hrp0089s7.3 | Bone | ESPE2018

Achondroplasia - New Hopes

Irving Melita

Achondroplasia is the most common form of genetic disproportionate short stature or dwarfism with an incidence of 1 in 20 000. It is caused by a recurrent mutation (G380R) in FGFR3, which encodes the transmembrane protein fibroblast growth factor receptor type 3, activating the FGFR3 signalling pathway in the absence of its FGF ligand. This disrupts both endochondral and intramembranous ossification, causing a number of bone modelling abnormalities with secondary comp...

hrp0089rfc2.5 | Bone, Growth Plate & Mineral Metabolism 1 | ESPE2018

Identification of Characteristic Neurological Complications in Infants with Achondroplasia by Routine MRI Screening

Dougherty Harry , Shaunak Meera , Irving Melita , Thompson Dominic , Cheung Moira S

Background: Achondroplasia is the commonest type of skeletal dysplasia with an incidence of 1 in 20,000 and is due to recurrent and dominantly transmitted, activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3). Complications during infancy include foramen magnum stenosis and hydrocephalus which may lead to neurological morbidity and sudden unexplained mortality. Early detection and appropriate neurosurgical management can prevent these complications. How...

hrp0094fc6.5 | Bone and Mineral Metabolism | ESPE2021

What is the natural history of cervicomedullary compression without signal change in infants with achondroplasia? Investigating foramen magnum stenosis evolution.

Harvey Charlotte , Brett Connor , Cocca Alessandra , D’Arco Felice , Irving Melita , Thompson Dominic , Cheung Moira ,

Background: Foramen magnum stenosis (FMS) is a common, serious complication of achondroplasia in infancy. The Achondroplasia Foramen Magnum Score (AFMS; 1-4) was developed to facilitate early detection of stenosis and inform appropriate neurosurgical management. All infants have a baseline screening MRI, of which approximately half of cases demonstrate AFMS3 (craniovertebral junction (CVJ) narrowing with flattening of the cervical cord) or AFMS4 (CVJ narrowing...

hrp0094p1-121 | Growth A | ESPE2021

Higher rates of non-skeletal complications in achondroplasia compared to the general population: a UK matched cohort study using the CPRD database

Pimenta Jeanne M. , Cheung Moira , Irving Melita , Mazzeo Louise , Landis Sarah , Mukherjee Swati ,

Objectives: Achondroplasia (ACH) is a rare, genetic skeletal dysplasia, resulting in impaired endochondral bone growth and leading to multisystem complications. We aimed to estimate rates of non-skeletal complications in ACH patients compared with general population controls.Methods: Retrospective cohort study using UK Clinical-Practice-Research-Datalink (CPRD-GOLD), identifying an ACH cohort. Study index date was define...

hrp0092p1-215 | GH and IGFs (1) | ESPE2019

Acromesomelic Dysplasia, Type Maroteaux (AMDM): Impact of Long-term (8 years) High-dose Growth Hormone Treatment on Growth Velocity and Final Height in Two Siblings

Arya Ved Bhushan , Raj Meena , Kapoor Ritika R , Chapman Simon A , Younes Maha , Irving Melita , Buchanan Charles R

Introduction: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate shortening of the extremities, predominantly affecting middle and distal limb segments. It results from loss-of-function mutations affecting the C-type natriuretic peptide (CNP) receptor (NPR-B), a transmembrane guanylyl cyclase receptor encoded by the NPR2 gene. Resistance to growth hormo...

hrp0094p2-284 | Growth and syndromes (to include Turner syndrome) | ESPE2021

Associations between height and health-related quality of life (HRQoL) and functional independence in children with achondroplasia

Irving Melita , Savarirayan Ravi , Arundel Paul , Polgreen Lynda E. , Mohnike Klaus , Ozono Keiichi , Saunders Michael , Fisheleva Elena , Huntsman-Labed Alice , Day Jonathan

