Short-limbed Skeletal Dysplasia Research Articles

Anesthetic dilemmas in an achondroplastic patient undergoing elective cesarean section.

Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.

OR27-03 Oral Infigratinib Treatment Is Well Tolerated And Significantly Increases Height Velocity In Children With Achondroplasia: Month 6 Results From The PROPEL 2 Dose-finding Study

Abstract Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Theracon. J. De Bergua: None. P. Arundel: None. J. Salles: None. V. Saraff: None. B. Delgado: None. A. Leiva-Gea: None. H. McDevitt: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. M. Salcedo: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. M. Skae: None. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M.B. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C.P. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. S. Raj: None. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by impaired endochondral ossification resulting from gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone growth. People with ACH are at risk for several significant co-morbidities, including compression of the brainstem due to foramen magnum stenosis, sleep-disordered breathing, chronic otitis media with conductive hearing loss, and symptomatic spinal stenosis. Infigratinib is an oral, selective FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of children with ACH in a phase 2 interventional study (PROPEL 2). Methods: PROPEL 2 (NCT04265651) is a phase 2 dose-finding, open-label study of infigratinib in children 3−11 years of age with ACH who participated for ≥6 months in PROPEL (NCT04035811), a non-interventional clinical assessment study. The PROPEL 2 dose-escalation (DE) phase comprises 5 ascending dose cohorts ranging from 0.016 mg/kg/day to 0.25 mg/kg/day. The primary endpoints are safety; change from baseline (BL) in annualized height velocity (AHV); and infigratinib pharmacokinetics in this population. Secondary endpoints include changes from BL in body proportions, and changes in quality of life. Other parameters of disease burden are evaluated as exploratory endpoints. Summary: Children enrolled in the PROPEL 2 DE phase completed ≥6 months of treatment at the assigned cohort dose. Cohorts 1-3 (n=37; doses 0.016, 0.032, and 0.064 mg/kg/day) did not show a significant increase in AHV and these doses were assessed as non-efficacious. Treatment at the cohort 4 dose (0.128 mg/kg/day) resulted in an increase in AHV from BL of 1.52 cm/year in children ≥5 years old (n=11; p=0.02). Infigratinib at the cohort 5 dose (n=10 with month 6 data, 0.25 mg/kg/day) resulted in a significant mean increase from BL of 3.03 cm/year (p=0.0022). In children considered responders (Δ in AHV ≥25% from BL, n=8/10), the mean change in AHV at the cohort 5 dose was +3.81±1.8 cm/year, with a median of +4.14 cm/year. Infigratinib was well tolerated with no serious AEs or AEs that led to study discontinuation, with most AEs mild or moderate in severity. At the cohort 5 dose level, no grade 3 AEs or treatment-related AEs were reported. Conclusion: Oral infigratinib in children with ACH, up to a dose of 0.25 mg/kg/day, was well tolerated and showed dose-dependent increases in AHV, with a significant mean change from BL of +3.03cm/year at the cohort 5 dose. The safety and efficacy of this oral, once-daily dose of infigratinib at 0.25 mg/kg/day will be further explored in a phase 3 randomized controlled study. If these phase 2 data are confirmed, infigratinib could potentially offer children with ACH the first safe and effective oral therapy to improve growth, enhance functionality and decrease medical complications. Presentation: Saturday, June 17, 2023

THU165 PROPEL, PROPEL 2 And PROPEL OLE Studies Of Infigratinib In Children With Achondroplasia: Design And Status Of 3 Ongoing Trials

