sequencing data obtained using a DNA-pool sequencing approach. We applied the fixation index (FST) and pooled heterozygosity (HP) statistics to identify signatures of selection related to small body size by contrasting dwarf with non-dwarf breeds and comparing dwarf breeds. We identified several genomic regions that contain genes previously linked to body dimensions in various species, including LCORL-NCAPG, COL2A1, GHRHR and CENPE. Functional enrichment analysis of genes within the top differentiated regions revealed biological terms related to skeletal development, further supporting the biological relevance of these loci. Additionally, the use of the latest version of the reference rabbit genome enabled the identification of a genomic region containing FGFR3, a gene linked to achondroplasia. Some genomic regions showed differentiation between the two dwarf breeds, suggesting that their small body size may, in part, arise through different genetic mechanisms. Overall, these findings support a polygenic architecture underlying small size in rabbits, influenced by a few major loci.
2025-01-16 | Fgfr3 enhancer deletion markedly improves all skeletal features in a mouse model of achondroplasia.
Achondroplasia, the most prevalent short-stature disorder, is caused by missense variants overactivating the fibroblast growth factor receptor 3 (FGFR3). As current surgical and pharmaceutical treatments only partially improve some disease features, we sought to explore a genetic approach. We show that an enhancer located 29 kb upstream of mouse Fgfr3 (-29E) is sufficient to confer a transgenic mouse reporter with a domain of expression in cartilage matching that of Fgfr3. Its CRISPR/Cas9-mediated deletion in otherwise WT mice reduced Fgfr3 expression in this domain by half without causing adverse phenotypes. Importantly, its deletion in mice harboring the ortholog of the most common human achondroplasia variant largely normalized long bone and vertebral body growth, markedly reduced spinal canal and foramen magnum stenosis, and improved craniofacial defects. Consequently, mouse achondroplasia is no longer lethal, and adults are overall healthy. These findings, together with high conservation of -29E in humans, open a path to develop genetic therapies for people with achondroplasia.
2023-08-08 | Hemiepiphysiodesis for Lower Extremity Coronal Plane Angular Correction in the Distal Femur and Proximal Tibia in Children With Achondroplasia.
Achondroplasia is the most prevalent form of skeletal dysplasia, affecting more than 250,000 individuals. Lower extremity angular deformities, particularly genu varum, are common in children with achondroplasia, often resulting in pain and limitation of function. The authors aim to determine the utility of lower extremity growth modulation with hemiepiphysiodesis in children with achondroplasia for correction of coronal plane deformities about the knee. The authors performed a retrospective chart review of a single center from 1/1/2000 to 12/31/2020 to identify pediatric patients with achondroplasia treated with hemiepiphysiodesis as their initial procedure at the distal femur and/or proximal tibia. Patients with adequate records and who had completed their treatment were included. Data collected included duration of treatment, complications, need for osteotomy, and radiographic measurements including initial and final mechanical axis deviation, knee mechanical axis zone, mechanical lateral distal femoral angle and medial proximal tibia angle. Ten patients with 17 limbs met our criteria. Nine patients (15 limbs) were treated for genu varum and 1 patient (2 limbs) was treated for genu valgum. Prior to treatment, the mechanical axis fell in zone 3 in 59% of limbs and zone 2 in 41%. Average correction in mechanical axis deviation was 26.1 mm. Average change in mechanical lateral distal femoral angle was 10.3 degrees per limb, and average change in medial proximal tibia angle was 7.1 degrees per limb. Average treatment duration was 909 days. At final follow up, 81% (14/17) of limbs had the mechanical axis in zone 1, with the remaining 18% (3/17) in zone 2. No patient/limb underwent subsequent distal femur or proximal tibia osteotomy for coronal plane alignment. Children with achondroplasia can successfully be treated with hemiepiphysiodesis to correct coronal plane deformities at the distal femur and proximal tibia. Using this technique, no patient in our series required an osteotomy for genu varum/valgum. Therapeutic level IV, Case series.
