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Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies., (© 2024. The Author(s).)

Competing Interests: We declare no competing interests.

Individuals with differing forms of skeletal dysplasias (SD) frequently report impaired mobility and symptoms. With the objetive to evaluate mobility and associated symptoms in people with SD at an Argentinian pediatric hospital, using an Argentinian version of the Screening Tool for Everyday Mobility and Symptoms (STEMS), a simple questionnaire that allows clinicians to quickly identify the presence of symptoms associated with mobility in people with SD, while considering different environmental settings and the use of assistive devices, an analytical study of a consecutive sample of patients older than 5 years with SD and their affected relatives was carried out.Diagnosis, comorbidities, socioenvironmental, therapeutic, auxological and mobility variables were recorded. The presence and intensity of symptoms was noted through use of both the STEMS and validated scales. Descriptive, association and correlation analyzes were performed. One hundred and nineteen individuals with SD were enrolled in the study and divided into groups: Osteogenesis Imperfecta (OI, n = 55), Achondroplasia (ACH, n = 36) and Other SD resulting in disproportionate short stature (n = 28). Mobility assistive devices were almost exclusively used by individuals with OI. They were more frequently used by individuals with overweight and obesity, more severe form of the disease and in the outdoor settings. Two thirds (66.4%) of the individuals assessed in this study reported pain, 87.4% reported fatigue, and 58.8% reported both pain and fatigue. The intensity of symptoms was similar between groups and correlated with age and auxological variables. The STEMS was clear, easy and quick to use for identifying presence of pain and fatigue in this population group. The STEMS proved to be a simple and useful tool for evaluating functional mobility and associated symptoms in our population of individuals with SD., (© 2024 Wiley Periodicals LLC.)

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility., Competing Interests: Declaration of competing interest Roberta Onesimo has received funding as principal investigator for a Sanofi clinical trial and from Biomarin as speaker in sponsored symposia. Giuseppe Zampino has received funding as principal investigator for Pfizer clinical trials., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: This study aimed to assess the real-world management of achondroplasia in Italy., Methods: Two online surveys addressed to (1) parents/caregivers of individuals with achondroplasia and (2) Italian clinicians managing individuals with achondroplasia were conducted to assess real-world perspectives on achondroplasia management. Both surveys collected data on either patient or clinician demographics, details on diagnoses and referrals, disease complications, and views/experiences with limb lengthening surgery., Results: In total, 42 parents/caregivers and 19 clinicians (from 18 hospitals) completed the surveys. According to parents/caregivers, achondroplasia diagnosis was most commonly made in the third trimester of gestation (55% of respondents), with a genetic test performed to confirm the diagnosis in all but one case. In contrast, the clinicians indicated that, while achondroplasia was typically suspected during the prenatal period (78%), diagnosis was more frequently confirmed postnatally (72%). Parents/caregivers reported that the greatest impact of achondroplasia-related complications occurred in their children between the ages of 2-5 years. The most significant complications were otitis, sleep apnoea, stenosis of the foramen magnum or pressure on the spinal cord, and hearing difficulties. Lengthening surgery had been presented as a treatment option to 92% of responding parents/caregivers, with 76% of clinicians viewing surgery favourably. Typically, clinicians' reasons for suggesting limb lengthening surgery were to improve patient quality of life, increase patient autonomy and self-acceptance, improve trunk-limb disproportion, short stature and walking, and ensure that all possible treatment options had been presented to the parents/caregivers., Conclusion: This survey provides insight into the real-world management of individuals with achondroplasia in Italy., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia., Competing Interests: Declaration of competing interest Roberta Onesimo has received funding as principal investigator for a Sanofi clinical trial and from Biomarin as speaker in sponsored symposia. Mohamad Maghnie has received research support from Merck Serono and Pfizer, and has consulted for BioMarin, Merck Serono, Novo Nordisk, Pfizer, and Sandoz. Giuseppe Zampino has received funding as principal investigator for Pfizer clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes., Methods: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes., Results: A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments., Conclusions: Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches., (© 2023. The Author(s).)

Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.

Background: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults., Methods: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes., Results: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes., Conclusions: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368., (© 2023. The Author(s).)