Background and Objectives: Achondroplasia (ACH) is characterized by severe short stature with a height deficit of approximately 6 SDS below that of average stature. Our objective was to evaluate the impact of height deficit on health-related quality of life (HRQoL) and functional independence in children with ACH.Methods: Height Z-score, HRQoL, and functional independence data were obtained from children with ACH who enr...

hrp0094p2-332 | Growth and syndromes (to include Turner syndrome) | ESPE2021

Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children with Achondroplasia: Design of the ACcomplisH Trial

McDonnell Ciara , Irving Melita , Zarate Yuri , B. Hove Hanne , Hogler Wolfgang , Hoernschemeyer Daniel , Zhang Ying , Viuff Dorthe , Hartoft-Nielsen Marie-Louise , Beckert Michael , Savarirayan Ravi ,

Achondroplasia (ACH) is the most common form of dwarfism, occurring in 1: 20,000 births. ACH is caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that interfere with endochondral ossification. Clinically significant morbidities are frequent in ACH; however, there are currently no approved therapies that target the underlying pathobiology. C-type natriuretic peptide (CNP) is an attractive target as it has the potential to inhi...

hrp0089fc15.6 | Growth and Syndromes | ESPE2018

Vosoritide for Children with Achondroplasia:a 30 Month Update from an Ongoing Phase 2 Clinical Trial

Irving Melita , Hoover-Fong Julie , Bacino Carlos , Charrow Joel , Cormier-Daire Valerie , Dickson Patti , Harmatz Paul , Labed Alice Huntsman , Jayaram Kala , Jeha George , Day Jonathan , Larimore Kevin , Phillips John , Savarirayan Ravi

Objectives: Achondroplasia (ACH), caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), leads to inhibition of endochondral bone growth. Vosoritide is a biological analogue of C-type natriuretic peptide (CNP), a potent stimulator of endochondral bone growth. A Phase 2, open-label, sequential cohort, dose-escalation study was conducted to evaluate the safety, tolerability, and efficacy of vosoritide for 24 months in children with ACH aged 5&#150...

hrp0095p1-306 | Growth and Syndromes | ESPE2022

Bone age in children with achondroplasia.

Savarirayan Ravi , Maria De Bergua Josep , Arundel Paul , Pierre Salles Jean , Leiva-Gea Antonio , Irving Melita , Saraff Vrinda , McDevitt Helen , Nicolino Marc , Cormier-Daire Valerie , Kannu Peter , Skae Mars , B. Bober Michael , Phillips III John , Burren Christine , Harmatz Paul , Saal Howard , Hoover-Fong Julie , Muslimova Elena , Cho Terry , Weng Richard , Rogoff Daniela

Background: Bone age (BA) is commonly used in pediatrics to define skeletal maturity for medical and non-medical purposes. Normal range is represented by 2 standard deviations (SDs) above and below the mean. A BA greater than ±2 SDs from the chronological age (CA) is considered abnormal. BA in achondroplasia (ACH) has not been fully characterized; calculation is challenging given difficulties in comparing x-rays with standard radiographs if using the Greuli...

hrp0094p1-125 | Growth A | ESPE2021

PROPEL2: a phase 2, open-label, dose-escalation and dose-expansion study of infigratinib in children with achondroplasia (ACH)

Savarirayan Ravi , Arundel Paul , Bergua Josep Maria De , McDevitt Helen , Cormier-Daire Valerie , Saraff Vrinda , Skae Mars , Santos-Simarro Fernando , Salles Jean Pierre , Rossi Massimiliano , Kannu Peter , Bober Michael B. , III John Phillips , Saal Howard , Harmatz Paul , Meireles Ana Beleza , Cho Terry , Muslimova Elena , Weng Richard , Rogoff Daniela , Irving Melita ,

Background: 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. Current treatment options are non-targeted, ineffective, or painful interventions aimed at preventing or treating complications. Infigratinib is an orally bioavailable and selective...