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Turner Syndrome

  1. Laura L Hall

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005688

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How to Cite

Hall, L. L. 2006. Turner Syndrome. eLS. .

Author Information

  1. Annapolis, Maryland, USA

Publication History

  1. Published Online: 27 JAN 2006

Introduction

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

The disorder Turner syndrome (TS) was named after Henry Turner, who in 1938 was the first person to identify its phenotype in adolescent girls – 8 years after Ullrich characterized the condition in younger girls. Although an estimated 99% of embryos and fetuses with TS are spontaneously miscarried in the early stages of pregnancy, about 1 in every 2000 live female newborns is affected. Many physical malformations are expressed to various degrees in TS, the most common and recognizable features being short stature and stalled reproductive maturation and function. The brain is not spared, as impairments in visuospatial abilities and nonverbal problem solving are often present.

The genetic cause of TS is the complete or partial loss of one of the X chromosomes in all or just a portion of cells, leaving a karyotype of 45,X or 45,X/46,XX or various X-chromosome deletions. Although X-chromosome inactivation (X-inactivation) is a normal epigenetic phenomenon that ensures that males and females experience the same dose of genes located on the X chromosome, not all X-chromosome genes are suppressed in this process; thus, it may be insufficient gene dose and expression, haploinsufficiency, and the escape of some genes from X-inactivation that underpin the pathology of TS. Scientists are probing both the molecular mechanisms of normal X-inactivation and the genes linked to the TS phenotype, including the cognitive traits. See also Chromosome X, and Chromosome X: General Features

X-inactivation

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

The presence of two X chromosomes in females is not correlated with double doses of most X-linked gene products when compared with the presence of a single X chromosome in males. To avoid such genetic overdosing, much of one of the X chromosomes is inactivated with, as Mary Lyon first discovered in 1961, its genes silenced from very early in development. The unique molecular mechanisms of X-inactivation used by mammals are slowly coming into focus. Several regions of the genome, referred to as cis-acting factors when they are on the X chromosome itself and trans-acting factors when they are elsewhere, are involved.

For example, one gene discovered in 1991, called X (inactive)-specific transcript (XIST), is located in a portion of the X chromosome called the X-inactivation center or XIC – a region of the chromosome that is essential for inactivation. XIST does not encode a protein but rather a large untranslated ribonucleic acid (RNA) molecule that functions in silencing the inactivated X chromosome. Other genes on the X chromosome, including X (inactive)- specific transcript, antisense (TSIX), and a trans-acting factor, CCCTC-binding factor (zinc-finger protein) (CTCF), have also been shown to participate in selecting and silencing the inactivated X chromosome in mammals. The elaborate process for X-inactivation shows that normal development and function hinge not only on the right set of genes, but also on the proper dosage of gene product. Relevant to TS is the fact that in normal females some regions of the X chromosome are not inactivated; that is, expression of genes on both copies of the X chromosome occurs and is, in fact, requisite. See also X-chromosome Inactivation, and X-chromosome Inactivation and Disease

Turner Syndrome Karyotype

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

In the late 1950s, the genetic malformation underpinning TS – the absence of one X chromosome in females – was realized. The complete loss of one X chromosome, karyotype 45,X, results in the fully developed syndrome. As often as not, however, the cells of an affected individual vary in their karyotype, showing both 45,X and 46,XX. The latter karyotype is referred to as mosaicism and it actually encompasses an assortment of karyotypes. The percentage of cells and tissues that show the 45,X karyotype in mosaicism can range widely, and different tissues can have different karyotypes. Another karyotype in this genetic family has the deletion of one arm of one X chromosome. In this case, the normal X chromosome will see its arm duplicated. Sometimes the ends of the chromosome may stick together, giving the appearance of a ring (a defect that, unlike TS, is associated with mental retardation). More rarely, individuals with TS may also have a partial Y chromosome present.

Scientists are just beginning to understand specific genes that contribute to TS and the resulting phenotype. It is well established that individuals with the 45,X karyotype generally show most or all of the abnormalities associated with TS, whereas mosaicism gives rise to many fewer and less severe problems. In fact, for mosaicism, correlations between the results of prenatal karyotyping and the degree to which TS pathologies are expressed have not been well documented.

Overview of the Turner Syndrome Phenotype

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

The two prototypic problems associated with TS are short stature and failure to mature and function reproductively.

Girls with TS fall behind in their growth: by the age of 5 or 6 years they generally fall below the third percentile, and ultimately they fail to realize growth spurts that normally occur in adolescence. By adulthood, TS is associated with a 21-cm difference in height, on average, when compared with unaffected women. Women with TS rarely achieve a height above 150 cm (or 5 feet). Researchers are working to identify both the genetic basis for short stature in TS (see below) and its pathophysiology, which seems to relate to bone development. On the treatment side, studies show that high doses of growth hormone over the course of a few years do stimulate growth, especially if started at a relatively young age (8–9 years) and if the artificial prompting of menstruation is delayed.

