Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study

Hoover-Fong JE, Schulze KJ, Alade AY, Bober MB, Gough E, Hashmi SS, Hecht JT, Legare JM, Little ME, Modaff P, Pauli RM, Rodriquez-Buritica DF, Serna ME, Smid C, Liu C, and McGready J. (2021) Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study – a multi-center retrospective cohort study of achondroplasia in the US. Orphanet Journal of Rare Diseases

Achondroplasia is a rare genetic skeletal disorder caused by autosomal dominant mutations in the fibroblast growth factor receptor type 3 (FGFR3) gene. FGFR3 is one of four fibroblast growth factor receptors in humans and influences cellular proliferation and is very prevalent on the surface of chondrocytes, which produce cartilaginous bone. A few characteristics of achondroplasia include small stature, short limbs and rhizomelic disproportion, macrocephaly, midfacial retrusion, small chest, and short fingers. Until more recently, growth curves had been based on hand-smoothed curves from US data published in 1977 and 1978 by Horton et al (1,2). Following this, growth curves have been produced for achondroplasia populations in US, Europe, Australia, Argentina, Egypt, and Japan with data collected from 1967 to 2019 and in populations consisting of 23 to 466 individuals, but most of these studies looked at only one or two measurements. To derive updated growth references, Hoover-Fong et al used the Achondroplasia Natural History Study (CLARITY) database which is the largest dataset to date made up of 1374 subjects. Anthropomorphic measurements collected from 1341 individuals were used (33 were removed due to incomplete anthropomorphic measurements) to produce a reference for length/height, weight, and head circumference.

Across the 1341 subjects, 37 349 data points were collected for length/height, weight, and head circumference and used to produce the growth curves. A great benefit to this data was that most subjects had longitudinal data with over half contributing 5 or more data points in the three categories, and one third of the group contributing 10 or more data points. Since growth rates differ across ages, instead of producing one large curve that covered all the ages in male and female participants, each measurement category was also split into 0-36 months and 2-18 years of age. As well, the data was separated into percentile curves with a 5th, 25th, 50th, 75th, and 95th percentile curve constructed for each graph.

Comparing the most recently published height-for-age curves from this study and those in other geographic locations shows that median height is very similar across different populations at 5 and 10 years of age. With increased age, though, differences begin to emerge. For example, 15-year-old Argentinian girls were 3-5 cm shorter than those from the US, Australia, and Europe (116 cm and 119-121 cm, respectively) and by 18 years of age the US and Argentinian girls were shorter than those from Europe at 120 cm compared to 124 cm, respectively. Interestingly, the boys from all locations had similar median heights at 15 years of age, but were more variable by 18 years of age, 127cm to 134cm, with those from the US being the shortest and the tallest from Australia. Hoover-Fong et al suggest that the variability seen with increased age could result from genetic differences influencing growth, environmental influences, timing of pubertal development, or the modelling approaches used to determine the median estimates. Due to this, it is suggested that each should be investigated further to clarify which answer, or combination of them, influence this irregularity.

As the accumulation of excess weight is one concern with achondroplasia, clinical use of updated growth curves could help to access weight for height trends. Comparable to previous growth curves, there is more overlap in weight than height which is consistent for a body morphology with a higher ratio of trunk to extremity size. As well, excess fat storage is a concern in this US population, and it is challenging to determine what a healthy weight is for their size. Until 10 years of age the median weights are very similar between the different datasets, but by 15 years of age US girls were 43 kg and the US boys were 42 kg while being 36-40 kg and 34-37 kg, respectively, in the other populations. This trend was also found at 17 years of age where the 17-year-old girls from the US were 47 kg compared to 41-44 kg at the other locations and the boys were 47 kg in the US and 48 kg in Europe, but 38 kg in Australia and 42 kg in Argentina. The variability here could be for the same reasons described above when discussing the variability in height, or that individuals with achondroplasia in the US weigh more than the other locations compared due to a difference in diet in the US.

Hoover-Fong et al have used the CLARITY dataset to construct growth reference curves for the achondroplasia community for length/height, weight, and head circumference. In addition to providing more data on the measurements collected, the purpose of updating the growth curves is to continue to improve the clinical utility of these references in this population. For a population with a higher risk of obesity, a growth curve that considers their stature and different body morphologies could provide use when determining healthy growth in children. The larger dataset may also help delineate more subtle effects caused by ethnic or environmental differences. However, there is a lot of variation in the data collected from the different sites and the authors suggest that each proposed reason should be investigated further to clarify which answer, or combination of them, influence these differences.

1.     Horton WA, Rotter JI, Kaitila I, Gursky J, Hall JG, Shepard TH, and Rimoin DL. (1977) Growth curves in achondroplasia. Birth Defects Original Article Series, 13(3C):101-107

2.     Horton WA, Rotter JI, Rimoin DL, Scott CI, and Hall JG. (1978) Standard growth curves for achondroplasia. The Journal of Pediatrics, 93(3):435–438