Abstract Disclosure: R. Savarirayan: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi. Consulting Fee; Self; BioMarin. Grant Recipient; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. Research Investigator; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Therachon. J. De Bergua: None. P. Arundel: None. H. McDevitt: None. V. Cormier-Daire: Advisory Board Member; Self; BioMarin. V. Saraff: None. M. Skae: None. B. Delgado: None. A. Leiva-Gea: None. M. Salcedo: None. J. Salles: None. M.P. Nicolino: None. M. Rossi: Advisory Board Member; Self; BioMarin. P. Kannu: Advisory Board Member; Self; Novartis, Ipsen. Grant Recipient; Self; CIHR. M. Bober: Advisory Board Member; Self; Biomarin. Consulting Fee; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Grant Recipient; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Ascendis Pharma, BioMarin, Pfizer, QED Therapeutics. J. Phillips III: None. H. Saal: Advisory Board Member; Self; Alexion. Grant Recipient; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. Research Investigator; Self; Alexion, BioMarin, Pfizer, QED Therapeutics. P. Harmatz: Consulting Fee; Self; Audentes, Aeglea, Homology, JCR, Denali, Inventiva, Paradigm, Capsida, Chiesi, Avrobio. Grant Recipient; Self; BioMarin, Inventiva. Research Investigator; Self; BioMarin, Shire/Takeda, QED Therapeutics, RegenXbio, Denali, Ascendis, Amicus, Allievex, JCR, Orphazyme, Idorsia, Sangamo. C. Burren: Grant Recipient; Self; Amgen, Pfizer, QED Therapeutics. Research Investigator; Self; Amgen, Pfizer, QED Therapeutics. T. Candler: None. T. Cho: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. E. Muslimova: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. R. Weng: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. D. Rogoff: Employee; Self; QED Therapeutics. Stock Owner; Self; QED Therapeutics. J. Hoover-Fong: Consulting Fee; Self; Pfizer/Therachon, BioMarin, QED Therapeutics, Sanofi, Ascendis Pharma. Grant Recipient; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. Research Investigator; Self; Pfizer/Therachon, BioMarin, Ascendis Pharma. M. Irving: Advisory Board Member; Self; Ascendis Pharma, BioMarin, QED Therapeutics, Sanofi, Therachon/Pfizer. Speaker; Self; BioMarin, QED Therapeutics. Background: Achondroplasia (ACH), the most common short-limbed skeletal dysplasia, is characterized by defective endochondral ossification resulting from gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Infigratinib is a selective, orally bioavailable FGFR1-3 tyrosine kinase inhibitor being investigated for the treatment of ACH in the observational and 2 interventional studies, as detailed below. Methods: PROPEL (NCT04035811) is a non-interventional clinical assessment study designed to characterize the natural history of ∼250 children 2.5 to <17 years of age with ACH over a 6−24-month period. Primary objective: collect baseline height velocity measurements in children who may participate in an interventional study with infigratinib. Primary endpoint: annualized growth velocity (AGV). Further objectives: collect other baseline growth measurements; evaluate exploratory biomarker indicators of growth; assess ACH-related medical events reported as medical history, or non-treatment adverse events (AEs), health-related quality of life, body pain, functional abilities and cognitive functions in children with ACH. PROPEL 2 (NCT04265651) is a phase 2, open-label study of infigratinib in children 3−11 years of age with ACH who completed ≥6 months of observation in PROPEL. This study includes dose-escalation (extended dose-finding treatment phase, n≥40), a pharmacokinetics sub-study (n≥18), and a dose-expansion phase (n≈20) to confirm the selected dose and provide evidence of efficacy. Primary endpoints: AEs; change from baseline in AGV; and infigratinib pharmacokinetics. Secondary endpoints: safety/tolerability of infigratinib; changes from baseline in anthropometric parameters. Exploratory outcomes: changes in quality of life (QoL) and other parameters of disease burden. PROPEL OLE (NCT05145010) is a phase 2, open-label extension study in ∼230 children who completed an interventional study with infigratinib and, potentially, in ≤50 infigratinib-naïve children. Primary objectives: safety, tolerability; and efficacy of long-term daily doses of infigratinib. Secondary objectives: changes in other indicators of growth/development, skeletal abnormalities, QoL/disease burden, and cognitive functions. Children may receive infigratinib until they reach final height. Summary: The PROPEL, PROPEL 2, and PROPEL OLE studies are ongoing. Together, they are intended to contribute to the understanding of the natural history of ACH, provide key evidence on the safety and efficacy of oral infigratinib, including QoL and skeletal changes in children with ACH, and inform the design of future studies in this setting. Presentation: Thursday, June 15, 2023

Clinical whole‐exome sequencing analysis reveals a novel missense COL11A1 mutation resulting in an 18‐week Iranian male aborted fetus with Fibrochondrogenesis 1: A case report