Typically, TS results in incomplete sexual development and reproductive function. In essence, ovarian senescence is accelerated. Ovarian follicles begin involuting while the female affected with TS is still a fetus, and ovarian failure is completed during their infancy. Menstruation hardly ever commences in individuals with the 45,X karyotype (and only does so in 20–30% of young women who have mosaicism). Even if menarche does occur, an ongoing menstrual cycle is rarely maintained in the 45,X karyotype. Naturally occurring ovulation and fertility are rare. Adult secondary sexual characteristics do not develop and the uterus remains preadolescent in structure.

The sexual and reproductive impairments that are prototypical of TS have increasingly retreated with modern treatments. Currently, the reproductive problems associated with TS are redressed largely with hormone replacement therapy, which also increases height and, over the long term, enhances cardiovascular, bone and other organs' health. In vitro fertilization with donor oocytes has also been successful in women with TS. Replacement estrogen undoubtedly also enhances brain maturation and function.

Other abnormalities associated with TS include congenital lymphedema that leads, for example, to a webbed neck and swollen hands and feet, coarctation of the aorta, abnormal structure and/or location of the kidney. Morbidity in adulthood includes increased risk of various disorders of the bone (e.g. osteoporosis, scoliosis and spinal fractures), endocrine systems (e.g. diabetes and thyroid disease), cardiovascular system (e.g. hypertension), and partial or complete deafness. As a result, life expectancy is reduced in adult women with TS.

Impact on Brain and Behavior

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

The brain is not spared the impact of TS, although the specific impairments and their root causes have proved to be subtle and elusive. Although early studies and lore implied that mental retardation was a correlate of TS, evidence clearly shows that overall intelligence quotient (IQ) is normal or potentially above average in females with TS. But affected individuals often have impairment of specific cognitive abilities, especially visuospatial skills. So whereas verbal and language skills are normal, or even better than normal in some individuals, performance IQ is decreased as are visuomotor skills and attention. Money and Alexander called this deficit ‘space–form blindness’, because identifying positions in space, mentally rotating geometric shapes, drawing geometric shapes and human figures, orienting to left–right directions, and even handwriting are all impaired. Girls with TS tend to have difficulty with mathematics and geography in school.

Beyond these cognitive skills, reports suggest that girls and women with TS may experience greater degrees of hyperactivity and may be more prone to depression and anorexia nervosa. Social and emotional maturity is often delayed and, as a group, women with TS report increased social isolation and lower self-esteem; they are less likely to be married and their professional success tends to be lower than that of their peers. It must be noted, however, that many women with TS go on to achieve personal, social and professional success and fulfillment.

Neuroimaging studies are beginning to identify structural correlates of the neurocognitive impairments in TS. A well-designed study using psychological testing and imaging technology (mass resonance imaging; MRI) did not reveal overall cerebral or subcortical volume differences, but the distribution of gray and white matter was significantly different in both the right and the left parietal regions. Specifically, both the right and the left parietal areas showed smaller total tissue volume ratios, but only the right parietal and occipital regions had a larger proportion of gray and white matter as compared with controls. Functional MRI and positron emission tomography – approaches that measure brain function – have shown that there is overall hypermetabolism in most brain areas but reduced functioning in the right parietal lobe.

The cause of these cognitive, emotional, behavioral and social problems is not clear, nor is it likely to be singular. Undoubtedly nature and nurture are interlocked in their contributions. Girls with TS are small and their sexual maturation does not occur on its own. The impact of social responses to these features (on the part of parents, educators, peers and others in the community) and the influence of sexual steroids (or the lack thereof) on the development and function of the brain are likely to contribute significantly. There might be also direct genetic effects on the structure and function of the brain, possibilities of which are discussed below.

Potential Genetic Mechanisms

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links

Because of the various phenotypic expressions of TS, several genes are thought to be involved. Short stature has been associated with haploinsufficiency of an X-chromosome region that escapes inactivation – the location of the short stature homeobox (SHOX) gene. The SHOX gene is expressed primarily in the limbs during development, and defects of this gene have been linked to short stature in various conditions. This gene is therefore a strong candidate for involvement in TS, although it is unlikely to explain fully the reduced growth.

Another candidate gene has been identified for the reproductive failure seen in TS. The gene D1APH2, a human homolog of a fruitfly gene involved in oogenesis, is known to escape X-inactivation and its location has been implicated in ovarian failure. But as with SHOX, it seems likely that other genes will be involved.

Insofar as the cognitive deficits are concerned, deletions on the X chromosome, where genes escaping inactivation are presumably located, have been linked to neurocognitive deficits similar to those seen in TS. Specifically, individuals missing only a small interval at the distal tip of Xp manifest TS-like impairments in neurocognition. Data from another study, as yet unreplicated, suggest that genomic imprinting may be involved in TS. In that study, girls with TS who had an X chromosome of paternal origin showed normal aspects of cognitive function as compared with those with an X chromosome of maternal origin. But, as noted above, this study has not been replicated and therefore has caused some controversy in the field. Much remains to be learned about the specific genetic and molecular mechanisms that underpin TS, as well as the kinds of interventions that can help girls and women with this genetic disorder to lead as healthy a life as possible.

Further Reading

  1. Top of page
  2. Introduction
  3. X-inactivation
  4. Turner Syndrome Karyotype
  5. Overview of the Turner Syndrome Phenotype
  6. Impact on Brain and Behavior
  7. Potential Genetic Mechanisms
  8. see also
  9. Further Reading
  10. Web Links