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Turner Syndrome (Nidhi Ravishankar)

= From Neurogenetic Diseases =

Turner Syndrome (TS) is a genetic disorder in which all or some part of the X-chromosome is absent (also falling under neurogenetic diseases). The disorder affects approximately 1 out of every 1900 female live births worldwide. Since Turner syndrome features vary considerably among individuals, identifying the genetic basis may give us some insight into differentiating between the broad spectrums. Currently, the impaired visual-spatial abilities characteristic of Turner’s syndrome individuals is reported to have resulted from the happloinsufficiency of one or more genes of the distal part of Xp (1) chromosome. Turner’s syndrome individuals also have significant differences in brain structure and anatomy than “normal individuals.” These include changes in temporal, intraparietal regions and other regions involved in spatial, social and numerical cognition (2) that are highly consistent with the hallmark symptoms associated with Turner’s. Since the presentation of Turner’s varies throughout the patient’s life, diagnostic methods are performed during various stages. Because Turner Syndrome is a chromosomal condition, there is no said cure for the disorder but therapeutic approaches are taken to minimize the effects of the symptoms.

**Contents**
1 Symptoms 1.1 Cognitive 1.2 Psychological 1.3 Other 2 Genetic Mechanism 2.1 The function and background of Xp 2.2 Mutations in Xp 3 Brain anatomical differences 3.1 Structural differences of Turners Syndrome vs. normal leading to Turner’s characterstics 4 Diagnosis, treatment 4.1 Methods of diagnosis 4.2 Treatment 5 See also 6 References 

=Symptoms=

As with any genetic disease, Turner Syndrome can cause a wide array of symptoms from minor cosmetic issues to premature ovarian failure. The most well defined symptoms of Turner syndrome stem from a neurological background, affecting cognition and having psychological effects. Other physical symptoms are also prevalent. 

Cognitive
Turner Syndrome is associated with many neurocognitive phenotypes including impaired visual and spatial abilities, executive and social functions. Visual-spatial ability is an essential brain function that enables one to select and process information with their visual field correlated with space. Visual-spatial intelligence is used when drawing pictures to express thought or emotion, decoding maps, constructing three-dimensional products and completing figures. Turners’ syndrome individuals however perform significantly lower in tests involving visual-spatial skills than controls, indicated through 50 years of Turner’s syndrome research (**Table 1**) as constructed by Hong, Kent and Kesler (3).

Tests Demonstrating Significantly Lower and/or Impaired Neuropsychological Performance in Females with TS. Copyright 2009. Hong, D., Kent, J.S. Kesler, S. Cognitive Profile of Turner Syndrome. //Dev Disabil Res Rev.// **15 (4),** 270-278 (2009).
 * ** Reference ** || ** Test/Index Name ** || ** Test Domain(s) ** ||
 * Shaffer, 1962 || Verbal IQ (VIQ) [|a] > Performance IQ (PIQ) [|a], Freedom from Distractibility (FFD) [|a] , Perceptual Organization Index (POI) [|a] , Benton Visual Retention Test  || Perceptual reasoning (+ processing speed, motor skills), attention, working memory, processing speed, visual–spatial processing, visual memory ||
 * Alexander et al., 1966 || Benton Visual Retention Test, Benton Visual Motor Gestalt Test, Draw a Person Test || Visual memory, space-form perception and orientation, visuoconstructive recognition, and performance ||
 * Waber, 1979 || FSIQ [|a] and VIQ [|a], Digit Span (backward) [|a] , FFD [|a] , Stroop, Word Fluency, Wisconsin Card Sorting Test (WCST), Rey Osterrieth Complex Figure (ROCF), Faces Upright, Consonant Tri-gram Visual, Roadmap Test, R-L Orientation, Finger Tapping  || General cognitive ability, verbal comprehension, working memory, response inhibition, processing speed, attention, verbal fluency, mental flexibility/switching, visual–spatial/construction/organization, L/R perception, fine motor coordination and speed ||
 * McCauley et al., 1987 || PIQ [|a], Arithmetic [|a] , Digit Span [|a] , Object Assembly [|a] , Picture Completion [|a] , VMI  || Perceptual reasoning, processing speed, working memory, motor skills, serial/sequential order, visuomotor skills ||
 * Swillen et al., 1993 || PIQ [|a], Object Assembly [|a] , Block Design [|a] || Perceptual reasoning, visuospatial reasoning/processing ||
 * Murphy et al., 1994 || FSIQ [|a], PIQ [|a] , VIQ > PIQ [|a] , POI [|a] , Stroop, Trails B, Wechsler Memory Scale, Category Naming, Ravens Progressive Matrices, Hiskey Nebraska Blocks, Extended Range Drawing, Block Tapping  || General cognitive ability, perceptual reasoning, short- and long-term verbal and visual memory, attention, visual–spatial reasoning/processing, response inhibition, visual tracking, switching, processing speed ||
 * Temple and Carney, 1995 || Street Task, Object Assembly, Draw-a-Man, Draw-a-Bicycle || Visual perceptive, visual constructive, visuomotor ||
 * Loesch et al., 2005 || VIQ[|a], JLO, Woodcock-Johnson (Numbers Reversed), Wechsler Memory Scale (Spatial span reversed) || Verbal ability, spatial orientation, working memory ||
 * Table 1 **

