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

Abstract

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.

Heart and Turner syndrome

“…In a recent French study, including 1501 patients with TS, the median age at diagnosis was 9.4 years [5] In Europe, the Danish cytogenetic register identified all cases (n= 781) of TS alive in Denmark, during the period from 1970 to 2001. Their median age at diagnosis was 15.1 years.…”

Prevalence and progression of aortic dilatation in adult patients with Turner syndrome: a cohort study

“…In the general population, its prevalence is 2-3% in males and 0.05% in females (4). It has been reported that the prevalence of BAV and other congenital cardiovascular malformations are more frequent in patients with a homogenous 45,X karyotype than in patients with 45,X/46,XX mosaicism (1,5). BAV is associated with proximal aortic dilatation (AD) and is a predisposing risk factor for subsequent aortic dissection (2).…”

The genetics of isolated congenital heart disease

“…Advances in next generation sequencing have allowed for increased sensitivity to detect mosaic variants and additional studies are necessary to fully assess mosaicism as a contributor to CHD. Cytogenetic studies have demonstrated that individuals with mosaic trisomies can have CHD without associated syndromic features (Fiot et al, ; Yokoyama, Narahara, Kamada, Tsuji, & Seino, ). The Leipzig heart collection was used to study mosaicism in cardiac tissue from patients with CHD.…”

“…Cytogenetic studies have demonstrated that individuals with mosaic trisomies can have CHD without associated syndromic features (Fiot et al, 2019;Yokoyama, Narahara, Kamada, Tsuji, & Seino, 1992). The…”