Objective: To investigate the prevalence of diagnosed Eustachian tube dysfunction and related otologic diagnoses among children with achondroplasia as compared to a control population., Methods: The TriNetX Analytics Network, a federated health research network that aggregates the de-identified electronic health record data of over 78 million patients across the United States, was queried for patients 18 years old or younger with achondroplasia. Patients in this group with any occurrence of diagnosed Eustachian tube dysfunction or specified otologic diagnoses were recorded and reported., Results: Out of 2,195 patients 18 years old or younger with diagnosed achondroplasia, 379 (17.27%, 95% CI: 15.71-18.91) had a diagnosis of Eustachian tube dysfunction with an 8.65 (95% CI: 7.89-9.48) times higher risk than children without achondroplasia (n = 12,818,655). Children with achondroplasia also had higher risks for diagnosed otitis media (RR: 2.21), tympanic membrane retraction (RR: 7.29), middle ear cholesteatoma (RR: 6.35), cleft palate (RR: 12.24), conductive hearing loss (RR: 12.15), and tympanostomy tube placement (RR: 9.71). Each increased risk was maintained when cleft palate patients were removed from the achondroplasia group., Conclusion: Children with achondroplasia are at a significantly higher risk for diagnosed Eustachian tube dysfunction and related middle ear diagnoses. Atypical craniofacial anatomy among children with achondroplasia may play a role in the dysfunction of the Eustachian tube and thus the observed epidemiology of otologic conditions. Children with achondroplasia should be monitored closely for middle ear conditions and the constellation of symptoms related to a dysfunctional Eustachian tube., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control., Methods: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing., Results: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward., Conclusion: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition., Competing Interests: Conflict of Interest All authors were investigators in this clinical trial except for C.A., K.L., K.G., G.J., C.M., E.F., A.H.-L., and J.D., who are employees of the funder (BioMarin). R.S. L.T., F.R., K.M., have received consulting fees and grants from BioMarin. M.I. and W.R.W. have received consulting fees from BioMarin. D.B. has received grants from BioMarin. J.C. has received honoraria from Genzyme, Applied Therapeutics, and CHIESI Farmaceutici S.p.A. P.A. has received honoraria from BioMarin. P.H. and C.B. have received consulting fees, honoraria and grants from BioMarin. J.H.F. has received consulting fees from BioMarin,Therachon AG and Ascendis, and grants from BioMarin. M.B. has received consulting fees and grants from BioMarin, Ascendis, Therachon, QED, Tyra Biosciences, and Alexion Pharmaceuticals, Inc, and grants from BioMarin, Ascendis, Therachon, QED, Medlife, SOBI, and Shire. K.K.W. has received consulting fees from BioMarin, grants from BioMarin, Ultragenyx, Pfizer, and Theracon, and royalties from UptoDate.com. L.P. has received consulting fees from BioMarin, Sanofi/Genzyme, and Therachon, and grants from Sanofi/Genzyme, Takeda/Shire, Pfizer, and SOBI. The other authors declare no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Associated congenital anomalies may be observed in cases with achondroplasia. The prevalence reported in the literature and the types of co-occurring congenital anomalies are variable between the reported studies. The aim of this study was to establish the prevalence and to describe the associated anomalies in cases with achondroplasia. This study included 25 cases ascertained from our registry of congenital anomalies including all terminations of pregnancy, stillbirths and live births between 1979 and 2007 in 387,067 consecutive births (the prevalence of achondroplasia was 6.4 per 100,000 births), and 223 cases ascertained from the French Little People organization built on the model of LPA (Little People of America, Inc.). Out of these 248 cases of achondroplasia 37 (14.9%) had associated anomalies including 4 (1.6%) cases with chromosomal abnormalities (2 trisomies 21, one 22 q11.2 deletion, and one 47, XXX), 2 (0.8%) cases with recognizable non-chromosomal conditions (one Moebius syndrome and one Pierre Robin sequence) and 31(12.5%) cases with MCA (multiple congenital anomalies). The 31 cases with MCA had 45 anomalies. Anomalies in the urogenital system (24.4%), the cardiovascular system (20.0%), the musculoskeletal system (15.5%), the central nervous system (11.1%), the eye (11.1%), and the orofacial system (8.8%) were the most common MCA. The overall prevalence of associated anomalies shows that the individuals with achondroplasia need a careful screening for other congenital anomalies., Competing Interests: Declaration of competing interest All authors declared that there are no conflicts of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: To estimate the cost of US hospital admissions and outpatient surgeries associated with achondroplasia. Materials & methods: Using 2017 data from nationally representative databases, this study identifies hospital admissions and outpatient encounters with an achondroplasia diagnosis. Descriptive measures are reported. Results: There were 1985 achondroplasia admissions nationwide. The most frequent admissions were neonatal care (33.7%) in children and musculoskeletal (22.7%) in adults. Average hospital length of stay was 6.8 days, 2.2 days longer than the US mean. Total mean inpatient costs were US$19,959, $7789 greater than the US mean. In the outpatient setting, children 5-14 years accounted for 56.9% of procedures. Conclusion: Achondroplasia is a serious condition with a wide range of lifelong complications frequently requiring hospitalization and surgical intervention.

Background: Achondroplasia (ACH) is a rare, genetic condition and is the most common skeletal dysplasia resulting in disproportionate short stature and numerous multi-systemic comorbidities. As we enter an era of new treatment options which may impact comorbidities, it is important to understand the background rates of these events to aid evaluation of potential treatment effects. Thus, the aim of this literature review was to provide a comprehensive quantification of prevalence estimates of comorbidities in achondroplasia by age for use as a compiled reference to assist in quantifying the risk/benefit of new treatment options and informing timely management of ACH., Methods: PubMed and Embase databases were searched, complemented by manual bibliography searching, for peer-reviewed articles published between 1975 and 2021, guided by PRISMA principles. Number of patients and the prevalence of specific comorbidities by age were extracted. We calculated exact 95 %-confidence limits for the proportion of affected patients (prevalence) and data were presented visually using forest plots. An a priori decision was made not to utilise meta-analytic techniques to pool estimates as we intended to understand the variability in comorbidities by displaying each estimate separately., Results: The literature search identified 206 articles of which 73 were eligible for inclusion. The majority of studies (n = 34) had been conducted in the USA or in Europe (n = 20). Study designs were mostly retrospective chart reviews (n = 33) or small cohort studies (n = 19). The availability of literature on particular conditions varied but trended towards a focus on assessment and prevention of severe conditions, such as respiratory conditions in children (21 studies), neurological manifestations (16 studies) and upper spine compression (15 studies). There was substantial heterogeneity in study design, type of clinical setting, populations and use of definitions in reporting comorbidities which need to be considered when interpreting study results. Despite the variability of the studies, comorbidity patterns by age were recognizable. In infants, a high prevalence (>20 %) was found for kyphosis, a range of neurological manifestations and sleep apnea. There was also an excess mortality in infancy (4-7.8/100 person-years). Conditions identified in infancy continued to prevail in childhood. Genu varum was highly prevalent from the age children started to walk (9-75 %). Other conditions started to emerge in children; those with a high prevalence (>20 %) were hearing loss and pain. In adolescence, neurological manifestations in the arm, neck or leg were reported (~15 %), consistent with symptomatic spinal stenosis or spinal compression. Fewer studies were available in older populations, especially in adults; however limited data suggest that pain and cardiovascular conditions, particularly excess weight and obesity, became more prevalent into adulthood. Mortality rates increased again in older age-groups., Conclusion: This review provides a reference base of current knowledge of the type and frequency of comorbidities in ACH. This not only allows future contextualisation of new treatment options but supports clinical decision-making on the timely medical management and intervention of ACH. This review also reflects the current medical priorities in the management of ACH, indicating a focus on pediatric care and the complex needs of individuals with ACH involving many different disciplines. Further studies into the natural history of this rare disease using more consistent definitions of comorbidities, especially into adulthood, are needed to elucidate the multi-systemic nature of this condition., (Copyright © 2022 BioMarin Pharmaceutical, INC. Published by Elsevier Inc. All rights reserved.)

Aim: To determine the rates of medical investigations, complications, interventions, and outcomes in children with achondroplasia., Method: Children and adolescents with achondroplasia born between 2000 and 2019, aged between 0 and 18 years of age, and seen at The Children's Hospital at Westmead skeletal dysplasia clinic were included. Data were collected retrospectively from clinical records. Standard descriptive statistics were used for analysis., Results: The study included 108 participants, 58 males and 50 females. Ninety-nine participants (91.7%) entered the study at birth. The other nine (8.3%) participants entered the study after birth (mean age = 2 years 4 months, SD = 1 year 8 months). The median age of exit from the study was 8 years 8 months (IQR = 8 years 9 months) with a median follow-up of 8 years 8 months (IQR = 8 years 9 months). Fifty-two (48%) participants presented with craniocervical stenosis, 15 (13.9%) with hydrocephalus, 66 (61.1%) with hearing impairment, 44 (40.7%) with sleep-disordered breathing, 46 (42.6%) with lower-limb malalignment, 24 (22.2%) with thoracolumbar kyphosis, 10 (9.3%) with symptomatic spinal stenosis, 12 (11.1%) with obesity, and 16 (14.8%) who had at least one admission for respiratory illness. Two children died during the study period., Interpretation: We report contemporary rates of medical complications in an Australian population of children with achondroplasia. Recommendations for surveillance in clinical practice are discussed. This information will help guide clinicians with their expectant management of achondroplasia and provide prognostic information to the families of children with achondroplasia., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry., Results: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient., Conclusion: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy., (© 2022. The Author(s).)