In addition, ** Table 1 ** also indicates low performance by TS individuals on tasks involving executive function such as processing speed, working memory, abstract reasoning, organization and mental flexibility as indicated through the Wisconsin Card Sorting Test (WCST), Contingency Naming Test (CNT), Raven’s Progressive Matrices (RPM) and also the Rey Osterrieth Complex Figure (ROCF) test. Several studies also suggest atypical social cognition in TS individuals as determined by the Benton Facial Recognition Task and face matching tasks with the inability to recognize emotions and expressions (4, 5). Studies involving directional eye gazing which represents social cues and joint attention (6, 7) were also atypical of Turners individuals, but Lawrence suggests that this could simply be influenced by the visual-spatial process underlying the task (5). Because of the high degree of overlap between visual-spatial, executive and social cognitive deficits, an impairment in one usually shows impairment in others.

Psychological
Though the studies involving cognitive impairments are prevalent in Turners syndrome, psychological function remains an area of limited research (as opposed to other genetic disorders such as Wilson's disease that have widespread psychological symptoms ). Many atypical psychological functioning of Turners is associated with other clinical features of Turners. For example, Hong and colleagues noted higher anxiety, depression, shyness and lower self-esteem with Turners individuals due to the concern of infertility (8). Many females reported that their infertility had a significant impact on any romantic relationships, in addition to suffering from depression knowing that they will never bear children (9). Another interesting finding was the impact the Turners characteristic short stature had on individuals. There was a deep psychological disturbance for individuals because of the years of teasing which reduced their trust and dependence on other people, as well as their concern that men will not view them as viable dating partners (9). A recent study by Suzigan et. al compared results of Turner’s affected women with their unaffected sisters and evaluated their performance (10). In contrast to earlier evidence, Suzigan et. al evaluated girls with Turners using Del-Prette Social Skills Inventory (SSI) which are individual interviews and found their performance to be just as good as their unaffected sisters. They found that social difficulties may not cause major problems for Turners individuals, or it may be an indicator that they have a tendency to not perceive their own difficulties. The authors report that the reason TS girls are socially isolated may be because of other factors like anxiety and/or shyness or that they are simply answering the questions in ways which they deem socially acceptable.

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Other


Along with neurologic impairments in TS, the most avid indicator of the disorder is the physical abnormalities. Present in all stages of life, the most obvious indicators for infants include small size, puffy hands and feet and webbed neck and fingers. From early childhood to teenage years, Turners individuals possess very short stature, hearing problems and early loss of ovarian function (**Figure 1**). Many girls receive [|hormone therapy] in order to promote ovarian function but are still unable or rarely conceive during maturity. During adulthood, individuals experience heart and lung problems in addition to the aforementioned. There is however a great degree of variability in the degree to which TS individuals are affected by the manifestations.