2021-08-28 | Targeted gene correction and functional recovery in achondroplasia patient-derived iPSCs
Abstract Background Achondroplasia (ACH) is the most common genetic form of dwarfism and belongs to dominant monogenic disorder caused by a gain-of-function point mutation in the transmembrane region of FGFR3 . There are no effective treatments for ACH. Stem cells and gene-editing technology provide us with effective methods and ideas for ACH research and treatment. Methods We generated non-integrated iPSCs from an ACH girl’s skin and an ACH boy’s urine by Sendai virus. The mutation of ACH iPSCs was precisely corrected by CRISPR-Cas9. Results Chondrogenic differentiation ability of ACH iPSCs was confined compared with that of healthy iPSCs. Chondrogenic differentiation ability of corrected ACH iPSCs could be restored. These corrected iPSCs displayed pluripotency, maintained normal karyotype, and demonstrated none of off-target indels. Conclusions This study may provide an important theoretical and experimental basis for the ACH research and treatment.
2018-11-29 | Optimizing CRISPR/Cas9 technology for precise correction of the Fgfr3-G374R mutation in achondroplasia in mice
CRISPR/Cas9 is a powerful technology widely used for genome editing, with the potential to be used for correcting a wide variety of deleterious disease-causing mutations. However, the technique tends to generate more indels (insertions and deletions) than precise modifications at the target sites, which might not resolve the mutation and could instead exacerbate the initial genetic disruption. We sought to develop an improved protocol for CRISPR/Cas9 that would correct mutations without unintended consequences. As a case study, we focused on achondroplasia, a common genetic form of dwarfism defined by missense mutation in the Fgfr3 gene that results in glycine to arginine substitution at position 374 in mice in fibroblast growth factor receptor 3 (Fgfr3-G374R), which corresponds to G380R in humans. First, we designed a GFP reporter system that can evaluate the cutting efficiency and specificity of single guide RNAs (sgRNAs). Using the sgRNA selected based on our GFP reporter system, we conducted targeted therapy of achondroplasia in mice. We found that we achieved higher frequency of precise correction of the Fgfr3-G374R mutation using Cas9 protein rather than Cas9 mRNA. We further demonstrated that targeting oligos of 100 and 200 nucleotides precisely corrected the mutation at equal efficiency. We showed that our strategy completely suppressed phenotypes of achondroplasia and whole genome sequencing detected no off-target effects. These data indicate that improved protocols can enable the precise CRISPR/Cas9-mediated correction of individual mutations with high fidelity. CRISPR/Cas9 is a powerful technology widely used for genome editing, with the potential to be used for correcting a wide variety of deleterious disease-causing mutations. However, the technique tends to generate more indels (insertions and deletions) than precise modifications at the target sites, which might not resolve the mutation and could instead exacerbate the initial genetic disruption. We sought to develop an improved protocol for CRISPR/Cas9 that would correct mutations without unintended consequences. As a case study, we focused on achondroplasia, a common genetic form of dwarfism defined by missense mutation in the Fgfr3 gene that results in glycine to arginine substitution at position 374 in mice in fibroblast growth factor receptor 3 (Fgfr3-G374R), which corresponds to G380R in humans. First, we designed a GFP reporter system that can evaluate the cutting efficiency and specificity of single guide RNAs (sgRNAs). Using the sgRNA selected based on our GFP reporter system, we conducted targeted therapy of achondroplasia in mice. We found that we achieved higher frequency of precise correction of the Fgfr3-G374R mutation using Cas9 protein rather than Cas9 mRNA. We further demonstrated that targeting oligos of 100 and 200 nucleotides precisely corrected the mutation at equal efficiency. We showed that our strategy completely suppressed phenotypes of achondroplasia and whole genome sequencing detected no off-target effects. These data indicate that improved protocols can enable the precise CRISPR/Cas9-mediated correction of individual mutations with high fidelity.
cell therapies
2026-01-28 | Spatiotemporal Regulation and Lineage Specification in Embryonic Endochondral Ossification.