Fibrochondrogenesis 1, an autosomal recessive syndrome, is a rare disease that causes short-limbed skeletal dysplasia. Mutations in the gene encoding the α1 chain of type XI collagen (COL11A1) are seen to be the main cause of this disease. We present an 18-week Iranian male aborted fetus with Fibrochondrogenesis 1 from consanguineous parents. Whole-exome sequencing revealed a novel missense variant from G to A in exon 45 of 68 in the COL11A1 gene (NM_080629.2: c.3440G > A, [p.G1147E, g.103404625]). The mutation was confirmed by Sanger sequencing and further, MutationTaster predicted this variant to be disease-causing. Bioinformatic analysis suggests that this variant is highly conserved in both nucleotide and protein levels, suggesting that it has an important function in the proper role of COL11A1 protein. In silico analysis suggests that this mutation alters the COL11A1 protein structure through a Glycine to Glutamic acid substitution.

PSAT105 Evaluation of Body Mass Index and Metabolic Parameters in Children with Achondroplasia Participating in the PROPEL Study

Abstract Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. Children and adults with ACH have disproportionate short stature and are at risk for several significant co-morbidities, including obstructive sleep apnea, chronic otitis media with conductive hearing loss, and spinal stenosis. Obesity is a health problem in ACH and aggravates breathing difficulties (i.e. sleep apnea), back and joint pain, and reduced mobility. Individuals with ACH are predisposed to abdominal obesity, although the cause is not completely understood. The metabolic effect of visceral obesity does not suggest an association with the development of a diabetic profile. The objective of this study is to evaluate body mass index (BMI) and metabolic parameters in children with ACH participating in the PROPEL study, a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development for ACH. Methods Data were analyzed from 86 children (mean age 6.1±2.5 years; female n=52) enrolled in PROPEL. BMI was calculated at enrollment and compared with sex- and age-specific BMI curves for children with ACH in the United States. Cholesterol, triglycerides, and hemoglobin A1c were measured centrally in a subset of children. Results BMI (mean±SD) was 21.2±2.2 in females (range 16.8–26.2) and 20.5±1.6 in males (range 17.9–24.6), with 8/52 girls (15%) and 1/34 boys (2.9%) presenting BMI above the 95% of the sex- and age-specific BMI curves for ACH. The mean±SD for cholesterol and triglycerides measured in a subset of 43 children were 4.2±0.7 mmol/L (normal range [NR] 2.59–4.66) and 0.9±0.5 mmol/L (NR 0.56–1.36), respectively. Cholesterol was elevated in 9/43 children (20.9%), while triglycerides were high in 8/43 (18.7%). Hemoglobin A1c (HbA1c) was measured in 28 children and had a mean±SD of 0.052±0.002 (NR Hb fraction 0.04–0.06). Although all values were within normal ranges, 19/28 (68%) of children had values above the mean for laboratory reference values. Conclusion Results from this work illustrate the importance of using BMI tables developed for children with ACH when providing guidance on weight management. Furthermore, our findings suggest that, in this cohort, average cholesterol and HbA1c levels, although normal, are above the mean for the reference population; this highlights the importance of a healthy diet, weight management and regular physical activity starting at young age. Additional studies are needed to understand the relationship between BMI and body composition in individuals with short stature and to further investigate the clinical relevance of these findings given that no association between increased BMI and metabolic syndrome has been described in adults with ACH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

RF26 | PMON326 Medical History of Children Enrolled in PROPEL: A Prospective Clinical Assessment Study in Children with Achondroplasia

