Turner Syndrome: Genotype and Phenotype

This study will examine the clinical and genetic factors related to Turner syndrome, a disorder of the female sex chromosomes. Humans 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 normally have two X chromosomes; however, patients with Turner syndrome have only a single X chromosome or one normal and one defective X chromosome. This abnormality can cause medical problems such as a webbed neck, low-set ears, and heart or kidney defects. It can also cause short stature, lack of sexual development and improperly functioning ovaries. Adult women with Turner syndrome have an increased risk of high blood pressure, diabetes mellitus and osteoporosis. This study will try to identify the genes responsible for the specific medical problems associated with the disorder.

Official Title

Conditions

– Turner’s Syndrome

Study Type

Observational

Study Design

Natural History

Further Details

Females 7 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 comprehensive physical examination, including (with the patient’s permission) photographs of abnormal physical findings to document characteristics of Turner syndrome. Patients will have their body measurements (height, weight, hip and waist) taken and blood drawn for clinical and research purposes. Patients will be given a “metabolic diet,” with meals designed to contain specific amounts of salt and carbohydrate to allow accurate measurements of blood pressure and glucose (sugar) metabolism. Participants will have a 24-hour urine collection for kidney evaluation, electrocardiogram, urinalysis and urine pregnancy test, wrist X-rays, magnetic resonance imaging (MRI) of the heart, computerized tomography (CT) scan of the lower spine to evaluate bone strength, blood pressure measurements, ear and hearing examination, kidney ultrasound, vaginal ultrasound to evaluate the ovaries, heel ultrasound to measure bone thickness. They will also have an oral glucose tolerance test, DEXA scan (a type of X-ray study to measure body fat, muscle and bone thickness), memory and visual-perceptual testing, and a psychosocial evaluation to assess the effects of the disorder on quality of life and social functioning. 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. 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 other tissue sample for genetic study to help understand how and why certain traits of Turner syndrome are expressed. All patients will be invited to participate in a genetic counseling session to discuss their concerns and difficulties related to living with Turner syndrome. Turner Syndrome (TS) is a sporadic disorder affecting approximately 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.

Study Start

Eligibility & Criteria

Genders Eligible for Study: Both Criteria INCLUSION CRITERIA – for TS Subjects:Phenotypic females greater or equal to 7 years of ageEvidence of X-chromosomal abnormalityThose with a karyotype of 45X/46XX must have at least 80% 45X lymphocytes.Euthyroid status documented by normal TSH obtained prior to admission.EXCLUSION CRITERIA – for TS Subjects:Co-existing autosomal defectsPregnancyINCLUSION CRITERIA – for the Parents of TS Subjects (for DNA only):Biological parent of a TS subjectWillingness to participateEXCLUSION CRITERIA – for the Parents of TS Subjects (for DNA only):

Total Enrolment

1200

Contact Details

[1] National Institute of Child Health and Human Development (NICHD) (US)