Clinical significance of the parental origin of the X chromosome in Turner syndrome

Context: The phenotype in Turner syndrome (TS) is variable, even in patients with a supposedly nonmosaic karyotype. Previous work suggested that there were X-linked parent-of-origin effects on the phenotype. Hypothesis: The TS phenotype is influenced by the parental origin of the missed X chromosome. Design: This was a multicenter prospective study of TS patients and both their parents, determining parental origin of the X-chromosome, and characterizing the clinical phenotype. Patients and Methods: Eighty-three TS patients and their parents were studied. Inclusion criteria were TS with karyotype 45,X or 46Xi(Xq). Four highly polymorphic microsatellite markers on the X-chromosome DMD49, DYSII, DXS1283, and the androgen receptor gene and three Y chromosome markers, SRY, DYZ1, and DYZ3. Outcome Measures: The study determined the correlation between the parental origin of the X chromosome and the unique phenotypic traits of TS including congenital malformations, anthropometry and growth pattern, skeletal defects, endocrine traits, education, and vocation. Results: Eighty-three percent of 45,X retained their maternal X (X^m), whereas 64% 46Xi(Xq) retained their paternal X (X^p, P < 0.001). Kidney malformations were exclusively found in X^m patients (P = 0.030). The X^m group had lower total and low-density lipoprotein cholesterol (P < 0.003), and higher body mass index SD score (P = 0.030) that was not maintained after GH treatment. Response to GH therapy was comparable. Ocular abnormalities were more common in the paternal X group (P = 0.017), who also had higher academic achievement. Conclusions: The parental origin of the missing short arm of the X chromosome has an impact on overweight, kidney, eye, and lipids, which suggests a potential effect of an as-yet-undetermined X chromosome gene imprinting.