Design and Baseline Demographics of a Five-Year, Multi-National Observational Cohort Study of Children With Achondroplasia (ACHieve Study)

Abstract Background: Achondroplasia (ACH) is the most common form of dwarfism occurring in 1 in 22,000 births (95% CI 18,500 to 26,000). This skeletal dysplasia is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4p16.3 and results in sustained activation of the FGFR3 pathway leading to impaired chondrogenesis and endochondral bone formation. Both typical childhood growth patterns and the impaired linear growth of ACH are modulated by the delicate balance between growth-inhibiting FGFR3/mitogen-activated phosphokinase and growth-promoting c-type natriuretic peptide/natriuretic peptide receptor B. Individuals with ACH frequently develop clinically significant comorbidities, many with onset during childhood. Currently, there are no therapies addressing the underlying pathology. Most available treatments are surgical with goals to alleviate the symptoms from specific comorbidities (i.e. foramen magnum and spinal stenosis or recurrent otitis media). Since the available therapies do not address the underlying etiology, individuals with ACH often undergo multiple surgeries and myriad other forms of supportive care throughout their lives. The precise timing of comorbidity onset and the natural history of many of the skeletal dysplasia features are incompletely defined. This information is needed to inform the design and conduct of pathology-targeted intervention studies. Aim: The purpose of this study is to gather information about the precise timing of comorbidity onset, the longitudinal growth trajectory, and the evolution of body proportionality in children with ACH. Methods and Future Results: The ACHieve study (NCT03875534) is a multi-center, longitudinal, observational cohort study in children with ACH from birth up to 8 years at enrollment. In this non-therapeutic study, children are evaluated every six months for up to 5 years in 25 centers from North America, Europe and Oceania. The first patient was enrolled in 2019 and a total of 84 children have been enrolled to date. At each assessment, children undergo comprehensive anthropometric studies, (including body proportionality measurements and recumbent or standing height) and information on the timing and nature of ACH-related comorbidities and their treatments are collected. Additional information about the baseline demographics, including sex, age distribution, race/ethnicity, and height standard deviation scores will be presented at the time of conference. Conclusions: The ACHieve study will provide additional insight into the natural history of growth, body proportionality, and comorbidities in children with ACH. These observations will serve as a benchmark for future intervention trials targeting the pathology of the underlying skeletal dysplasia.