The study aimed to explore how having achondroplasia affects older children and adolescents' day-to-day functioning and well-being. Individual/focus group interviews were conducted with older children/adolescents between the ages of 9 to <18 years and diagnosed with achondroplasia to elicit key concepts. An adapted grounded theory approach informed the qualitative analysis of interview data. Thirty-two children and adolescents completed interviews. Study results revealed five impact domains, including physical health, functioning, school impacts, emotional well-being, and social well-being. Frequently reported impacts on physical health included low stamina/tiring easily (81%) and back pain (69%). Key impacts in the functioning domain were difficulty with reaching objects or high places (84%) and walking long distances (75%). Emotional impacts included feeling different (63%), worried/scared (47%), and embarrassed/self-conscious (47%). Impacts on social well-being included difficulty with sports or physical play (81%) and others treating child as younger than their actual age (75%). The most frequent school impact was trouble participating in physical education (81%). A preliminary theoretical model depicting the experiences of older children/adolescents with achondroplasia was constructed based on the analysis. The preliminary theoretical model of older children and adolescents' experiences of living with achondroplasia may be used to inform future research and clinical practice., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Purpose: Achondroplasia is the most common short stature skeletal dysplasia (1:20,000-30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia., Methods: Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included., Results: Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values, 1,631 PSGs and 10,727 imaging studies., Conclusion: This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared., (© 2021. The Author(s).)

Aim: To assess the clinical picture underlying apparent life-threatening events (ALTEs) occurring in infants with achondroplasia and provide guidance for evaluation after an event., Methods: A population of 477 individuals with achondroplasia was retrospectively reviewed, and information regarding possible ALTEs was recorded in a REDCap database., Results: ALTEs occurred in the first year of life in 18 of 477 individuals (3.8%). Most (14/18, 78%) occurred in the first 6 months of life and presented as episodes of apnoea and/or seizures. Of affected infants, 8/18 (44%) had more than one episode. Many of the initial ALTEs arose while infants were in car seats (11/18, 61%). Assessment following ALTEs most often demonstrated either craniocervical junction concerns and/or seizures, with 12/18 (67%) patients undergoing cervicomedullary decompression and 5/18 (28%) starting on anti-epileptic medications after the event., Conclusion: Although this study is limited in size and was retrospective, it shows that infants with achondroplasia appear to be at high risk for ALTEs. Evaluation after an event should include neuroimaging of the foramen magnum, inpatient hospital observation including respiratory monitoring and electroencephalography, and a car seat challenge., (©2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

The aim of this study was to estimate the childhood prevalence of achondroplasia, trends over time in birth prevalence, and age at diagnosis in Australia. Children born between 1990 and 2019 with a clinical and radiological and/or molecular diagnosis of achondroplasia were identified from a tertiary hospital servicing New South Wales (NSW) and the Australian Capital Territory (ACT) and compared with population data from the Australian Bureau of Statistics. Childhood prevalence of achondroplasia, based on children ≤19 years of age and resident in NSW/ACT on June 30, 2019 (n = 109), was 5.2 per 100,000. A total of 127 individuals with achondroplasia were born in 1990-2019 in NSW/ACT. Birth prevalence rates increased across birth decades, from 3.3 per 100,000 live births in 1990-1999 to 5.3 per 100,000 in 2010-2019 (p < 0.0001). Median age at diagnosis decreased to 17 days in 2010-2019 compared with 30 days in 1990-1999 (p = 0.035), although the overall decreasing trend across consecutive decades did not reach statistical significance. This is the first study to show a rising birth prevalence rate for achondroplasia in Australia with a concurrent decreasing age at diagnosis, both of which were statistically significant after 2 decades., (© 2021 Wiley Periodicals LLC.)

Background: Previous studies have found a high prevalence of obstructive sleep apnea (OSA) in children with achondroplasia, but clinical studies on this complication in adults with achondroplasia are lacking., Objectives: This population-based, cross-sectional study investigated the prevalence, severity, and predictive factors of OSA in Norwegian adults with achondroplasia., Methods: We collected clinical data on 49 participants. Participants without a preexisting diagnosis of OSA had an overnight sleep registration. OSA was defined as an apnea-hypopnea index (AHI) ≥ 5 plus characteristic clinical symptoms, or AHI ≥ 15. We used the Berlin Questionnaire to assess clinical symptoms of OSA., Results: OSA was found in 59% (29/49) of the participants (95% confidence interval 44 to 73%), of whom 59% (17/29) had moderate to severe OSA (AHI ≥ 15), and 48% (14/29) were previously undiagnosed. Variables predictive of OSA were: excessive daytime sleepiness; unrested sleep; loud snoring; observed nocturnal breathing stops; hypertension; age > 40 years; and BMI > 30 kg/m 2 ., Conclusion: OSA was highly prevalent in Norwegian adults with achondroplasia, which we believe is representative of this population worldwide. Follow-up of adults with achondroplasia should include assessment of symptoms and signs of OSA, with a low threshold for conducting an overnight sleep registration if findings suggestive of OSA are present.

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus., (© 2021 Wiley Periodicals LLC.)