Long bone formation in vertebrates proceeds via endochondral ossification, a sequential process that begins with mesenchymal condensation, advances through cartilage anlage formation, and culminates in its replacement by mineralized bone. Recent advances in inducible lineage tracing and single-cell genomics have revealed that, rather than being a uniform event, mesenchymal condensation rapidly segregates into progenitor pools with distinct fates. Centrally located Sox9+/Fgfr3+ chondroprogenitors expand into the growth plate and metaphyseal stroma, peripheral Hes1+ boundary cells refine condensation via asymmetric division, and outer-layer Dlx5+ perichondrial cells generate the bone collar and cortical bone. Concurrently, dorsoventral polarity established by Wnt7a-Lmx1b and En1 ensures that dorsal progenitors retain positional identity throughout development. These lineage divergences integrate with signaling networks, including the Ihh-PTHrP, FGF, BMPs, and WNT/β-catenin networks, which impose temporal control over chondrocyte proliferation, hypertrophy, and vascular invasion. Perturbations in these programs, exemplified by mutations in Fgfr3, Sox9, and Dlx5, underlie region-specific skeletal dysplasias, such as achondroplasia, campomelic dysplasia, and split-hand/foot malformation, demonstrating the lasting impacts of embryonic patterning errors. Based on these insights, regenerative strategies are increasingly drawing upon developmental principles, with organoid cultures recapitulating ossification centers, biomimetic hydrogels engineered for spatiotemporal morphogen delivery, and stem cell- or exosome-based therapies harnessing developmental microRNA networks. By bridging developmental biology with biomaterials science, these approaches provide both a roadmap to unravel skeletal disorders and a blueprint for next-generation therapies to reconstruct functional bones with the precision of the embryonic blueprint.
2025-02-03 | Early evaluation and treatment of thoracolumbar kyphosis in children with achondroplasia.
Thoracolumbar kyphosis (TLK) is frequently reported in children with achondroplasia. The combination of TLK and the narrow spinal canal in achondroplasia increases the risk of developing symptomatic spinal stenosis. However, there is no consensus on the optimal management of TLK. This retrospective cohort study evaluated children under four years old with achondroplasia, monitoring TLK every six months. Pathologic TLK was defined as a Cobb angle of 20 degrees or more between T10 and L2. Management involved either a wait-and-see policy, which prohibited unsupported sitting, or bracing. Surgery was reserved for severe progressive TLK or spinal stenosis cases. TLK was evaluated over time. A receiver operating characteristic curve determined the baseline threshold where wait-and-see management failed to resolve TLK below 20 degrees. Multiple linear regression compared bracing versus wait-and-see management for cases exceeding 40 degrees. Sixty-two patients were included, with a median age of 10 months and a median follow-up of 31 months. TLK prevalence decreased from 85% at baseline to 42% at final follow-up. The mean Cobb angle decreased from 31 ± 11 degrees to 22 ± 16 degrees (p < 0.001). The threshold for ineffective wait-and-see management was identified as 33 degrees. Bracing resulted in significantly more TLK reduction than wait-and-see management for cases exceeding 40 degrees (15 degree difference, 95% CI 2-28, p = 0.023). Three patients required surgery. TLK is highly prevalent in achondroplasia, necessitating careful monitoring. A wait-and-see policy with restrictions on unsupported sitting is recommended initially, but early bracing should be considered for more severe cases.
2024-12-23 | Resolving the design principles that control postnatal vascular growth and scaling.
After birth, tissues grow continuously until reaching adult size, with each organ exhibiting unique cellular dynamics, growth patterns, and (stem or non-stem) cell sources. Using a suite of experimental and computational multiscale approaches, we found that aortic expansion is guided by specific biological principles and scales with the vertebral column rather than animal body weight. Expansion proceeds via two distinct waves of arterial cell proliferation along blood flow that are spatially stochastic, yet temporally coordinated. Each wave exhibits unique cell cycle kinetics and properties, with the first wave exhibiting cell cycle durations as fast as 6 hours. Single-cell RNA sequencing showed changes in fatty acid metabolism concomitant with an increase in cell size. Mathematical modeling and experiments indicated endothelial cell extrusion is essential for homeostatic aortic growth and balancing excess proliferation. In a genetic model of achondroplasia, the aorta achieves proper scaling through enhanced cell extrusion while maintaining normal proliferation dynamics. Collectively, these results provide a blueprint of the principles that orchestrate aortic growth which depends entirely on differentiated cell proliferation rather than resident stem cells.
2023-12-04 | Achondroplasia Natural History Study (CLARITY): 60-year experience with hydrocephalus in achondroplasia from four skeletal dysplasia centers.
