Hepatic abnormalities in youth with Turner syndrome.

BACKGROUND & AIMS: Liver disease in children with Turner Syndrome (TS) is poorly understood relative to associated growth, cardiac and reproductive complications. This study sought to better characterize hepatic abnormalities in a large national cohort of youth with TS. METHODS: Using electronic health record data from PEDSnet institutions, 2145 females with TS were matched to 8580 females without TS on eight demographic variables. Outcomes included liver enzymes (AST and ALT) stratified as normal, 1-2 times above the upper limit of normal (ULN), 2-3 times ULN and >3 times ULN, as well as specific liver disease diagnoses. RESULTS: Fifty-eight percent of youth with TS had elevated liver enzymes. Patients with TS had higher odds of enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), 2-3 times ULN (OR: 2.7, 95% CI: 1.7-3.3) and >3 times ULN (OR: 1.7, 95% CI: 1.3-2.2). They also had higher odds of any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0) and liver tumour/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In a multinomial model, age, BMI and presence of cardiovascular disease or diabetes significantly increased the odds of elevated liver enzymes in girls with TS. CONCLUSIONS: Youth with TS have higher odds for elevated liver enzymes and clinically significant liver disease compared with matched controls. These results emphasize the need for clinical screening and additional research into the aetiology and treatment of liver disease in TS. LAY SUMMARY: Turner Syndrome, a chromosomal condition in which females are missing the second sex chromosome, is often associated with short stature, infertility and cardiac complications. Liver abnormalities are less well described in the literature. In this study, nearly 60% of youth with TS have elevated liver enzymes. Furthermore, patients with TS had a diagnosis of liver disease more often than patients without TS. Our results support the importance of early and consistent liver function screening and of additional research to define mechanisms that disrupt liver function in paediatric TS females.

Outcomes in hospitalisations of women with Turner syndrome compared to women without Turner syndrome.

OBJECTIVE: To evaluate outcomes in patients with Turner Syndrome, especially those with cardiac conditions, compared to those without Turner syndrome. DESIGN: Retrospective cohort study utilising hospitalisation data from 2006 to 2012. Conditional logistic regression models are used to analyse outcomes of interest: all-cause mortality, increased length of stay, and discharge to home. PARTICIPANTS: We identified 2978 women with Turner syndrome, matched to 11,912 controls by primary diagnosis. RESULTS: Patients with Turner syndrome were more likely to experience inpatient mortality (odds ratio 1.44, 95% confidence interval 1.02-2.02, p = 0.04) and increased length of stay (OR 1.31, CI 1.18-1.46, p = 0.03) than primary diagnosis matched controls, after adjusting for age, race, insurance status, and Charlson comorbidity index. Patients with Turner syndrome were 32% less likely to be discharged to home (OR 0.68, CI 0.60-0.78, p < 0.001). When restricting the sample of patients to those admitted with a cardiac diagnosis, the likelihood of mortality (OR 3.10, CI 1.27-7.57, p = 0.01) and prolonged length of stay (OR 1.42, CI 1.03-1.95, p = 0.03) further increased, while the likelihood of discharge to home further decreased (OR 0.55, CI 0.38-0.80, p = 0.001) in Turner syndrome compared to primary diagnosis matched controls. Specifically, patients with congenital heart disease were more likely to have prolonged length of stay (OR: 1.53, CI 1.18-2.00, p = 0.002), but not increased mortality or decreased discharge to home. CONCLUSIONS: Hospitalised women with Turner syndrome carry a higher risk of adverse outcomes even when presenting otherwise similarly as controls, an important consideration for those treating them in these settings.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors - ZFX and ZFY - encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.

Further Delineation of Liver Involvement in Girls and Women with Turner Syndrome: Case Report of a 2-Year-Old with Liver Dysfunction and Review of Patients Followed in the MassGeneral Hospital Turner Syndrome Clinic.

BACKGROUND: Liver function test (LFT) abnormalities, which may reflect underlying pathophysiology, are a well-known feature of Turner syndrome. Less frequently, liver findings may include vascular changes and, rarely, severe liver disease. Although previous studies on children and adolescents suggest a frequency of LFT abnormalities of up to 60%, less is known about the age at onset and natural history. METHODS: We report a now 19-year-old young woman with Turner syndrome mosaicism with elevated transaminase levels first detected at the age of 2 years. We also present a retrospective analysis of 179 girls and women followed in the MassGeneral Hospital Turner Syndrome Clinic. RESULTS: In the index case, the severity of liver function test abnormalities fluctuated without complete resolution from 2 to 18 years of age. In the full cohort of 179 patients, when lab results were available, elevated ALT levels occurred in 16 (11%) subjects of all ages, and in 5 (10%) patients ≤18 years of age. Significant and persistent ALT elevations occurred in 2 patients <10 years of age. CONCLUSION: The updated Clinical Practice Guidelines for the care of girls and women with Turner syndrome recommend annual liver function tests throughout the lifespan, starting at the age of 10 years. Based on our data showing persistent elevation of at least one liver enzyme, we recommend a prospective and more comprehensive study of liver function in younger patients with Turner syndrome. An improved estimate of prevalence could better inform age-adjusted guidelines.