This cross-sectional Physical Fitness Study compared cardiorespiratory fitness (VO 2 peak), six-minute walk test (6MWT), muscle strength (30sSTS), balance (BESS), and self-reported physical activity level (IPAQ) in Norwegian adults with achondroplasia (ACH) to reference values of average-statured individuals. The feasibility of the physical fitness tests and IPAQ was explored. Forty-three adults (22 women) participated. Mean age was 38 years (range 16-69 years). Mean differences (95% CI) for men and women with ACH compared to reference values were: VO 2 peak. -7.0 m/min/kg (-13.6 to -0.5, p = .037), and - 7.9 ml/kg/min (-11.6 to -4.3, p < .001); 6MWT -270.8 m (-340.4 to -201.2, p < .001), and - 196.7 m (-244.3 to -149.0, p = .001); 30sSTS -4.6 repetitions (-7.8 to -1.5, p = .006), and - 1.1 repetitions (-3.4 to 1.1, p = .335). There were no differences within ACH participants, except for VO 2 peak, where men performed better. Sufficient physical activity (> 600 metabolic equivalent of task weekly) was achieved by 79% of the participants. The feasibility of the 6MWT and 30sSTS was good. There was a strong correlation between the VO 2 peak and 6MWT (men: r = 0.63, p = .007; women: r = 0.71, p < .001). The findings indicate that the 6MWT and 30sSTS test are useful in assessing functional exercise capacity and muscle strength in adults with ACH., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Purpose: An increased cardiovascular mortality has been reported in achondroplasia. This population-based, case-control study investigated cardiovascular risk factors and body composition in Norwegian adults with achondroplasia., Methods: We conducted anthropometric, clinical, and laboratory assessments in 49 participants with achondroplasia, of whom 40 completed magnetic resonance imaging (MRI) for body composition analysis. Controls consisted of 98 UK Biobank participants, matched for body mass index (BMI), sex, and age., Results: Participants were well matched for BMI (33.3 versus 32.5 kg/m 2 ) and sex, but achondroplasia participants were younger than controls (mean age 41.1 versus 54.3 years). Individuals with achondroplasia had lower age-adjusted mean blood pressure, total and low-density lipoprotein (LDL) cholesterol, and triglycerides compared with controls, but similar fasting glucose and HbA1c values. Age-adjusted mean visceral fat store was 1.9 versus 5.3 L (difference -2.7, 95% confidence interval [CI] -3.6 to -1.9; P < 0.001), abdominal subcutaneous fat was 6.0 versus 11.2 L (-4.7, 95% CI -5.9 to -3.4; P < 0.001), and liver fat was 2.2 versus 6.9% (-2.8, 95% CI -5.2 to -0.4; P = 0.02)., Conclusion: Despite a high BMI, the cardiovascular risks appeared similar or lower in achondroplasia compared with controls, indicating that other factors might contribute to the increased mortality observed in this condition.

Studies examining quality of life (QoL) in adults with achondroplasia are limited. We report on QoL and psychiatric illness diagnoses in a modern cohort of adults with achondroplasia. SF-36 Health Survey scores from adults with achondroplasia were compared to general population scores. Demographics, physical measurements, and psychiatric illness diagnoses were recorded from medical records. The achondroplasia population had lower scores than the general population in all categories. Most people with achondroplasia (56%) had a diagnosed psychiatric illness. Those with a diagnosed psychiatric illness had lower scores in physical functioning, role limitations due to physical and emotional health, and mental health. Pain, energy/fatigue, and general health scale scores were roughly equivalent (<2 points difference). Social functioning was >15 points higher in individuals with psychiatric illness diagnoses. Adults with achondroplasia report significantly lower physical and mental well-being and had nearly 3× the rate of psychiatric illness diagnosis than the general population, highlighting the importance of total care for this population. Healthcare providers must understand the physical and mental comorbidities of achondroplasia, beyond short stature and orthopedic issues, so they can proactively improve QoL across the lifespan for patients and families., (© 2020 Wiley Periodicals LLC.)

More information is available concerning risks of craniocervical junction issues in infancy than at later ages. Therefore, we elected to quantify the risks at greater than 1 year of age through a retrospective analysis of 477 individuals with achondroplasia using a REDCap database. Evaluation of these 477 individuals revealed 77 (16.1%) who had pathologic neurologic manifestations after 1 year of age related to the craniocervical junction. Within this subpopulation of 77 individuals, 43 (55.8%) underwent craniocervical decompression surgery, or 9.0% of the total population. Whether decompressed or not, most individuals with craniocervical junction issues after infancy had a normal outcome, without long-term neurological sequelae (57/77, 74.0%). The remaining 20 had various long-term neurological issues. This is the first cohort based estimate of risks related to the upper cervical spine in individuals with achondroplasia specifically beyond infancy., (© 2020 Wiley Periodicals LLC.)

This study's purpose was to provide qualitative evidence to support the development of two observer-reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty-six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM-Symptom and ACEM-Impact. ACEM-Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM-Impact consisted of 31 major impacts in the domains of daily functioning, emotional well-being, social well-being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation-ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Third-trimester scans are increasingly used to try to prevent adverse outcomes associated with abnormalities of fetal growth. Unexpected fetal malformations detected at third-trimester growth scans are rarely reported., Objective: To determine the incidence and type of fetal malformations detected in women attending a routine third-trimester growth scan., Study Design: This was a population-based study of all women with singleton pregnancy attending antenatal care over a 2-year period in Oxfordshire, UK. Women who had a viable singleton pregnancy at dating scan were included. Women had standard obstetrical care including the offer of a routine dating scan and combined screening for trisomies; a routine anomaly scan at 18 to 22 weeks; and a routine third-trimester growth scan at 36 weeks. The third-trimester scan comprises assessment of fetal presentation, amniotic fluid, biometry, umbilical and middle cerebral artery Dopplers, but no formal anatomic assessment is undertaken. Scans are performed by certified sonographers or clinical fellows (n=54), and any suspected abnormalities are evaluated by a team of fetal medicine specialists. We assessed the frequency and type of incidental congenital malformations identified for the first time at this third-trimester scan. All babies were followed-up after birth for a minimum of 6 months., Results: There were 15,244 women attending routine antenatal care. Anomalies were detected in 474 (3.1%) fetuses as follows: 103 (21.7%) were detected before the anomaly scan, 174 (36.7%) at the anomaly scan, 11 (2.3%) after the anomaly scan and before the third-trimester scan, 43 (9.1%) at the third-trimester scan and 143 (30.2%) after birth. The 43 abnormalities were found in a total of 13,023 women who had a 36 weeks scan, suggesting that in 1 out of 303 (95% confidence interval, 233-432) women attending such a scan, a new malformation was detected. Anomalies detected at the routine third-trimester scan were of the urinary tract (n=30), central nervous system (5), simple ovarian cysts (4), chromosomal (1), splenic cyst (1), skeletal dysplasia (1), and cutaneous lymphangioma (1). Most urinary tract anomalies were renal pelvic dilatation, which showed spontaneous resolution in 57% of the cases., Conclusion: When undertaking a program of routine third-trimester growth scans in women who have had previous screening scans, an unexpected congenital malformation is detected in approximately 1 in 300 women., (Copyright © 2020. Published by Elsevier Inc.)

