Genomic imprinting in Turner syndrome: Effects on response to growth hormone and on risk of sensorineural hearing loss

Context: Evidence exists for X-linked parent-of-origin effects in Turner syndrome, because phenotypic and cognitive profiles differ between 45, X-maternal and 45, X-paternal individuals. Objective and Design: We evaluated the parent-of-origin effect of the intact X chromosome on spontaneous growth, GH-stimulated height gain, and frequency of sensorineural hearing loss in 54 subjects with Turner syndrome recruited from a Canadian randomized, controlled trial of GH supplementation to adult height. Methods and Results: Microsatellite analyses revealed that 72% of nonmosaic 45, X subjects retained an X-maternal, whereas 86% of nonmosaic 46, X, i(Xq) subjects carried an intact X-paternal. No significant differences were noted between X-maternal and X-paternal subjects for parents' heights, birth weight and length, and height, age, or bone age at study entry. In all subjects, and in those with X-maternal, baseline height SD score correlated with midparental height (all: r = 0.511, P < 0.001; X-maternal: r = 0.535, P = 0.001) and with mother's height (all: r = 0.510, P < 0.001; X-maternal: r = 0.574, P < 0.001) but only weakly with father's height (all: r = 0.334, P = 0.015; X-maternal: r = 0.292, P = 0.094). Using a linear model including age and height at GH initiation, subjects with X-maternal had a greater mean height gain than those with X-paternal (SD score difference and 95% confidence interval for all karyotypes was +0.43 and 0.04 - 0.82, P = 0.030, and for 45, X was +0.64 and 0.06 - 1.21, P = 0.031); X-linked imprinting explained 36 - 53% of the GH response. After pure tone audiometry testing, X-maternal subjects were also less likely (P = 0.040) to have sensorineural hearing loss than X-paternal subjects. Conclusion: This study provides evidence of an X-linked imprinting effect on GH response and on sensorineural hearing loss in Turner syndrome and should fuel the search for candidate genes.