Abstract Background Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 live births. People with ACH are at risk for several significant co-morbidities, including foramen magnum stenosis, obstructive sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, and a propensity towards obesity. PROPEL is a prospective, non-interventional study designed to examine baseline growth parameters and health status in children being assessed for potential enrollment into interventional studies with infigratinib, an oral FGFR1–3 inhibitor in development as a therapeutic option for ACH. Here we describe the medical complications reported as medical history in the PROPEL study. Methods Children with ACH between the ages of 2.5 and 10 years are eligible for enrollment in PROPEL and are evaluated at screening/baseline, month 3, month 6, and every 6 months thereafter. Medical history collected at screening/baseline is summarized using system organ class and preferred terms. Results A total of 86 children with ACH (60% female, mean±SD age 6.1±2.5 years) have been enrolled to date at 19 sites in Europe, Australia and North America. Fifty-eight children had undergone surgical and medical procedures with a mean of 2.9 procedures per child (1–11 surgeries/subject). The most common procedures were pressure-equalizing ear tube insertion, adenoidectomy and tonsillectomy. Twenty-one (24%) children had undergone at least 1 surgery (1–5 surgeries/child) for spine or cranial decompression. History of infections and respiratory disorders were reported in 46 (53%) and 40 (47%) children, respectively, the most common being ear infections and obstructive sleep apnea. Musculoskeletal disorders were described in 33 (38%) children, with kyphosis being the most common. Hydrocephalus was reported in 2 children, while 4 had ventriculomegaly without intracranial hypertension. Congenital cardiovascular abnormalities were found in 4 children, 2 of whom presented with patent ductus arteriosus and 2 had patent foramen ovale. A comprehensive summary of medical histories will be presented at the conference. Conclusions The PROPEL study has a planned total enrollment of 200 children and seeks to contribute to the deeper understanding of the natural history of ACH. Data described here highlight the significant complications and high number of interventions that children with ACH undergo throughout infancy and childhood. This stresses the importance of expert management of this complex condition. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:05 p.m. - 1:10 p.m.

A registry of achondroplasia: a 6-year experience from the Czechia and Slovak Republic

BackgroundAchondroplasia (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.ResultsIn 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.ConclusionThe 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.

Infigratinib in children with achondroplasia: the PROPEL and PROPEL 2 studies.

Background:Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia.Objectives:The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites.Design:PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy.Methods and analysis:Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase.Ethics:PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable.Discussion:PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia.Registration:ClinicalTrials.gov: NCT04035811; NCT04265651.

Pseudoachondroplasia: Phenotype and genotype in 11 Indian patients.

Pseudoachondroplasia (PSACH) is an autosomal dominant disorder characterized by rhizomelic short-limbed skeletal dysplasia. The primary clinical and radiographic features include disproportionate dwarfism, joint laxity and hyperextensibility, exaggerated lumbar lordosis, and late ossification of the epiphyses. Identification of disease-causing variants in heterozygous state in COMP establishes the molecular diagnosis of PSACH. We examined 11 families with clinical features suggestive of PSACH. In nine families, we used Sanger sequencing of exons 8-19 of COMP (NM_000095.2) and in two families exome sequencing was used for confirming the diagnosis. We identified 10 de novo variants, including five known variants (c.925G>A, c.976G>A, c.1201G>T, c.1417_1419del, and c.1511G>A) and five variants (c.874T>C, c.1201G>C, c.1309G>A, c.1416_1421delCGACAA, and c.1445A>T) which are not reported outside Indian ethnicity. We hereby report the largest series of individuals with molecular diagnosis of PSACH from India and reiterate the well-known genotype-phenotype corelation in PSACH.

Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress, Inflammation, and Block of Autophagy.

Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol.

Al-Gazali Skeletal Dysplasia Constitutes the Lethal End of ADAMTSL2-Related Disorders.

Lethal short-limb skeletal dysplasia Al-Gazali type (OMIM %601356), also called dysplastic cortical hyperostosis, Al-Gazali type, is an ultra-rare disorder previously reported in only three unrelated individuals. The genetic etiology for Al-Gazali skeletal dysplasia has up until now been unknown. Through international collaborative efforts involving seven clinical centers worldwide, a cohort of nine patients with clinical and radiographic features consistent with short-limb skeletal dysplasia Al-Gazali type was collected. The affected individuals presented with moderate intrauterine growth restriction, relative macrocephaly, hypertrichosis, large anterior fontanelle, short neck, short and stiff limbs with small hands and feet, severe brachydactyly, and generalized bone sclerosis with mild platyspondyly. Biallelic disease-causing variants in ADAMTSL2 were detected using massively parallel sequencing (MPS) and Sanger sequencing techniques. Six individuals were compound heterozygous and one individual was homozygous for pathogenic variants in ADAMTSL2. In one of the families, pathogenic variants were detected in parental samples only. Overall, this study sheds light on the genetic cause of Al-Gazali skeletal dysplasia and identifies it as a semi-lethal part of the spectrum of ADAMTSL2-related disorders. Furthermore, we highlight the importance of meticulous analysis of the pseudogene region of ADAMTSL2 where disease-causing variants might be located. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effect of periosteal resection on longitudinal bone growth in a mouse model of achondroplasia