The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers. The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information. A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of hydrocephalus at a median age of 14.4 months. There was considerable variation in the percentage of patients treated for hydrocephalus by center and decade of birth, ranging from 0% to 28%, although in the most recent decade, all centers treated less than 6% of their patients, with an average of 2.9% across all centers. Undergoing a cervicomedullary decompression (CMD) was a strong predictor for treatment of hydrocephalus (OR 5.8, 95% CI 3.9-8.4), although that association has disappeared in those born since 2010 (OR 1.1, 95% CI 0.2-5.7). In patients born since 1990, treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) has become more common; it was used as the first line of treatment in 38% of patients in the most recent decade. Kaplan-Meier analysis suggests that a single ETV will treat hydrocephalus in roughly half of these patients. While many children with achondroplasia have features of hydrocephalus with enlarged intracranial CSF spaces and relative macrocephaly, treatment of hydrocephalus in achondroplasia patients has become relatively uncommon in the last 20 years. Historically, there was a significant association between symptomatic foramen magnum stenosis and treatment of hydrocephalus, although concurrent treatment of both has fallen out of favor with the recognition that CMD alone will treat hydrocephalus in some patients. Despite good experimental data demonstrating that hydrocephalus in achondroplasia is best understood as communicating in nature, ETV appears to be reasonably successful in certain patients and should be considered an option in selected patients.
2023-03-25 | Humeral lengthening: Systematic Review and Meta Analysis
Background: The humerus lengthening was mostly regarded an aesthetic procedure.Recent study indicates, however, that the objectives of bilateral humeral lengthening in achondroplasia are not just cosmetic, but also to restore proportions between the upper and lower limbs, extend reach, and enhance the capacity to perform perineal personal hygiene.This study's objective was to conduct a comprehensive evaluation and analysis of the outcomes of humeral lengthening.Methods: During this systematic review and meta-analysis preparation, we adhered to the PRISMA statement criteria and followed the Cochrane handbook for systematic reviews of interventions.Results: We identified eight studies discussing humeral lengthening including a total number of 158 humeri in 129 patients.The age range of patients across the studies ranged between 6.5 and 20 years.The male gender was common and ranging from 33% to 78%.The humeral lengthening was conducted among 158 humeri among them 34 in the right side.The mean length achieved was 7.7 cm among the included eight145 studies ranging from 5.1 cm to 9 cm.Pooled analysis of the involved trials showed significant association between length pre and post humeral lengthening (OR = -6.08;95% CI: [-6.79, -5.38]; P = <0.00001).The pooled studies were not heterogenous (I2 = 0%, P < 0.46).Conclusions: The lengthening of the humerus was regarded mostly as a cosmetic procedure.Using a variety of external fixators and intramedullary (IM) nails, the humerus was extended by distraction osteogenesis.There is a statistically significant link between length before and after humeral lengthening, although neither range of motion nor functional score are affected.
small molecules
2026-08-11 | Computational Evaluation of Dabogratinib and C-Type Natriuretic Peptide Analogue Co-treatment in Achondroplasia
Achondroplasia is usually caused by an overactive form of FGFR3, a receptor that normally slows bone growth. Dabogratinib (TYRA-300) blocks FGFR3, while C-type natriuretic peptide (CNP) analogues act further down the same signalling network. This computer study asked whether combining these two approaches could restore growth-plate signalling better than either approach alone. Four ordinary differential equations represented active FGFR3, CNP-driven cGMP/PKG signalling, MAPK/ERK and STAT1. Two further outputs represented cell proliferation and matrix/differentiation. A 21 × 21 grid tested 441 pairs of normalised treatment intensities. Combination effects were measured with Bliss independence and highest-single-agent (HSA) scores. The untreated disease state lowered the proliferation index from 1.000 to 0.563. The strongest qualifying pair was T = 0.20 for dabogratinib and C = 0.30 for the CNP analogue. Its Bliss score was 0.216 and its HSA score was 0.457. Eighty-one pairs met the study's synergy rule, 360 were approximately additive and none were antagonistic. In 3,000 tests with varied parameter values, 97.2% of samples still met the synergy rule. At high intensities, the result became additive because the output had already reached its upper limit. These findings support an intermediate-intensity synergy hypothesis within the model. They do not prove that the drug combination is safe or effective in people. Laboratory data are needed to test and improve the model.