Achondroplasia is a genetic disorder that results in disproportionate short stature. The true prevalence of achondroplasia is unknown as estimates vary widely. This systematic literature review and meta-analysis was conducted to better estimate worldwide achondroplasia birth prevalence. PubMed, Embase, Scielo, and Google Scholar were searched, complemented by manual searching, for peer-reviewed articles published between 1950 and 2019. Eligible articles were identified by two independent researchers using predefined selection criteria. Birth prevalence estimates were extracted for analysis, and the quality of evidence was assessed. A meta-analysis using a quality effects approach based on the inverse variance fixed effect model was conducted. The search identified 955 unique articles, of which 52 were eligible and included. Based on the meta-analysis, the worldwide birth prevalence of achondroplasia was estimated to be 4.6 per 100,000. Substantial regional variation was observed with a considerably higher birth prevalence reported in North Africa and the Middle East compared to other regions, particularly Europe and the Americas. Higher birth prevalence was also reported in specialized care settings. Significant heterogeneity (Higgins I 2 of 84.3) was present and some indication of publication bias was detected, based on visual asymmetry of the Doi plot with a Furuya-Kanamori index of 2.73. Analysis of pooled data from the current literature yields a worldwide achondroplasia birth prevalence of approximately 4.6 per 100,000, with considerable regional variation. Careful interpretation of these findings is advised as included studies are of broadly varying methodological quality., (© 2020 BioMarin. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Symptomatic spinal stenosis (SSS) is a well-known medical complication in achondroplasia. The reported prevalence of SSS is 10 to 30%, an estimate based on small studies or selected populations. No population-based studies exist currently. Furthermore, the relationship between SSS and physical functioning has not been investigated in detail. The aims of this study were to describe the prevalence of SSS in Norwegian adults with achondroplasia, and to explore the impact of SSS on physical functioning., Methods: This was a population-based study on Norwegian community-dwelling adults with genetically confirmed achondroplasia. Prevalence of SSS was defined by clinical symptoms, and confirmed by imaging or surgical reports. Physical functioning was assessed by walking capacity (6-min walk test), hand strength (Grippit), and activities of daily living (the Health Assessment Questionnaire, HAQ). Pain was assessed by pain site locations and intensity (Numeric Rating Scale, NRS)., Results: In total, 50 participants were included (27 males, 23 females). Median age was 41 years (range 16 to 87 years), 34 (68%) had SSS. The estimated median age at first symptom onset was 33 years (95% confidence interval (CI) 29 to 43 years), range 10 to 67 years. The majority had multiple spinal levels affected. The walking distance was 110 m shorter in the SSS group (95% CI - 172 to - 40 m) as compared with the non-SSS group (p < 0.01). There was no considerable difference in hand strength between the two groups. Mean HAQ scores (0-3) for walking and hygiene were significantly higher in the SSS group, reflecting more activity limitations. Mean differences were 0.9 (95% CI 0.3 to 1.4, p < 0.01) and 0.6 (95% CI 0.2 to 1.0, p < 0.01). Pain intensity (NRS 0-10) was also significantly higher in the SSS group with a mean difference of 3.2 (95% CI 0.6 to 5.6, p = 0.02)., Conclusions: SSS was highly prevalent in Norwegian adults with achondroplasia, with symptom onset at young age, and multiple spinal levels affected. The presence of SSS was associated with reduced walking distance, activity limitations, and more pain. The findings underline the importance of thorough assessment and monitoring of SSS in achondroplasia, including a formal assessment of physical functioning.

There are virtually no data regarding appropriate oral intake in infants with dwarfing disorders such as achondroplasia, nor is there clear information regarding appropriate weight gain velocity in this population. Yet, these individuals are at increased risk for both early failure to thrive and, later in life, for obesity. Having appropriate expectations regarding weight gain and reasonable goals in management is imperative. We sought to clarify the rate of weight gain in infants with achondroplasia during the first year of life through analysis of data from 60 infants with achondroplasia seen at least twice during the first year of life in the Midwest Regional Bone Dysplasia Clinic, University of Wisconsin-Madison between 1998 and 2018. The mean weight gain velocity during the first 3 months was 23 g/day which contrasts with 30 g/day in average statured infants. Mean weight gain from 0 to 12 months of age was 13 g/day. The 3% of weight gain velocity during the first year of life was 8 g/day, and this rate did not differ between 0-3 months and 0-12 months of age. Infants with achondroplasia slightly more than doubled their birth weights by 1 year of age in contrast to averaged statured infants who typically triple birth weights by 1 year. Infants with achondroplasia can be thriving but erroneously assessed as failing to thrive if the incorrect reference values are used. This article describes infant weight gain velocity reference data for this population., (© 2019 Wiley Periodicals, Inc.)

Currently accepted birth prevalence for osteochondrodysplasias (OCDs) is about 2 per 10,000 births. Our main goal is to estimate the prevalence of OCDs in Argentina and compare it with other surveillance systems. We examined 1,663,610 births among 160 hospitals of RENAC (Red Nacional de Anomalías Congénitas - National Network of Congenital Anomalies) between November 2009 and December 2016. Cases were detected and registered according to a pre-established protocol, ranked in three diagnostic evidence levels according to available clinical documentation, and categorized according to the 9th edition of the nosology and classification of genetic skeletal disorders. Within our dataset, the most frequent groups were Group-1 (FGFR3, chondrodysplasia) and Group-25 (Osteogenesis Imperfecta and decreased bone density). Birth prevalence per 10,000 for the main OCD types, were: Achondroplasia 0.47 (95% CI: 0.38-0.59), Thanatophoric Dysplasia 0.37 (95% CI: 0.29-0.48), and the Osteogenesis Imperfecta group 0.34 (95% CI: 0.26-0.44). For total OCD, birth prevalence was 2.20 per 10.000 births (95% CI: 1.98-2.44). RENAC prevalence of total OCDs was found to be lower than that reported by the Latin-American Study of Congenital Malformations (ECLAMC) and Utah Birth Defect Network but higher than EUROCAT. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Achondroplasia is a rare genetic disorder resulting in short-limb skeletal dysplasia. We present the largest European population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991-2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14-4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011-2015 vs. 36% in 1991-1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia., (© 2019 Wiley Periodicals, Inc.)

