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. 2024 Dec;194(12):e63819.
doi: 10.1002/ajmg.a.63819. Epub 2024 Jul 17.

Prevalence, diagnostic features, and medical outcomes of females with Turner syndrome with a trisomy X cell line (45,X/47,XXX): Results from the InsighTS Registry

Natalia Klamut  1   2 , Samantha Bothwell  1   2 , Alexandra E Carl  1   2 , Vaneeta Bamba  3 , Jennifer R Law  4 , Wendy J Brickman  5 , Karen O Klein  6 , Roopa Kanakatti Shankar  7 , Catherina T Pinnaro  8 , Patricia Y Fechner  9 , Siddharth K Prakash  10 , Iris Gutmark-Little  11 , Susan Howell  1   2 , Nicole Tartaglia  1   2 , Marybel Good  12 , Kelly C Ranallo  12 , Shanlee M Davis  1   2
Affiliations

Prevalence, diagnostic features, and medical outcomes of females with Turner syndrome with a trisomy X cell line (45,X/47,XXX): Results from the InsighTS Registry

Natalia Klamut et al. Am J Med Genet A. 2024 Dec.

Abstract

Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS-related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly more likely to have structural renal anomalies (18% vs. 3%; p = 0.03). They were twice as likely to have congenital heart disease (32% vs. 15%, p = 0.08) and less likely to experience spontaneous menarche (46% vs. 75% of those over age 10, p = 0.06), although not statistically significant. Congenital anomalies, hypertension, and hearing loss were primarily attributable to a higher proportion of 45,X cells, while preserved ovarian function was most associated with a higher proportion of 46,XX cells. In this large TS cohort, 45,X/47,XXX was more common than previously reported, individuals were phenotypically less affected than those with 45,X, but did have trends for several more TS-related diagnoses than individuals with 45,X/46,XX.

Keywords: Trisomy X syndrome; Turner syndrome; mosaicism; phenotype; sex chromosome aneuploidy.

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Conflict of interest statement

CONFLICT OF INTEREST STATEMENT :

WJB, JRL, KOK, PYF, IGL, and SMD are site investigators for Ascendis Pharma clinical trial in Turner syndrome and JRL has received consultant funds. VB is involved in research sponsored by Pfizer and Lumos. RKS has received research funding from Biomarin for an investigator-initiated study. IGL and VB are involved in research sponsored by Novo Nordisk. None of these companies had any involvement in the study.

Figures

Figure 1.
Figure 1.
Density plots of age at Turner syndrome diagnosis by karyotype for those diagnosed postnatally. Dashed vertical lines represent the median age at diagnosis. Plot excludes one outlier diagnosed with 45,X/46,XX at 30 years of age.
Figure 2.
Figure 2.
Reasons for Postnatal Diagnosis between Karyotype Groups. Percent represents the % indicated to receive genetic getting due to these outcomes, not the prevalence of the outcome in the sample
Figure 3.
Figure 3.
Medical Outcomes between Karyotype Groups for variables with significant difference in prevalence (p < 0.05) compared to 45,X/47,XXX
Figure 4.
Figure 4.
Odds of experiencing medical outcomes between Karyotype Groups with 45,X as the reference. Only variables with significant difference (p < 0.05) in either 45,X/46,XX or 45,X/47,XXX compared to 45,X are shown.
Figure 5.
Figure 5.
Odds of neurodevelopmental and psychological diagnoses between Karyotype Groups with 45,X as the reference. Only variables with significant difference (p < 0.05) in either 45,X/46,XX or 45,X/47,XXX compared to 45,X are shown. No other neurodevelopmental conditions had a significantly different prevalence from 45,X.
Figure 6.
Figure 6.
Density plots of age at thelarche and menarche by karyotype group. Dashed vertical lines represent the median age thelarche and menarche.
See this image and copyright information in PMC

References

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