BACKGROUND: Pseudoachondroplasia (PSACH) is a rare dwarfing condition characterized by short limbs and fingers, and multiple skeletal abnormalities/complications. There are few natural history studies delineating the medical problems in PSACH leaving a gap in many areas, especially oral health. Our study aimed to obtain information pertaining to oral health and other health-related problems (pregnancy and childbirth, skeletal health, joint pain) in patients with PSACH.
METHODS: To ascertain this information, an online Qualtrics survey was distributed to members of Little People of America, a support group, and through a PSACH online chatroom.
RESULTS: Ninety-nine of 115 surveys were completed and included in the descriptive and multivariable analyses. PSACH individuals regularly sought dental care, but flossing was challenging because of short fingers. Untreated carries (5%), bleeding gums (16%) malocclusion (37%), obstructive sleep apnea (9%), and TMJ disorder (3%) occurred less frequently compared to the general population. Delivery was by Caesarean section in 100% of female respondents who delivered a baby. Bowlegs (74%), scoliosis (43%) and osteoarthritis (36%) were the most common skeletal complications. Joint pain was reported by 85% of respondents.
CONCLUSIONS: This study provides novel insights into oral health, pregnancy and childbirth while confirming previously identified skeletal complications in PSACH. Our findings suggest that oral healthcare in PSACH presents unique challenges.

While randomized, placebo-controlled, double-blinded clinical studies are the gold standard for evaluating the efficacy of investigational drugs, the use of placebo in children with achondroplasia should be limited because it provides no clinical benefit while exhausting study participants\' treatment window. Recifercept is an investigational drug for treating children with achondroplasia aged 2-10 years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi-variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post-recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12 months post-recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug.

BACKGROUND: Achondroplasia is a common skeletal dysplasia with a high prevalence of obesity in adulthood. Bariatric surgery has been shown to be effective in treating obesity and related comorbidities, but its feasibility and effectiveness in patients with achondroplasia have not been clearly established.
OBJECTIVE: The objective of this study was to evaluate the feasibility and effectiveness of bariatric surgery in patients with achondroplasia.
METHODS: This study was performed in France, and bariatric surgeons from the Société Française et Francophone de Chirurgie de l\'Obésité et des Maladies Métaboliques (French Francophone Society of Surgery for Obesity or Metabolic Diseases) were asked to participate.
METHODS: Two adult women with confirmed achondroplasia and a high BMI were selected for laparoscopic sleeve gastrectomy. Preoperative data were collected, including demographic information, comorbidities, and follow-up at 1, 3, and 6 months and 1 year after surgery. Complications were monitored and recorded.
RESULTS: Both patients had good excess weight loss outcomes, with an average excess weight loss of 60.5% 1 year after surgery. One patient had a follow-up of 3 years and an excess weight loss of 44%. The surgery was well-tolerated, and no major complications were observed.
CONCLUSIONS: Bariatric surgery is feasible and effective in patients with achondroplasia, with good outcomes for excess weight loss and related comorbidities. These findings suggest that bariatric surgery should be considered a treatment option for patients with achondroplasia and obesity.

Bilateral femoral distraction osteogenesis in patients with achondroplasia is insufficiently reported. We aimed to perform the first study that exclusively analyzed simultaneous bilateral femoral distraction osteogenesis with motorized intramedullary lengthening nails via an antegrade approach in patients with achondroplasia focused on reliability, accuracy, precision, and the evolving complications.
In this retrospective singlecenter study we analyzed patients with achondroplasia who underwent simultaneous bilateral femoral lengthening with antegrade intramedullary lengthening nails between October 2014 and April 2019. 15 patients (30 femoral segments) of median age 14 years (interquartile range [IQR] 12-15) were available for analysis. The median follow-up was 29 months (IQR 27-37) after nail implantation.
The median distraction length per segment was 49 mm (IQR 47-51) with a median distraction index of 1.0 mm/day (IQR 0.9-1.0), and a median consolidation index of 20 days/cm (IQR 17-23). Reliability of the lengthening nails was 97% and their calculated accuracy and precision were 96% and 95%, respectively. The most common complication was temporary restriction of knee range of motion during distraction in 10 of 30 of the lengthened segments. 1 patient was treated with 2 unplanned additional surgeries due to premature consolidation.
The method is reliable and accurate with few complications.