2026-08-09 | Longitudinal growth pattern of Hungarian children with achondroplasia: The evaluation of treatment-related growth changes
Background: Achondroplasia is characterized by a distinctive growth pattern involving disproportionate short stature, limb shortening, macrocephaly and altered growth velocities throughout childhood. Objective: The project aims to examine the impact of vosoritide (VOXZOGO®) treatment on growth patterns in children with achondroplasia and to assess the applicability of the European achondroplasia-specific growth references to a Hungarian achondroplasia cohort. Subjects and methods: The longitudinal study was initiated in October 2025. To date, 20 Hungarian children with achondroplasia, aged 2–13 years, have been enrolled at the Department of Paediatrics, Semmelweis University, Budapest, Hungary. Anthropometric assessments are conducted at baseline and repeated at 3‑month intervals throughout the follow-up period. Measurements include body weight, body height/length, sitting height, arm span, lengths of the upper and lower limb segments, trunk and limb circumferences and breadths, as well as head dimensions. The observed growth patterns are evaluated relative to the growth channels defined by the European achondroplasia-specific reference standards. Results: In this pilot study, analyses focused on body weight, body height/length, body mass index and head circumference. The preliminary findings demonstrate the applicability of the European achondroplasia-specific reference standards for monitoring individual growth trajectories. At this preliminary stage, the analyses focus on determining whether the observed growth patterns remained within or deviated from the growth channels of the achondroplasia-specific references. Conclusion: Our newly developed anthropometric protocol provides a standardized framework for the longitudinal assessment of growth in children with achondroplasia and includes an extensive set of body and head measurements that enable detailed monitoring of body proportions and cranial growth throughout childhood. Extended follow-up will be required to clarify the influence of vosoritide treatment on the overall growth patterns of children with achondroplasia.
2026-07-17 | Genetic Bone Diseases: A Scoping Review of Pathology, Symptoms, Diagnosis, Treatment, and New Horizons.
Genetic bone diseases are a rare group of afflictions suffered by the general population. However, their rarity should not diminish research efforts to help patients understand and treat their diseases. This review summarizes the pathology, symptoms, diagnosis, and treatment insight into six well-known genetic bone diseases. Only six bone diseases are included due to the relatively low prevalence of them as whole limiting our scope to ensure accurate information and attention is provided for each disease individually. A literature search of PubMed is conducted, including studies published within the past five years (January 2020-December 2025). Thirty-six studies met inclusion criteria, and no significant risk of bias is identified among the selected articles. Study findings are synthesized into disease overview, clinical and radiographic features, and diagnostic and treatment approaches. Actively developing or novel therapies relevant to each disease are also included. These treatments include: fresolimumab for osteogenesis imperfecta, small interfering ribonucleic acid (RNA) therapy for Osteopetrosis, denosumab for Paget's disease of bone, vosoritide/recifercept/infigratinib for achondroplasia, mesenchymal stem cell therapy for craniosynostosis, and combination losartan and atenolol therapy for Marfan syndrome. These treatments are generally more recently acknowledged in literature and are either actively undergoing research or require further research to determine their efficacy.
2026-04-19 | Evaluating the impact of vosoritide on complications of achondroplasia.
Impaired endochondral bone growth in people with achondroplasia causes complications that impair function, cause pain, require surgery, and contribute to mortality. Rates of complications in participants with achondroplasia enrolled in clinical trials of vosoritide, a targeted treatment, were analyzed and compared with published natural history (NH) rates. Prevalence (medical history + new events post-treatment initiation) and incidence (new/worsening events posttreatment initiation) were calculated for complications across 6 clinical trials (2.5-30 μg/kg/day vosoritide) in children with achondroplasia, stratified by age at treatment initiation (<5 years/≥5 years). Complication-related procedures and mortality rates were examined. By August 2024, 230 participants received vosoritide (68 aged <5 years at treatment initiation [exposure, 289.1 person-years]; 162 aged ≥5 years at treatment initiation [exposure, 834.5 person-years]). Prevalence for most complications was consistent with or lower than NH rates. Incidence of leg malalignment; foramen magnum stenosis; spinal stenosis; kyphosis; lordosis; hydrocephalus; ear, nose, and throat complications; and pain was generally lower than NH rates. Foramen magnum decompression frequency was 3.0% overall (5.9% in participants who initiated treatment aged <2 years). Crude mortality was lower than NH rates. Vosoritide was not associated with worsening of complications in children with achondroplasia and may reduce their frequency.