TransCon CNP is a C-type natriuretic peptide (CNP-38) conjugated via a cleavable linker to a polyethylene glycol carrier molecule, designed to provide sustained systemic CNP levels upon weekly subcutaneous administration. TransCon CNP is in clinical development for the treatment of comorbidities associated with achondroplasia. In both mice and cynomolgus monkeys, sustained exposure to CNP via TransCon CNP was more efficacious in stimulating bone growth than intermittent CNP exposure. TransCon CNP was well tolerated with no adverse cardiovascular effects observed at exposure levels exceeding the expected clinical therapeutic exposure. At equivalent dose levels, reductions in blood pressure and/or an increase in heart rate were seen following single subcutaneous injections of the unconjugated CNP-38 molecule or a daily CNP-39 molecule (same amino acid sequence as Vosoritide, USAN:INN). The half-life of the daily CNP-39 molecule in cynomolgus monkey was estimated to be 20 minutes, compared with 90 hours for CNP-38, released from TransCon CNP. C max for the CNP-39 molecule (20 µ g/kg) was approximately 100-fold higher, compared with the peak CNP level associated with administration of 100 µ g/kg CNP as TransCon CNP. Furthermore, CNP exposure for the daily CNP-39 molecule was only evident for up to 2 hours postdose (lower limit of quantification 37 pmol/l), whereas TransCon CNP gave rise to systemic exposure to CNP-38 for at least 7 days postdose. The prolonged CNP exposure and associated hemodynamically safe peak serum concentrations associated with TransCon CNP administration are suggested to improve efficacy, compared with short-lived CNP molecules, due to better therapeutic drug coverage and decreased risk of hypotension. SIGNIFICANCE STATEMENT: The hormone C-type natriuretic peptide (CNP) is in clinical development for the treatment of comorbidities associated with achondroplasia, the most common form of human dwarfism. The TransCon Technology was used to design TransCon CNP, a prodrug that slowly releases active CNP in the body over several days. Preclinical data show great promise for TransCon CNP to be an effective and well-tolerated drug that provides sustained levels of CNP in a convenient once-weekly dose, while avoiding high systemic CNP bolus concentrations that can induce cardiovascular side effects., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Short-stature (SS) is multifactorial pathologic condition that originates from either genetic or environmental factors. The diagnosis is based on family history, clinical findings, radiological examination and genetic analysis. A variety of genes have been reported for SS, among which FGFR-3 was the main gene in achondroplasia and hypochondroplasia. In other forms of SS, the gene involved varies from one patient to another. Whole exome sequencing (WES) and comparative genomic hybridization (CGH) have recently introduced a growing body of genes annually. The present study performed a WES analysis on an Iranian family suffering from an inherited form of SS aiming to diagnose the causative gene. The father and all of his four sons were diagnosed as SS., Methods: The blood samples were collected from the proband and his available family members. Genomic DNA was extracted using salting-out method. The DNA of the proband was analyzed using WES and confirmed through polymerase chain reaction (PCR)-sequencing. The WES-extracted variant was evaluated in silico using software aiming to determine whether this nucleotide change is pathogenic. The presence of the variant was traced in other affected family members using PCR-sequencing., Results: Following segregation analysis, variant c.896 G>A of the COMP gene was found in all of the affected individuals in a heterozygous form. This variant resulted in substitution of glycine 299 with arginine and was previously predicted as pathogenic in the Human Gene Mutation Database dataset, although it represents the first report in Iran., Conclusions: The findings of the present study suggest consideration of the c.896 G>A variant of the COMP gene with respect to the genetic counseling of inherited skeletal dysplasia in Iran., (© 2019 John Wiley & Sons, Ltd.)

There is a lack of knowledge about longitudinal growth during childhood in achondroplasia. We report patterns of linear growth and height growth velocity references. The sample consisted of 84 children, 41 girls and 43 boys. Growth data was collected from birth until mid-childhood. The median (interquartile range) number of measurements per child was 13.5 (12, 15). Individual growth curves were estimated by fitting the Reed 1st model to each individual's height for age data. Height growth velocities references for age centiles were calculated by LMS method. Mean (SD) birth length was 46.14 cm (2.17) and 45.53 cm (2.16), for boys and girls respectively. Individual growth curves were analyzed. Shifts in growth channels were seen: out of 84 infants, 41 (48.8%) changed more than 1 SDS between birth to 5 years old. The numbers of infants shifting upward were similar (20/84) to the infants shifting downward (21/84). Height growth velocity curves show that after a period of fast decreasing growth velocity since birth, with a mean of 15.5 cm/year and 9.5 cm/year at 6 month and 1 year old, the growth velocity is stable in late preschool years, with a mean of 4.3 cm/year. Shifts in growth channels were seen between birth and 5 years old. Professionals who follow up them must consider this phenomenon during infancy. ACH children experienced a period of fast decreasing growth during infancy and the growth curve was similar in shape and lesser in magnitude than the general population., (© 2019 Wiley Periodicals, Inc.)

Achondroplasia is a condition characterized by a genetic mutation affecting long bone endplate development. Current data suggests that the bone mineral content (BMC) and bone mineral density (BMD) of achondroplasic populations are below age matched individuals of average stature (controls). Due to the disproportionate limb-to-torso length compared to controls however, the lower BMC and BMD may be nullified when appropriately presented. The aim of this study was to measure whole-body and segmental body composition in adult males with achondroplasia (N = 10, 22 ±3 yrs), present data relative to whole-body and whole-limb values and compare all values to age matched controls (N = 17, 22 ±2 yrs). Dual X-ray absorptiometry (DEXA) was used to measure the in vivo mass of the whole-body and 15 segments, from which BMD, BMC, fat free mass (FFM) and body fat mass were measured. BMC of lumbar vertebrae (L1-4) was also measured and presented as a volumetric BMD (BMDVOL). The achondroplasic group had less BMC, BMD and FFM, and more body fat mass than controls as a whole-body measure. The lower achondroplasic BMC and BMD was somewhat nullified when presented relative to whole-body and whole-limb values respectively. There was no difference in lumbar BMDVOL between groups. Whole-body BMD measures presented the achondroplasic group as 'osteopenic'. When relative to whole-limb measures however, achondroplasic BMD descriptions were normal. Further work is needed to create a body composition database for achondroplasic population's, or for clinicians to present achondroplasic body composition values relative to the whole-limb., Competing Interests: The authors have declared that no competing interests exist.

OBJECTIVE The goal of this study was to determine the rates of screening and surgery for foramen magnum stenosis in children with achondroplasia in a large, privately insured healthcare network. METHODS Rates of screening and surgery for foramen magnum stenosis in children with achondroplasia were determined using de-identified insurance claims data from a large, privately insured healthcare network of over 58 million beneficiaries across the United States between 2001 and 2014. Cases of achondroplasia and screening and surgery claims were identified using a combination of International Classification of Diseases diagnosis codes and Current Procedural Terminology codes. American Academy of Pediatrics (AAP) practice guidelines were used to determine screening trends. RESULTS The search yielded 3577 children age 19 years or younger with achondroplasia. Of them, 236 met criteria for inclusion in the screening analysis. Among the screening cohort, 41.9% received some form of screening for foramen magnum stenosis, whereas 13.9% of patients were fully and appropriately screened according to the 2005 guidelines from the AAP. The screening rate significantly increased after the issuance of the AAP guidelines. Among all children in the cohort, 25 underwent cervicomedullary decompression for foramen magnum stenosis. The incidence rate of undergoing cervicomedullary decompression was highest in infancy (28 per 1000 patient-years) and decreased with age (5 per 1000 patient-years for all other ages combined). CONCLUSIONS Children with achondroplasia continue to be underscreened for foramen magnum stenosis, although screening rates have improved since the release of the 2005 AAP surveillance guidelines. The incidence of surgery was highest in infants and decreased with age.