Achondroplasia (ACH) is the most common form of short-limbed skeletal dysplasia. Patients with ACH sometimes undergo lower limb lengthening to get functional and psychological achievements. The periosteal resection (PR) is a known mechanism to increase longitudinal bone growth without osteotomy, although the results are not predictable. It could be alternative for limb lengthening in a minimally invasive technique. The purpose of this study is to evaluate the effect of PR on acceleration of bone growth in a mouse model of ACH (Fgfr3ach). We performed a circumferential resection of periosteum on the proximal tibia to both wild-type and Fgfr3ach mice at the age of four weeks. The second PR was done one week later in each mouse, which was subsequently sacrificed at the age of six weeks for micro-computed tomography (micro-CT) scan and histological examinations. We measured tibial bone length, bone volume, and metaphyseal trabecular bone parameters, including bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N) by reconstructed micro-CT images. We also quantified the entire width of the growth plate of the proximal tibial from the sections stained with hematoxylin and eosin. Tibial bone length and bone volume of the PR side were significantly larger than the sham side in wild-type mice, while they were not statistically significant in Fgfr3ach mice. The BV/TV and Tb.N in the metaphysis were significantly decreased in the PR side of both mice. The histological analysis revealed that the growth plate of the proximal tibia was significantly wider in the PR side of wild-type mice while it showed no difference in width between the PR side and the sham side in Fgfr3ach mice. PR promoted longitudinal bone growth in wild-type mice, but it exhibited only a marginal effect on bone growth in Fgfr3ach mice.

Novel Clinical and Radiological Findings in a Family with Autosomal Recessive Omodysplasia

Autosomal recessive omodysplasia (GPC6-related) is a rare short-limb skeletal dysplasia caused by biallelic mutations in the GPC6 gene. Affected individuals manifest with rhizomelic short stature, decreased mobility of elbow and knee joints as well as craniofacial anomalies. Both upper and lower limbs are severely affected. These manifestations contrast with normal height and limb shortening restricted to the arms in autosomal dominant omodysplasia (FZD2-related). Here, we report 2 affected brothers of Pakistani descent from Denmark with GPC6-related omodysplasia, aiming to highlight the clinical and radiological findings. A homozygous deletion of exon 6 in the GPC6 gene was detected. The pathognomonic radiological findings were distally tapered humeri and femora as well as severe proximal radioulnar diastasis. On close observations, we identified a recurrent and not previously described type of abnormal patterning in all long bones.

Abnormal Newborn Screening Follow-up for Severe Combined Immunodeficiency in an Amish Cohort with Cartilage-Hair Hypoplasia

Cartilage-hair hypoplasia (CHH) is an autosomal recessive, short limb skeletal dysplasia with a variable immunologic phenotype. The spectrum of immune function ranges from clinically normal to severe combined immunodeficiency (SCID). Multiple studies have shown that abnormal immune parameters may not predict severe outcomes. Newborn screening (NBS) using T cell receptor excision circle (TREC) assay can now effectively identify infants with severe T cell deficiency who are at risk for SCID. NBS has allowed for cost-effective identification of patients with SCID and improved outcomes with hematopoietic stem cell transplant (HSCT). Ohio reports two abnormal TREC results: decreased and absent TREC. This study evaluated the laboratory and clinical differences in eight Amish patients with CHH with an abnormal TREC result on the NBS. There were four patients with absent TREC and four patients with decreased TREC. The absent TREC patients had lower CD3, CD4, naïve CD4, CD8 cells, and phytohemagglutinin (PHA)-induced lymphocyte proliferation. Three patients with absent TREC were diagnosed with SCID and two underwent successful HSCT. Patients with absent TREC experienced more CHH-related morbidity including anemia requiring transfusion, Hirschsprung's disease, and failure to thrive. No patients with decreased TREC required HSCT. Our study indicates that CHH patients with absent TREC tend to have more severe immunological and clinical phenotype than patients with decreased TREC. Confirmation of these trends in a larger group would guide providers and parents in a timely referral for HSCT, or cost-effective surveillance monitoring of children with a life-threatening illness.