BACKGROUND: Transosseous distraction osteosynthesis is prioritized in orthopedic care for children with achondroplasia. However, difficulties encountered during treatment and rehabilitation directly impact patients\' quality of life. Using rod external fixators within a semicircular frame for osteosynthesis is less traumatic compared to spoke circular devices. Their straightforward assembly and mounting on the limb segment can help significantly reduce treatment duration, thereby improving children\'s quality of life during treatment and rehabilitation.
OBJECTIVE: This study aimed to conduct a comparative analysis of the quality of life (measured by postoperative pain syndrome, physical activity, and emotional state) among children with achondroplasia undergoing paired limb lengthening using either an external fixator with modified distraction control or a circular multiaxial system developed by the authors.
METHODS: This was an observational, prospective, nonrandomized, and longitudinal study with historical control. The study group consisted of 14 patients ranging from 5 to 15 (mean 7.6, SD 2.3) years old with a genetically confirmed diagnosis of achondroplasia. All patients underwent paired limb lengthening with a rod external fixator and a modified distraction control developed by the authors. A total of 28 limb segments, among them 4 (14%) humeri, 8 (29%) femurs, and 16 (57%) tibias, were lengthened in 1 round. Unpublished data from the previous study served as the control group, comprising 9 patients (18 limb segments) of the same age group (mean age at surgery 8.6, SD 2.3 years), who underwent limb lengthening surgery using a circular multiaxial system-2 (11%) humeri, 6 (33%) femurs, and 10 (56%) tibias. The Wong-Baker Faces Rating Scale was used to measure pain symptoms, while the Russified Pediatric Quality of Life (PedsQL) v4.0 questionnaire assessed quality of life.
RESULTS: During the latent phase (7 to 10 days after surgery), a more pronounced decrease in the indicators of physical activity and emotional state on the PedsQL v4.0 questionnaire was noted in the control group (mean 52.4, SD 4.8 versus mean 52.8, SD 5.5 points according to children\'s responses and their parents\' responses, respectively) compared to the experimental group (mean 59.5, SD 6.8 points and mean 61.33, SD 6.5 points according to the children\'s responses and their parents\' responses, respectively). The differences between the groups were statistically significant (P<.05 for children\'s responses and P<.01 for parents\' responses). Importantly, 6 months after surgery, these quality-of-life indicators, as reported by children in the experimental group, averaged 70.25 (SS 4.8) points. Similarly, their parents reported a mean of 70.54 (SD 4.2) points. In the control group, the corresponding values were 69.64 (SD 5.6) and 69.35 (SD 6.2), respectively. There was no statistically significant difference between the groups.
CONCLUSIONS: The external fixator with modified distraction control developed by the authors provides a higher standard of living compared with the circular multiaxial system during the latency phase.