Purpose: Co-sleeping is common in children with co-morbid conditions. The aim of the study was to analyze the prevalence and determinants of parent-child co-sleeping in children with co-morbid conditions and sleep-disordered breathing and the impact on parental sleep., Methods: Parents of consecutive children undergoing a sleep study filled in a questionnaire on co-sleeping., Results: The parents of 166 children (80 boys, median age 5.7 years (0.5-21) participated in this study. The most common co-morbid conditions of the children were Down syndrome (17%), achondroplasia (11%), and Chiari malformation (8%). The prevalence of parent-child co-sleeping was 46%. Reasons for co-sleeping were mainly reactive and included child's demand (39%), crying (19%), nightmares (13%), medical reason (34%), parental reassuring or comforting (27%), and/or over-crowding (21%). Sixty-eight percent of parents reported that co-sleeping improved their sleep quality because of reassurance/comforting (67%), reduced nocturnal awakening (23%), and child supervision (44%). Forty percent of parents reported that co-sleeping decreased their sleep quality because of nocturnal awakenings or early wake up, or difficulties initiating sleep (by 77% and 52% of parents, respectively), whereas both positive and negative associations were reported by 29% of the parents. Co-sleeping was more common with children < 2 years of age as compared to older children (p < 0.001)., Conclusions: Parent-child co-sleeping is common in children with co-morbid conditions and sleep-disordered breathing. Co-sleeping was mainly reactive and had both positive and negative associations with parental sleep quality. Co-sleeping should be discussed on an individual basis with the parents in order to improve the sleep quality of the family.

Achondroplasia is the most prevalent form of dwarfism, and there is little evidence about the optimal management of pregnant women with achondroplasia. We presented a 25-year-old primigravid woman with achondroplasia who was followed up during the pregnancy period and performed elective caesarean section with combined spinal-epidural anaesthesia at the 38th week of gestation. Frequent obstetric follow-up visits and invasive prenatal diagnostic tests should be offered during the antenatal period due to the increased risk for obstetric complications, such as premature delivery and fetal anomalies. Prenatal detailed counselling, comprehensive evaluation of the potential risks, obstetric and perioperative management should be performed by a multidisciplinary care team, including an obstetrician, anaesthesiologist, pulmonologist, cardiologist and neonatologist., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Achondroplasia is an autosomal dominant disorder, the most common genetic cause of short stature in humans. Reference curves for head circumference, weight, height, and BMI are needed in clinical practice but none exist for the Australian population. This study aimed to produce head circumference, height, weight, and BMI reference percentile curves for Australian children and adolescents with achondroplasia. Measurements of head circumference, height and weight taken at clinical visits were retrospectively extracted from the electronic medical record. Age was corrected for prematurity. Patients were excluded from head circumference analysis if they had significant neurosurgical complications and from the weight and BMI analysis when they had a clinical diagnosis of overweight. Measurements were available on 138 individuals (69 males and 69 females) taken between 1970 and 2015, with over 50% collected since 2005. A total of 3,352 data points were available. The LMS method was used to produce growth charts with estimated centiles (10, 25, 50, 75, and 90th) separately for males and females. For females birth weight was 3 kg (2.5-3.5 kg), birth length 48 cm (44-50 cm) and head circumference 37.5 cm (36-39 cm), adult height was 125 cm (116-132 cm), weight 42 kg (34-54 kg), and head circumference 58 cm (55.5-60.5 cm) all 50th centile (10-90th). For males birth weight was 3.5 kg (3-4 kg), length 49 cm (46-52 cm) and head circumference 38.5 cm (36-41 cm), adult height was 134 cm (125-141 cm), weight 41 kg (24.5-57 kg) and head circumference 61 cm (58-64 cm). The curves are similar to previously published reference data from the USA and have expected population wide variation from curves from an Argentinian population. Despite limitations of our curves for adolescents (12 years and older) due to data paucity, these Australian growth charts for children and adolescents with achondroplasia will be a useful reference in clinical practice., (© 2017 Wiley Periodicals, Inc.)

The height-for-age (HA) reference currently used for children with achondroplasia is not adaptable for electronic records or calculation of HA Z-scores. We report new HA curves and tables of mean and standard deviation (SD) HA, for calculating Z-scores, from birth-16 years in achondroplasia. Mixed longitudinal data were abstracted from medical records of achondroplasia patients from a single clinical practice (CIS, 1967-2004). Gender-specific height percentiles (5, 25, 50, 75, 95th) were estimated across the age continuum, using a 2 month window per time point smoothed by a quadratic smoothing algorithm. HA curves were constructed for 0-36 months and 2-16 years to optimize resolution for younger children. Mean monthly height (SD) was tabulated. These novel HA curves were compared to reference data currently in use for children with achondroplasia. 293 subjects (162 male/131 female) contributed 1,005 and 932 height measures, with greater data paucity with age. Mean HA tracked with original achondroplasia norms, particularly through mid-childhood (2-9 years), but with no evidence of a pubertal growth spurt. Standard deviation of height at each month interval increased from birth through 16 years. Birth length was lower in achondroplasia than average stature and, as expected, height deficits increased with age. A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z-score calculations. This is an important contribution to clinical care and research endeavors for the achondroplasia population., (© 2017 Wiley Periodicals, Inc.)

Background: Children with achondroplasia often have breathing problems, especially during sleep. The most important treatments are adenotonsillectomy (for treating upper obstruction) and/or neurosurgery (for resolving cervicomedullar junction stenosis)., Data Sources: We reviewed the scientific literature on polysomnographic investigations which assessed the severity of respiratory disorders during sleep., Results: Recent findings have highlighted the importance of clinical investigations in patients with achondroplasia, differentiating between those that look for neurological patterns and those that look for respiratory problems during sleep. In particular, magnetic resonance imaging (MRI) and somatosensory evoked potentials are the main tools to evaluate necessary neurosurgery and over myelopathy, respectively., Conclusions: The use of polysomnography enables clinicians to identify children with upper airway obstruction and to quantify disease severity; it is not suitable for MRI and/or neurosurgery considerations.