2026-04-09 | Dkk1 inhibition restores mandibular growth in an achondroplasia mouse model.
Meckel's and condylar cartilages are key to mandible development, with Meckel's cartilage acting as a template and condylar cartilage as a growth center. In achondroplasia, the most common form of genetic dwarfism, abnormalities of these cartilages lead to micrognathia, with significant functional repercussions for affected individuals. How FGFR3 overactivation in achondroplasia disrupts Meckel's and condylar cartilages is largely unknown. Our aim was to identify the pathways driving these disruptions by analyzing the genes expressed in these cartilages in a mouse model mimicking achondroplasia. Using cartilage laser-microdissection and RNA-sequencing analyses, we first compared the transcriptome of Meckel's and condylar cartilages from E16.5 embryos of control and Fgfr3Y367C/+ mice. Over 900 genes were differentially expressed, including the Dkk1 gene, which encodes an inhibitor of β-catenin-dependent Wnt signaling and was significantly overexpressed in chondrocytes of Fgfr3 mutants in both Meckel's and condylar cartilages. Immunostaining of sections of the cartilages confirmed the high expression at the protein level. Primary cultures of Meckel's cartilage chondrocytes showed that, in Fgfr3Y367C/+ mutants, activation of the canonical Wnt pathway with Wnt3a was reduced, while a Dkk1 antagonist increased Wnt activity, suggesting that Dkk1 overexpression was responsible for decreased canonical Wnt activity in mutants. In a mandible organ culture model, inhibition of Dkk1 also significantly increased the mandible size, due to an increased elongation of the condylar cartilage of mutants, as seen after tissue clearing and Sox9 immunolabeling. In this cartilage, increased proliferation and defective differentiation into hypertrophic chondrocytes was partially corrected by Dkk1 inhibition. Our data suggest that dysregulation of Wnt/β-catenin activity due to Fgfr3 gain-of function mutation constitutes an important underlying mechanism in craniofacial defects observed in achondroplasia.
proteins
2026-09-17 | Consensus statement on the management of Achondroplasia in the Middle East
Achondroplasia is the most common skeletal dysplasia and presents as a lifelong, multi-system condition characterized by disproportionate short stature, rhizomelic limb shortening, macrocephaly with frontal bossing, and a spectrum of neurological, respiratory, orthopedic, and psychosocial complications. Effective management requires anticipatory surveillance, coordinated multidisciplinary care, and early recognition of life-threatening complications. Therapeutic options have expanded in recent years with the introduction of vosoritide, a C-type natriuretic peptide analog that targets the underlying pathophysiology and has demonstrated significant improvements in linear growth and body proportionality in eligible children. However, global advances have not been uniformly translated into clinical practice across the Middle East, where challenges such as delayed diagnosis, inconsistent access to genetic testing, limited multidisciplinary infrastructure, and inequities in treatment availability continue to impact patient outcomes. In this document, a panel of pediatric endocrinologists and clinical geneticists from the Middle East convened to develop a set of regionally relevant, evidence-informed consensus statements on the diagnosis and management of achondroplasia in light of novel advances in the management of this condition. Using a modified Delphi process, the panel achieved consensus on 25 statements covering diagnosis, surveillance, multidisciplinary management, psychosocial support, pharmacologic interventions, transition to adult care, and research priorities. This consensus, endorsed by the Arab Society for Pediatric Endocrinology and Diabetes (ASPED) and the MENA Medical Genetics Association, aims to standardize and enhance the quality of care for individuals with achondroplasia across the region by integrating international best practices with local healthcare realities. The author panel believes that the implementation of these recommendations has the potential to improve early detection, optimize long-term outcomes, strengthen family support, and expand equitable access to emerging therapies.
2026-06-25 | Second drug approved for achondroplasia
Navepegritide (Yuviwel), a C-type natriuretic peptide analog, is the second drug to be approved for the treatment of achondroplasia. It is administered subcutaneously once weekly. The retail cost for navepegritide is expected to be almost half a million dollars annually.
