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Genomic Imprinting in Turner Syndrome: Effects on Response to Growth Hormone and on Risk of Sensorineural Hearing Loss

Division of Experimental Medicine (C.E.H., C.L.D.), McGill University, Montreal, Québec, Canada H3A 1A3; Endocrinology Service and Research Center (C.E.H., C.L.D.), Hôpital Ste-Justine, Montreal, Québec, Canada H3T 1C5; Statistics (G.A.), Lilly Research Laboratories, Toronto, Ontario, Canada M4G 2P1; Endocrinology (C.A.Q.), Lilly Research Laboratories, US Medical, Indianapolis, Indiana 46258; and Department of Pediatrics (C.L.D.), University of Montreal, Montreal, Québec, Canada H3C 3J7

Address all correspondence and requests for reprints to: Cheri Deal, Ph.D., M.D., F.R.C.P.C., Endocrinology Service and Research Center, Hôpital Ste-Justine, 3175 Côte Ste-Catherine, Montreal, Québec, Canada H3T 1C5. E-mail: Cheri.L.Deal{at}umontreal.ca.

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.

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