Background: Anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) injuries and their subsequent reconstructions are common in the general population, but there has been no research regarding ACL or PCL injuries in patients with achondroplasia, the most common skeletal dysplasia. Our goals were to (1) evaluate the prevalence of ACL and PCL injuries in adolescents and adults with achondroplasia, (2) compare this prevalence with that reported for the general population, (3) determine how many patients with ACL or PCL injuries underwent ligament reconstruction as treatment, and (4) determine patient activity levels as they relate to the rate of ACL/PCL injuries and reconstructions., Methods: We reviewed medical records of 430 patients with achondroplasia seen in the senior author's clinic from 2002 through 2014. Demographic data were reviewed, as well as any documentation of ACL or PCL injury or reconstruction. We called all 430 patients by telephone, and 148 agreed to participate in our survey, whereas 1 declined. We asked these patients about their history of ACL or PCL injury or reconstruction, as well as current and past physical activity levels., Results: No ACL or PCL injuries were found on chart review. One patient reached by telephone reported an ACL injury that did not require reconstruction. This yielded a theoretical prevalence of 3/430 (0.7%). Of the 148 patients surveyed, 43 (29%) reported low physical activity, 75 (51%) reported moderate physical activity, and 26 (17%) reported high physical activity. There was no significant difference in the rate of ACL injury when stratified by physical activity level (P=0.102)., Conclusions: ACL and PCL injuries and reconstructions are extremely rare in patients with achondroplasia, which cannot be completely ascribed to a low level of physical activity. One possible explanation is that patients with achondroplasia, on an average, have a more anterior tibial slope compared with those without achondroplasia, which decreases the force generated within the ACL and may protect against ACL injury. Further research is needed to explore possible causes., Level of Evidence: Level IV-retrospective review.

This study explores the psychological wellbeing of twenty-two (n = 22) adults with achondroplasia. The sample was composed of seven (n = 7) males and fifteen (n = 15) females between the ages of 21 and 75 (mean age = 39.6). Each individual completed four self-administered questionnaires: the Beck Depression Inventory (BDI-l), the Beck Anxiety Inventory (BAI), the Beck Hopelessness Scale (BHS), and Derogatis Symptom Check-list-90-Revisited (SCL-90-R). They also filled out a socio-demographic questionnaire. We found that 31.8% of the sample reported at least one comorbid condition such as, hypertension, diabetes, rheumatoid arthritis, asthma, scoliosis, thyroid problems, neuropathy, psoriasis, gastritis and/or sleep apnea; 32% reported mild to severe depressive symp- toms; 55% reported mild to severe symptoms associated to anxiety and 18% reported mild to severe symptoms associated with hopelessness; 22.7% reported mild to severe symptoms in at least one of the sub-scales in Derogatis Symptom Checklist-90-Revisited (SCL-90-R) particularly the obsessive-compulsive, paranoid and depressive subscales. Chi Square correlations (X2) were made to observe if there was interdependence between the socio-demographic variables and the administered tests. In general, no significant correlations were found between BDI-Il, BAI, BHS, SCL-90-R and civil status, gender, income and age. However, a significant correlation was found between age and the somatization sub-scale of the SCL-90-R (rs = 0.510, p < 0.05). Our findings suggest that this particular sample is at risk for developing psycho-medical conditions. There is a marked lack of research in Puerto Rico associated to achondroplasia. The development of preventive and cultural sensitive interventions is suggested in order to protect and treat individuals with the condition.

Background: Compared to research on short-statured adults, quality of life (QoL) of children has been rarely studied. One reason for this might be the lack of appropriate disease-specific questionnaires., The Aim of the Work: The aim of this study was to analyse the quality of life in a sample of short-statured children with achondroplasia, using generic and disease-specific instruments. In addition, a comparison of patient and population norms is presented., Materials and Methods: The sample included children (8-28 years) with achondroplasia and parents of participating children (8-17 years). Quality of life was analyzed with the KIDSCREEN, the DISABKIDS and the disease-specific Quality of Life in Short Stature Youth (QoLISSY) questionnaire. In addition group differences according to clinical and sociodemographic data were analyzed within the sample and compared to available KIDSCREEN representative population data., Results: The physical QoL was rated poorly in this sample of short-statured patients, while the emotional QoL was rated more favorably. Compared to the KIDSCREEN population norm, parents of children with achondroplasia rate the QoL lower., Discussion: The QoLISSY questionnaire is a reliable tool to assess the subjective wellbeing of patients with skeletal dysplasia. The instrument can now be used clinically as a screening for patient wellbeing, as an outcome criterion in clinical research and as a psychosocial indicator in orthopedic cohort studies.

Short-limbed short stature is a heterogeneous condition that can result from many diseases such as bone disorder, metabolic disease, and multiple malformation syndrome. We conducted a questionnaire survey of council members of the Japanese Society of Pediatric Endocrinology and doctors of affiliated hospitals in 2010 to investigate short-limbed short stature. Among 91 hospitals, responses were obtained from 61 hospitals (67% response rate). This study also examined data of 193 short-limbed short stature patients, among whom FGFR3-related chondrodysplasia such as achondroplasia (n = 109; 56.5%) was found the most frequently. Second to achondroplasia, hypochondroplasia (n = 47; 24.4%) was the most frequently observed. Along with achondroplasia and hypochondroplasia, 31 patients with disorders of 13 other kinds and six undiagnosed patients were identified. Genetic testing for hypochondroplasia was conducted for only 27.7% of all hypochondroplasia patients, although hypochondroplasia is a heterogeneous condition with many causes, only one of which is FGFR3 mutation. We conducted a genetic analysis of 25 patients who had been clinically diagnosed as having "hypochondroplasia". In these patients, other diseases such as acromicric dysplasia, geleophysic dysplasia, and Aarskog-Scott syndrome were included in addition to FGFR3-related hypochondroplasia (n = 10). Clinical diagnosis of each disorder causing short-limbed short stature is difficult. Therefore, not only clinical diagnosis but also genetic diagnosis play an important role in the diagnosis of short-limb short stature. Diagnostic strategies must be created for each disorder., (© 2014 Japan Pediatric Society.)

Respiratory difficulties and breathing disorders in achondroplasia are thought to underlie the increased risk for sudden infant death and neuropsychological deficits seen in this condition. This review evaluates literature regarding respiratory dysfunctions and their sequelae in patients with achondroplasia. The limited number of prospective studies of respiratory disease in achondroplasia means that observational studies and case series provide a large proportion of the data regarding the spectrum of respiratory diseases in achondroplasia and their treatments. Amongst clinical respiratory problems described, snoring is the commonest observed abnormality, but the reported incidence of obstructive sleep apnoea (OSA) shows wide variance (10% to 75%). Reported treatments of OSA include adenotonsillectomy, the use of CPAP, and surgical improvement of the airway, including mid-face advancement. Otolaryngologic manifestations are also common. Respiratory failure due to small thoracic volumes is reported, but uncommon. Mortality rate at all ages was 2.27 (CI: 1.7-3.0) with age-specific mortality increased at all ages. Sudden death was most common in infants and children. Cardiovascular events are the main cause of mortality in adults. Despite earlier recognition and treatment of respiratory complications of achondroplasia, increased mortality rates and other complications remain high. Future and ongoing evaluation of the prevalence and impact of respiratory disorders, particularly OSA, in achondroplasia is recommended., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)