Vosoritide is a recombinant C-type natriuretic peptide analogue that increases annualised growth velocity in children with achondroplasia aged 5-18 years. We aimed to assess the safety and efficacy of vosoritide in infants and children younger than 5 years.
This double-blind, randomised, placebo-controlled, phase 2 trial was done in 16 hospitals across Australia, Japan, the UK, and the USA. Children younger than 60 months with a clinical diagnosis of achondroplasia confirmed by genetic testing and who had completed a baseline growth study or observation period were enrolled into one of three sequential cohorts based on age at screening: 24-59 months (cohort 1); 6-23 months (cohort 2); and 0-5 months (cohort 3). Each cohort included sentinels who received vosoritide to determine appropriate daily drug dose, with the remainder randomly assigned (1:1) within each age stratum (except in Japan, where participants were randomly assigned within each cohort) to receive daily subcutaneous injections of vosoritide (30·0 μg/kg for infants aged 0-23 months; 15·0 μg/kg for children aged 24-59 months) or placebo for 52 weeks. Participants, caregivers, investigators, and the sponsor were masked to treatment assignment. The first primary outcome was safety and tolerability, assessed in all participants who received at least one study dose. The second primary outcome was change in height Z score at 52 weeks from baseline, analysed in all randomly assigned participants. This trial is registered with EudraCT, 2016-003826-18, and ClinicalTrials.gov, NCT03583697.
Between May 13, 2018, and March 1, 2021, 75 participants were recruited (37 [49%] females). 11 were assigned as sentinels, whereas 32 were randomly assigned to receive vosoritide and 32 placebo. Two participants discontinued treatment and the study: one in the vosoritide group (death) and one in the placebo group (withdrawal). Adverse events occurred in all 75 (100%) participants (annual rate 204·5 adverse events per patient in the vosoritide group and 73·6 per patient in the placebo group), most of which were transient injection-site reactions and injection-site erythema. Serious adverse events occurred in three (7%) participants in the vosoritide group (decreased oxygen saturation, respiratory syncytial virus bronchiolitis and sudden infant death syndrome, and pneumonia) and six (19%) participants in the placebo group (petit mal epilepsy, autism, gastroenteritis, vomiting and parainfluenza virus infection, respiratory distress, and skull fracture and otitis media). The least-squares mean difference for change from baseline in height Z score between the vosoritide and placebo groups was 0·25 (95% CI -0·02 to 0·53).
Children with achondroplasia aged 3-59 months receiving vosoritide for 52 weeks had a mild adverse event profile and gain in the change in height Z score from baseline.
BioMarin Pharmaceutical.

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.

UNASSIGNED: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.
UNASSIGNED: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).
UNASSIGNED: Forty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.
UNASSIGNED: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.
UNASSIGNED: Ascendis Pharma, A/S.

The natural history of skeletal complications in achondroplasia (ACH) is well-described. However, it remains unclear how the rates of non-skeletal complications, surgical procedures, healthcare needs and mortality differ between individuals with ACH and the general population. This study aimed to contextualise the extent of these outcomes by comparing event rates across the lifespan, between those with ACH and matched controls in a United Kingdom (UK) population.
This retrospective, matched cohort study used data from national UK databases: the Clinical Practice Research Database (CPRD) GOLD from primary care, the secondary care Hospital Episode Statistics (HES) databases and the Office of National Statistics mortality records. ACH cases were identified using disorder-specific Read Codes or International Classification of Diseases 10th Revision codes. For each ACH case, up to four age- and sex-matched controls (defined as those without evidence of skeletal/growth disorders) were included. Event rates per 100 person-years were calculated for a pre-defined set of complications (informed by reviews of existing ACH literature and discussion with clinical authors), healthcare visits and mortality. Rate ratios (RRs) with 95% confidence intervals (CIs) were used to compare case and control cohorts.
541 ACH cases and 2052 controls were identified for the CPRD cohort; of these, 275 cases and 1064 matched controls had linkage to HES data. Approximately twice as many non-skeletal complications were reported among individuals with ACH versus controls (RR [95% CI] 1.80 [1.59-2.03]). Among ACH cases, a U-shaped distribution of complications was observed across age groups, whereby the highest complication rates occurred at < 11 and > 60 years of age. Individuals with ACH had greater needs for medication, GP referrals to specialist care, medical imaging, surgical procedures and healthcare visits versus controls, as well as a mortality rate of almost twice as high.
Patients with ACH experience high rates of a range of both skeletal and non-skeletal complications across their lifespan. To manage these complications, individuals with ACH have significantly increased healthcare needs compared to the general population. These results underscore the need for more coordinated and multidisciplinary management of people with ACH to improve health outcomes across the lifespan.

Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.