Lymphedema, Low-grade Inflammation and the Vasculature in Turner Syndrome

Background:

Patients with Turner syndrome (TS) are at risk of many complications during childhood, adolescence, and adulthood, including reduced final height, estrogen deficiency, infertility, lymphedema, ischemic heart disease, aortic dilation and dissection, congenital heart defect, hypertension, stroke, and autoimmune diseases in general.

The aim of this study is to evaluate the lymphatic and cardiovascular system in a cohort of adult women with TS to elucidate any defects, abnormalities or dysfunctions that may explain the myriad of complications related to TS.

Hypotheses:

1. Both the lymphatic and cardiovascular system are affected in TS with alterations in both anatomy, flow, and function. 2. Changes in the lymphatic system are more prevalent than previously assumed, affecting both central and peripheral lymphatic vessels. 3. Changes in lymphatic transportation and development of cardiovascular malformations occur simultaneously in early fetal life, thus disease in either system may interplay with malfunctions in the other. 4. The vascular structure in both lymph- and cardiovascular tissue is affected throughout the body and low-grade inflammation could be a possible factor in this pathogenesis in TS. 5. Changes in the vascular structure affects flow through the systems resulting in increased stress point on vessel walls leading to a possible entry site for a dissection which can be detected through flow analyses. 6. Genomic examination of multiple tissues will help in understanding the underlying genomic background for the congenital malformations seen in TS

Design:

100 women with karyotype verified TS, previously examined at 4 study visits during a 19-year period will be asked to participate in a 5th study visit. Healthy age-matched females will be included as controls in a ratio 2:1.

The lymphatic system will be examined using three different techniques to assess changes in both anatomy and function.

1. The investigators will use Near infrared light to evaluate the lymphatic system and grade dysfunction and detect subclinical lymphedema. Indocyanine Green will be injected subcutaneously in the foot and hand and used to assess the flow 5-60 minutes after injection. 2. A novel MRI technique to illustrate slow moving fluids, thus visualizing lymphatic fluid, will be used to display the contrast between fluids and tissue to view the thoracic duct and more peripheral lymphatic vessels and quantify their function, abnormalities and morphology. 3. A DEXA scan will be performed to calculate and differentiate between subdermal fat and lymphatic drainage or edema.

To evaluate the cardiovascular system, the investigators will use MRI of the heart and aorta to asses both function and morphology to calculate, among others, mean cardiac output, stroke volume, ejection fraction and asses myocardial fibrosis. A novel technique is to use a PET-CT, as this has been associated with atherosclerosis, because it can visualize macrophage rich atherosclerotic plaques and thus detect otherwise undetectable low-grade inflammation and disease in the cardiovascular system which may contribute to the development of cardiovascular complications.

The investigators will also evaluate the flow in the aorta using 4D-flow measurements based on customized MRI protocols to evaluate stress on the aortic wall and analyze the risk of aortic wall rupture and dissection. The potential of this analysis is the possibility to identify patients at high risk and need for medical or surgical intervention at an early stage and thus prevent or minimize this acute life-threatening complication to TS.

Genomic studies: Samples will be taken from multiple tissues (Blood, fat, muscle, skin, buccal swaps, urine) and DNA and RNA will be isolated using standard methodology.

• MRI evaluation and description of vascular abnormalities in Turner Syndrome [Срок оценки: 3 years]
• Cardiac MRI to evaluate function [Срок оценки: 3 years]
• Cardiac MRI to evaluate fibrosis of the myocardium [Срок оценки: 3 years]
• Mapping DNA-methylations patterns in multiple tissues [Срок оценки: 3 years]
• Immunologic changes in Turner Syndrome [Срок оценки: 3 years]