X chromosome gene dosage as a determinant of congenital malformations and of age-related comorbidity risk in patients with Turner syndrome, from childhood to early adulthood

in European Journal of Endocrinology
Correspondence should be addressed to J Léger; Email: juliane.leger@aphp.fr

† (Details of the French Turner Syndrome Study Group are presented in the Acknowledgement section)

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Objective

Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.

Design and methods

This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).

Results

Median age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders.

Conclusion

These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

Downloadable materials

  • Supplemental data table S1: Prevalence of congenital cardiac and renal malformations in all patients with known karyotype, after exclusion of the 429 patients for whom the diagnostic method for karyotyping analyses was unknown, and by karyotype subgroup
  • Supplemental data table S2: Probability of the occurrence of comorbid conditions including autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, hypertension and liver dysfunction, at the ages of 10, 20 and 30 years, after exclusion of the 429 patients for whom the diagnostic method for karyotyping analyses was unknown, and by karyotype subgroup
  • Figure Supplementary data S1: Kaplan-Meier estimates of the cumulative incidence of the development of comorbid conditions, including autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, hypertension and liver dysfunction in patients with Turner Syndrome, by karyotype subgroup, and after the exclusion of patients (n = 429) for whom the karyotyping method was unknown.

 

     European Society of Endocrinology

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    Flow chart of patients.

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    Kaplan–Meier estimates of the cumulative incidence (and 95% confidence interval) of the development of comorbid conditions, including autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, hypertension and liver dysfunction, in patients with Turner Syndrome.

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    Kaplan–Meier estimates of the cumulative incidence of the development of comorbid conditions, including autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, hypertension and liver dysfunction in patients with Turner Syndrome, by karyotype subgroup. (The incidence of the comorbidities is not known in a French reference population between the ages of 10–30 years.)

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