Clinical Manifestations of Turner Syndrome: A Review of Congenital Ovarian Hypoplasia Syndrome

Turner syndrome (TS), also known as Congenital ovarian hypoplasia syndrome, occurs when the X chromosome is partially or completely missing in females. Its main clinical manifestations include growth disorders, reproductive system abnormalities, cardiovascular abnormalities, and autoimmune diseases. TS is highly prevalent in China. Timely diagnosis is crucial, and non-invasive prenatal DNA testing can identify TS and other diseases.

Turner's syndrome, or monosomy X, is defined as the total or partial loss of the second sex chromosome. The clinical phenotype is highly variable and includes short stature, gonadal dysgenesis, pterygium colli, cubitus valgus and low hairline. The variable expressivity of height and other physical features may be only partially related to the chromosomal formula. Currently, the delay in the diagnosis of Turner's syndrome remains a problem, as only 15–30% of patients are diagnosed during their first year of life.

Turner syndrome (TS) is a condition among phenotypic females with a karyotype containing one X chromosome and complete or partial absence of the second sex chromosome, associated with one or more typical clinical manifestations of TS, such as short stature, hypergonadotropic hypogonadism, infertility, middle ear infection, congenital malformations, or other frequent occurring stigmata. It was described many years ago by different researchers and it now carries the name of one of these researchers—Henry H. Turner; however, other researchers such as Giovanni Battista Morgagni (1768) and N. A. Shereshevski (1925)in Russia probably also described the syndrome, as did Otto Ullrich in 1938 , when he presented a case that later was shown to have 45,X . Later on the chromosomal background was described by Charles Ford and colleagues.

Turner syndrome results from a deletion or the non-functioning of one X chromosome in females. About half of the population with Turner syndrome have monosomy X (45,XO). The other 50% of the population has a mosaic chromosomal component (45,X with mosaicism). 

Some types of anomalies in the X chromosome that can lead to a nonfunctioning X chromosome are as follows:

# Isochromosome Xq, where there are two copies of the long arm of the chromosome that are connected head-to-head.

# Ring chromosome, where a part of the ends of short and long arms of the X chromosome is missing

# Xp or Xq deletion, where the deletion of part of the short arm of the X chromosome takes place

Epidemiology

As per the literature, Turner syndrome is seen in about 1 in 2000 to 1 in 2500 live female births.  However, the true prevalence remains unknown as many patients with a mild phenotype may remain undiagnosed or are diagnosed late in adulthood.

Pathophysiology

Most instances of Turner syndrome are not inherited. When monosomy X is the cause, the chromosomal abnormality is a random event during the formation of reproductive cells in the person’s parent. An error in cell division is called nondisjunction and can result in reproductive cells with an abnormal number of chromosomes. For example, a sex chromosome can become lost from an egg or a sperm cell due to nondisjunction. If an atypical reproductive cell contributes to the genetic makeup of a child, each cell will possess a single X chromosome, and the other sex chromosome will be missing.

Cardiovascular features

Congenital structural heart diseases affect approximately 40% of TS patients and are an important cause of early mortality. These anomalies include narrowing of the aorta, a bicuspid aortic valve and abnormal pulmonary venous returns. Aortic dilatation occurs in 15–30% of girls with TS and depending on the size, carries a significant risk of dissection. 

Endocrine and reproductive features

A greater susceptibility to endocrine and autoimmune diseases is well-documented in these patients. Thyroid disease has been reported in up to 30%, with hypothyroidism secondary to Hashimoto thyroiditis being the most prevalent affection. Moreover, a pro-atherogenic lipid profile and glucose intolerance with progression to type II diabetes mellitus are also frequent (2–4 times higher risk than the general population), abnormalities which, with a probable intrinsic vasculopathy, explains the high mortality rates by coronary and cerebrovascular diseases.

Morbidity and Mortality

Population-based studies on morbidity and mortality in TS are mainly from 3 European countries—Denmark, Sweden, and Great Britain. Overall mortality is increased across all karyotypes and caused by increases in all causes of death, with cardiovascular disease accounting for the majority (40%) of excess deaths. Females with the karyotype with isochrome Xq appear to be most vulnerable.

Epidemiological estimates concerning the occurrence of psychiatric diagnosis and use of psychotropic medication among women with TS are still partly lacking, but a new Swedish study shows a clearly elevated risk of psychiatric disorders, and especially schizophrenia, eating disorders, and autism spectrum disorders. They also reported a surprising 8-fold increased risk of developmental delay, which was not explained further, but perhaps could be linked to specific karyotypes, for example, the presence of a ring chromosome, which has in previous studies been linked to a severely increased risk of developmental delay.

Therapeutic care

Growth hormone (rhGH) treatment

Short stature affects about 95% of patients, with adult heights spontaneously reaching values about 20 cm lower than the average for other women of the same ethnic origin and target parental height. The decrease in height velocity is progressive, generally beginning at the age of 18 months.

Prospects for diagnosis and treatment of TS

TS is a rare disease in which all or part of the X chromosome is missing, and patients' growth and lives are heavily affected. Timely diagnosis and treatment is crucial. The incidence of cardiovascular diseases and bone abnormalities in TS is currently being studied. In addition to unusual physical phenotypes, patients with TS exhibit characteristic neurocognitive features that involve deficits in visual spatial processing.

Given trends in biomedical development, the next generation of treatment will be based on stem cells and regenerative medicine. Stem cell research has become an area of interest. Stem cells are cells that have the potential to proliferate, differentiate, and self-renew. Somatic cells are dedifferentiated into pluripotent stem cells by introducing foreign genes, and those stem cells are known as induced pluripotent stem (iPS) cells. The major advantage of iPS cells over embryonic stem (ES) cells is that iPS cells can be derived from a patient's own somatic cells, thus avoiding immunological rejection and ethical issues.