Turner Syndrome: Genotype and Phenotype
Turner Syndrome: Genotype and Phenotype
This study examines the clinical and genetic factors related to Turner syndrome, a disorder
 of the sex chromosomes. Humans usually have 23 pairs of chromosomes-thin strands of DNA-in
 the nucleus of every cell, which contain genes that determine our hereditary makeup. One pair
 of chromosomes is the sex chromosomes, designated X and Y. Females usually have two X
 chromosomes; however, patients with Turner syndrome have only a single X chromosome or one
 normal and one defective X or Y chromosome. This abnormality can cause medical problems such
 as short stature, premature ovarian failure and heart or kidney defects. Individuals with
 Turner syndrome have an increased risk of thyroid disorders, high blood pressure, diabetes
 mellitus, abnormal liver function, hearing loss and osteoporosis. This study will try to
 identify the genes responsible for the specific medical problems associated with the
 disorder.

 Females 10 years of age and older with X chromosome defects may be eligible for this 3- to 5-
 day inpatient study at the National Institutes of Health Clinical Center in Bethesda,
 Maryland. Participants will have a physical examination, body measurements (height, weight,
 hip and waist) and blood drawn for clinical and research purposes.

 Participants will have a comprehensive cardiovascular evaluation, including an
 electrocardiogram (ECG), 24 hour blood pressure monitoring, magnetic resonance imaging (MRI)
 of the heart and aorta, ultrasound imaging of the heart (cardiac echo) and expert
 consultation with the NIH Cardiology Service. Women 35 years of age and older may have a
 computerized tomography (CT) scan of the coronary arteries to investigate possible blockage
 of the heart blood supply.

 Risk for diabetes is investigated by studies of the body fat content and an oral glucose
 tolerance test. The risk for coronary artery disease is assessed by measurement of
 cholesterol and other known risk factors in the blood. Thyroid function and presence of
 antibodies to the thyroid gland are also evaluated by blood tests.

 Liver function is tested by measurement of products of liver metabolism in the blood and by a
 liver ultrasound. Ovary function is investigated by blood tests of estrogen and FSH levels
 and pelvic untrasound which visualizes the uterus.

 Bone structure and strength are evaluated by routine X-rays of the wrists and spine, and DEXA
 scan (a type of X-ray study that measures body fat, muscle and bone thickness). Adults will
 also have bone density of the spine and abdominal fat content measured by CT, which is more
 accurate than DEXA. Vitamin D levels are measured in blood tests.These are state of the art
 diagnostic tests which may uncover unsuspected anatomic problems such as abnormalities of the
 aorta or aortic valve which have serious clinical implications and would indicate the need
 for close medical follow-up, as well as uncover potential risk for development of diabetes or
 osteoporosis in the future, which would also indicate the need for changes in lifestyle or
 medical management. Study participants are invited to return for re-evaluation at 1-3 year
 intervals. A major goal of follow-up visits is to determine whether there is any enlargement
 of aortic diameter or impairment of cardiac function over time.

 Some patients may be asked to undergo a skin biopsy (removal of a small sample of skin
 tissue) to obtain more information about genetic make-up of cells. Parents of patients may be
 contacted (with the patient's permission) to provide a blood or saliva sample for genetic
 study to help understand how and why certain traits of Turner syndrome are expressed.
Turner syndrome (TS) is a sporadic disorder affecting ~ 1/2500 live female births. It is
 caused by the absence of all or significant parts of one sex-chromosome. Major developmental
 consequences include severe short stature, ovarian failure and distinctive cognitive and
 behavioral traits, with renal and cardiovascular defects affecting a minority. Adults with TS
 have excessive rates of osteoporosis, hypertension and diabetes mellitus and experience
 morbidity and mortality several-fold higher than the general population. Many of the problems
 of TS result from haplo-insufficiency for X-chromosome encoded genes, most of which remain
 unknown. Previous studies attempting to correlate genotype with phenotype in TS have been
 limited due to small numbers of subjects, limited genetic methodology and incomplete
 phenotypic characterization. This study aims to correlate TS phenotypes and genotypes using
 advanced clinical and genetic diagnostic methodologies, with the goal of identifying
 X-chromosome genes and epigenetic mechanisms causing the different features of TS. For TS
 subjects with a 45X genotype, the parental origin of the single normal X-chromosome will be
 traced to identify genomically imprinted features of the disorder. X chromosomal structural
 defects will be analyzed using high-resolution physical mapping in relation to emerging
 sequence data from the Human Genome Project. The elucidation of genetic mechanisms in TS will
 help improve the diagnosis and treatment of girls and women with this disorder and will
 further our understanding of gene dosage effects in general.
-  INCLUSION CRITERIA - for TS Subjects:

 Phenotypic females greater than or equal to 10 years of age

 Evidence of X-chromosomal abnormality

 Those with a karyotype of 45X/46XX must have at least 80% 45X lymphocytes.

 EXCLUSION CRITERIA - for TS Subjects:

 Co-existing autosomal defects

 Pregnancy

 INCLUSION CRITERIA - for the Parents of TS Subjects (for DNA only):

 Biological parent of a TS subject

 Willingness to participate

 EXCLUSION CRITERIA - for the Parents of TS Subjects (for DNA only):

 None