Epidemiology of achondroplasia: A population-based study in Europe.

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.

ABNORMAL TREC RESULTS ON THE OHIO NEWBORN SCREEN IN CHILDREN WITH CARTILAGE-HAIR HYPOPLASIA

Introduction While newborn screening (NBS) using T-cell receptor excision circle (TREC) analysis was introduced primarily to screen for severe combined immunodeficiency (SCID), it also identifies T-cell lymphopenia or low naive T-cell numbers due to other etiologies. Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder caused by mutations in the RMRP gene that result in short limbed skeletal dysplasia and a range of immunologic deficits involving both cellular and humoral immune function. The immune defect can range from minor abnormalities to a SCID phenotype. Methods We analyzed the NBS TREC results performed in Ohio between July 2013 and July 2018. We reviewed the results of the immunologic workup in patients with abnormal TREC results who were later confirmed to have CHH. Results A total of 693,706 unique infants had NBS performed between July 2013 and July 2018, with 192 (0.027%) having abnormal TREC results. Eight infants with abnormal TREC results were diagnosed with CHH. This included 6 cases of non-SCID T-cell lymphopenia and 2 children with SCID phenotypes. In the children with abnormal screening and a diagnosis of CHH, the absolute CD4 lymphocyte counts on initial immunophenotyping ranged from 76 – 757 cells/mm3 (median = 552 cells/mm3). The two CHH patients with SCID received bone marrow transplants. Conclusions CHH is a rare genetic disorder associated with widely varying levels of T-cell lymphopenia ranging from clinically insignificant to SCID. The T-cell lymphopenia may cause an abnormal result on the NBS TREC analysis, allowing for early diagnosis of a significant immunodeficiency and institution of life-saving therapies.

Clinical dosage of meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (Cmax) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.

Pseudoachondroplasia: A Rare Cause of Short Limbed Dwarfism

: Pseudoachondroplasia is a rare type of short-limbed skeletal dysplasia. It is usually found as an autosomal dominant inheritable disorder. Children are normal at birth and they present developmental delay in walking by the age of 2, an abnormal waddling gait or deformities of the lower limb. Diagnosis is based on characteristic clinical and radiological findings. This study reports on a 6-year-old boy with classical features of pseudoachondroplasia.

Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.

OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3ach mice and 6.125 ± 2.029 in meclozine-treated Fgfr3ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3ach mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.

Low bone mineral density in achondroplasia and hypochondroplasia.

Achondroplasia (ACH) and hypochondroplasia (HCH) are the most common form of short-limb skeletal dysplasias caused by activated fibroblast growth factor receptor 3 (FGFR3) signaling. Although decreased bone mass was reported in gain-of-function mutation in Fgfr3 mice, both disorders have never been described as osteoporotic. In the present study, we evaluated bone mineral density (BMD) in ACH and HCH patients. We measured spinal BMD (L1-L4) in 18 ACH and four HCH patients with an average age of 19.8 ± 7.5 years (range, 10-33 years). BMD Z-score in each individual was calculated for normalizing age and gender. Correlation between body mass index (BMI) and BMD was analyzed. Moreover, BMD and Z-score were compared between ACH patients and HCH patients. The average BMD of ACH/HCH patients was 0.805 ± 0.141 g/cm(2) (range, 0.554-1.056 g/cm(2) ), resulting in an average Z-score of -1.1 ± 0.8 (range, -2.4 to 0.6) of the standard value. A slightly positive correlation was observed between BMI and BMD (r = 0.45; P = 0.13). There was no significant difference in BMD and Z-score between ACH and HCH patients. Spinal BMD was reduced in ACH/HCH patients, and was mildly correlated with individual BMI. We should carefully monitor BMD and examine osteoporosis-related symptoms in adolescent and adult ACH/HCH patients. © 2016 Japan Pediatric Society.