Normative growth charts for individuals with Costello syndrome

Costello syndrome is a rare condition due to heterozygous germline mutations in the proto-oncogene HRAS. It affects multiple organ systems and includes severe failure-to-thrive, short stature, and macrocephaly. The goal of this study was to develop Costello syndrome-specific growth curves. We collected height, weight, and head circumference (OFC) measurements from 94 individuals (45 males and 49 females). Their HRAS mutation spectrum reflects previously published cohorts, with p.G12S in 77.7%. Participants received medical care, therefore our data does not reflect natural history per se, but rather growth with nutritional support. Due to limited cohort size, we analyzed data from males and females together. Weight-for-age data included 417 separate measurements from 80 individuals age 0-36 months, and 585 measurements from 82 individuals for age 0-10 years. Height-for-age data were derived from 391 measurements from 77 individuals age 0-36 months, and 591 measurements from 90 individuals age 0-10 years. Measurements obtained after growth hormone exposure in 15 individuals were excluded in this analysis. The OFC curve was derived from 221 measurements from 55 individuals age 0-36 months. Centiles (5th, 50th, and 95th) were estimated across the age continuum for each growth parameter, and compared to gender-specific curves for average stature individuals. The resulting curves demonstrate very slow weight gain in the first 2 years. Short stature is seen in many, but after age 4 years the 95th centile for height falls within the low normal range for average stature children. Head circumference curves largely overlap those for average stature, reflecting relative macrocephaly.