2026-06-03 | Navepegritide: First Approval.
Navepegritide (YUVIWEL®) is a prodrug of C-type natriuretic peptide (CNP) developed by Ascendis Pharma for the treatment of achondroplasia and is being investigated for hypochondroplasia. Navepegritide is administered once weekly and designed to provide sustained release and continuous exposure of active CNP, which is needed to counteract the overactive fibroblast growth factor receptor 3 signaling in achondroplasia, resulting in improved growth velocity. Navepegritide recently received accelerated approval in the USA for increasing linear growth in paediatric patients aged ≥ 2 years with achondroplasia with open epiphyses. This article summarizes the milestones in the development of navepegritide leading to this first approval for achondroplasia.
2026-05-26 | Co-Occurrence of Achondroplasia and 16p11.2 Deletion Syndrome in a Child With Group 4 Medulloblastoma: Expanding the Spectrum of Dual Genetic Diagnoses.
Achondroplasia (OMIM #100800), the most common skeletal dysplasia, results from the recurrent FGFR3 c.1138G > A (p.Gly380Arg) gain-of-function variant, which constitutively activates fibroblast growth factor receptor 3 signaling and impairs endochondral ossification. The 16p11.2 microdeletion (OMIM #611913) is a recurrent ~600 kb copy-number variant associated with developmental delay, autism spectrum disorder, epilepsy, and obesity, encompassing dosage-sensitive genes including MAPK3, KCTD13, and PRRT2. Recent genome-wide analyses have linked 16p11.2 deletion to a 13.9-fold increased risk of neuroblastoma, though no association with medulloblastoma has been documented. Medulloblastoma, the most common malignant pediatric brain tumor, is classified into molecularly defined subgroups-WNT-activated, SHH-activated, Group 3, and Group 4-each with distinct genetic drivers and clinical outcomes. We describe a 13-year-old male with achondroplasia confirmed by the pathogenic FGFR3 c.1138G > A variant and a de novo 16p11.2 microdeletion who developed metastatic non-WNT/non-SHH (Group 4) medulloblastoma with leptomeningeal dissemination (M3) at age 12. Despite multimodal therapy including resection, craniospinal irradiation, and combination chemotherapy, the tumor recurred and progressed. The patient died at age 13. To our knowledge, this is the first report of co-occurring achondroplasia and 16p11.2 deletion complicated by medulloblastoma. Although neither condition independently confers established risk for this tumor, both perturb MAPK/ERK signaling-a pathway implicated in Group 4 medulloblastoma biology. This case underscores the importance of recognizing multilocus pathogenic variation and supports further investigation of potential interactions between developmental and oncogenic signaling networks.
2026-05-25 | Navepegritide: First Approval
DeclarationsAuthorship and Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Connie Kang is a salaried employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to this article and are responsible for its content.Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability Not applicable.
Additional information about this Adis Drug Review can be found here.
Abstract
Navepegritide (YUVIWEL®) is a prodrug of C-type natriuretic peptide (CNP) developed by Ascendis Pharma for the treatment of achondroplasia and is being investigated for hypochondroplasia. Navepegritide is administered once weekly and designed to provide sustained release and continuous exposure of active CNP, which is needed to counteract the overactive fibroblast growth factor receptor 3 signaling in achondroplasia, resulting in improved growth velocity. Navepegritide recently received accelerated approval in the USA for increasing linear growth in paediatric patients aged ≥ 2 years with achondroplasia with open epiphyses. This article summarizes the milestones in the development of navepegritide leading to this first approval for achondroplasia.
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2026-02-21 | Foramen Magnum Stenosis in Achondroplasia: Imaging-Based Surgical Indications, Synchondrosis Fusion, and the Role of Ventriculomegaly.
