Skeletal and Cranial Growth Among Children with Achondroplasia
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Abstract
Study to characterize the cranial growth of individuals with achondroplasia with an emphasis on the morphometrics of the foramen magnum. Specifically, to describe the performance of a cross-sectional imaging based quantitative morphovolumetric study of the posterior cranial fossa and craniocervical junction in achondroplastic children and compare to normal growth of these metrics in children to investigate possible associations with ventriculomegaly, cervicomedullary compression, hydrocephalus, and sleep apnea. The multicenter nature of this proposal enabled a well-powered analysis of this rare and poorly understood disease.
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Achondroplasia, the most common form of disproportionate short stature, is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Affected children may experience severely impaired foramen magnum growth during the first years of life, which may necessitate neurosurgical intervention. The skeletal abnormalities seen in achondroplasia can result in respiratory and neurologic comorbidities, including cord compression at the cervicomedullary junction, ventriculomegaly, hydrocephalus, and sleep apnea. These result in part from foramen magnum narrowing. There is a critical need to identify natural and modified history of foramen magnum growth in normal children and children with achondroplasia in order to develop predictive imaging biomarkers of spinal cord compression.
Study Aims
- To develop and evaluate computable phenotypes for patients with achondroplasia <20 years-old, a subset undergoing head/neck imaging, and matched controls for both groups.
- Describe the sociodemographic, clinical, and healthcare utilization characteristics of patients with achondroplasia, overall and by several subgroups.
- Examine the cranial morphometric characteristics for patients with and without achondroplasia.
- Develop fully anonymized synthetic dataset from the achondroplasia patients dataset.
Study Design
The study used retrospective cohort and cross-sectional study designs. The cohorts were comprised of patients with and without achondroplasia and the primary outcome was cranial morphometric biomarkers. Below we repeat the study aims and add their study designs.
Cohort Description
Cohorts of interest included:
- Patients under 20 y identified by the achondroplasia computable phenotype which requires 1 or more diagnosis codes during an inpatient or outpatient physician visit.
- Control Group 1. Patients matched 4:1 to each patient with achondroplasia.Each patient with achondroplasia is matched on the following variables with 4 controls without achondroplasia:
a. Age in years
b. Calendar year of birth
c. Gender
d. Duration of follow-up, rounded to nearest year integer
e. Number of height measurements on unique days
f. Institution
Exclusions are identified by the Pediatric Medical Complexity Algorithm to exclude patients with complex or noncomplex chronic condition any time before cohort entrance age; this includes genetic growth problems. - Subset of Cohort 1. Patients with achondroplasia identified with a head/neck MRI/MRA/CT scan. Patients will be selected based on the computable phenotype identified in Aim 1. The age range restricted to less than 7 years-old.
- Control Group 2. Patients without achondroplasia with a head/neck MRI scan matched 1:1 to patients in cohort (3).
Inclusion criteria:
Occurrence of procedure codes for head/neck MRI/MRA/CT scan Explore: requiring that this control sample be a subset of the control group 1. Age <7 years-old at the time of the scan
Exclusion criteria:
Noncomplex or complex chronic disease based on the Pediatric Medical Complexity Algorithm. Evidence of traumatic head/neck injury that can influence the imaging study.
Matching variables:
- Age in years
- Calendar year of birth
- Gender
- Institution
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