Foramen magnum stenosis (FMS) and ventriculomegaly are frequent in achondroplasia due to cranial base hypoplasia. While FMS can cause spinal cord compression, the optimal treatment strategy remains debated. We reviewed our single-center experience and explored factors influencing surgical decisions. We retrospectively analyzed 18 children with achondroplasia evaluated between 2008 and 2024. MRI was used to assess FMS by anterior-posterior diameter and cerebrospinal fluid (CSF) area at the foramen magnum level. Ventriculomegaly was defined as an Evans Index ≥0.30. CT was used to evaluate foramen magnum morphology and synchondrosis fusion. Surgical indications were based on imaging findings of compression and intramedullary changes. The median age at initial imaging was 9.5 months. Thirteen patients underwent foramen magnum decompression (FMD) and 5 were managed conservatively. The surgical group showed significantly smaller craniocervical junction CSF spaces compared with nonsurgical cases (p < 0.05). Synchondrosis fusion occurred earlier in achondroplasia than in controls. Ventriculomegaly was present in 66%, but its severity did not correlate with FMD. All surgical cases achieved decompression without major complications. Of the 13 surgical patients, 9 were followed for more than 1 year (median follow-up: 122 months). Within this subgroup, 4 developed radiological bone regrowth with re-stenosis, but all remained asymptomatic and none required reoperation. FMS in achondroplasia poses major risks, yet its natural history and management remain unclear. Our findings support early imaging-based screening and timely intervention in cases with cord compression. While FMD effectively relieves compression, it does not address underlying ossification abnormalities, requiring continued surveillance. Premature synchondrosis fusion may play a key role, and future studies should consider combined surgical and medical approaches to improve outcomes.
2024-02-10 | Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report
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 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 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 FGFR3(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 FGFR3 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, FGFR3 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.
2021-08-31 | The Effect of Wnt Family Member 5a Gene Silencing on the Proliferation of Achondroplasia Using a DNAzymes-CoOOH Nanocomposite.
Achondroplasia is a kind of congenital dysplasia due to the defect of endochondral ossification. Achondroplasia is considered to be a protein folding disease leading to endoplasmic reticulum stress. Endoplasmic reticulum stress may lead to disease by affecting the function and survival state of chondrocytes, but the specific mechanism requires further study. In this study, bioinformatics methods, online database mining, screening of differentially expressed genes for pathway enrichment, and interaction analysis were conducted to detect the Wnt family member 5a (Wnt5a) gene. Additionally, we designed a novel DNAzymes-based nanocomposite that can simultaneously silence Wnt5a genes in chondrocytes. The nanocomposite was composed of amino-functionalized cobalt oxyhydroxide nanoflakes modified by DNAzymes that target the Wnt5a gene. Further, we conducted in vitro experiments to verify that Wnt5a can mediate the mitogen-activated protein kinase signaling pathway through the endoplasmic reticulum stress pathway to affect the proliferation of chondrocytes.
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Drug Discovery Landscape
12 orphan drug designations for Achondroplasia, including 3 approved therapies.
12 orphan drug designations for Achondroplasia, including 3 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
selective small molecular inhibitor of fibroblast growth factor receptor 2 (FGFR2) and fibroblast growth factor receptor 3 (FGFR3) | small molecules | FDA | Abbisko Therapeutics Co., Ltd. | |
Small molecule fibroblast growth factor receptor 3 selective tyrosine kinase inhibitor | small molecules | FDA | Tyra Biosciences | |
Anti-fibroblast growth factor receptor 3 antigen-binding fragment (anti-FGFR3 Fab) | antibodies | FDA | Genzyme Corporation, a Sanofi Company | |
Infigratinib | small molecules | FDA | QED Therapeutics, Inc. | |
Infigratinib | small molecules | EMA | BridgeBio Pharma Europe B.V. | |
Humanised monoclonal antibody derivative against fibroblast growth factor receptor 3 | antibodies | EMA | Sanofi B.V. | |
C-type natriuretic peptide conjugated to multi-arm polyethylene glycol carrier through a cleavable linker | proteins | EMA | Ascendis Pharma Growth Disorders A/S | |
navepegritide [Yuviwel] | proteins | FDA | Approved | Ascendis Pharma Growth Disorders A/S |
Recombinant human fibroblast growth factor receptor 3 | proteins | FDA | Pfizer Inc. | |
Recifercept | proteins | EMA | Pfizer Europe MA EEIG | |
Modified recombinant human C-type natriuretic peptide [Voxzogo] | proteins | EMA | Approved | BioMarin International Limited |
vosoritide [Voxzogo] | peptides | FDA | Approved | BioMarin Pharmaceutical, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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