Genetic Mechanism
As a genetic disorder, the genetic underlying of Turner syndrome is important to determine the cause of the disorder. It affects mainly females and arises from the complete absence or mutation in the X chromosome material, mostly on one of the two sets of X chromosomes.

**Figure 2** Slot blot, hybridized with XIST cDNA probe isolated from human cell lines or mouse-human cell hybrids showing active or inactive X chromosome; probe only hybridized to samples that contain an inactive X chromosome. Copyright 1991 Nature Publishing Group. Brown, C. J. et al, Nature 349, 38-44 (1991)



The Function and background of Xp
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The X chromosome is one of the two sex chromosomes in an animal species (other being Y). Each cell contains 23 pairs of chromosomes and the sex chromosome forms one of these pairs. Females have two X chromosomes, while males have one X and one Y chromosome. Early in female embryonic develo- pment, one of the X chromosomes is inactivated or silenced individually in each cell by //XIST// (**Figure 2**) at the XIC (X-inactivation centre a newly acquired regulatory genetic element). This is to ensure that both male and female have one working X chromosome and females do not get a toxic double dosage of X-linked genes. The X chromosome is then reactivated during blastocyst stage (**Figure 3**) and then re-inactivated. Though no explicit reason is given for this activation and inactivation, one hypothesis suggests that reactivation reduces burden of having all X-chromosome gene expression on the other X (11). There are many genes contained within the X chromosome, particularly in the short arm of the chromosome, including those for height, neurocognition and sexual maturity.

A large body of data indicates that most Turner Syndrome symptoms arise due to the reduced genes in the short arm of the X chromosome (Xp). [|Phenotypic mapping] and [|mutational analysis]now makes it possible to assess how individual genes give rise to the Turner Syndome phenotype. **Figure 4** shows the specific genes in the short arm of the X chromosome that may contribute to TS characteristics as shown by Zinn et.al. 

Mutations in Xp
Another study conducted by Zinn et. al suggests that Xp22.3 contains one or more genes that influence the cognitive ability in Turner’s individuals (1). This region contains 31 marked genes and //STS// and //NLGN4X// were highlighted as strong candidates. The mean TSCS (Turner Syndrome Cognitive Summary) for 28 women differed greatly from controls and from women with Xq deletions (another short arm) proving that Xp was indeed involved with Turner’s cognitive profile. Zinn et. al report deletions in this region to affect visual–spatial skills, working memory, attention-impulse control, and executive function reported in Turner syndrome. The regions restricted to Xp22.3 deletions (<Xp22.3) are shown here to be very similar to those with 45, X Turners (**Table 2**) supporting the conclusion that Xp22.3 may be sufficient to affect Turner’s cognition. with specific X chromosome abnormality. Copyright 2007. Zinn, A.R., et al. A Turner syndrome neurocognitive phenotype maps to Xp22.3//.// //Behavioral and Brain Functions// **3,** 1-14 (2007).
 * || **n** || **Age, yr** || **Height SD score** || **TSCS score** ||
 * 45, X TS || 127 || 33.0 ± 10.4 || -2.7 ± 1.1 || 58.3 ± 17.5 ||
 * controls || 104 || 29.8 ± 9.7 || 0.1 ± 1.0 || 68.7 ± 17.5 ||
 * Xp deletion || 28 || 34.1 ± 10.7 || -2.1 ± 1.1 || 53.1 ± 20.8 ||
 * Xp22.3 || 13 || 31.7 ± 12.2 || -2.5 ± 1.0 || 51.3 ± 20.2 ||
 * Xq deletion || 19 || 32.4 ± 8.3 || -0.2 ± 1.9 || 68.7 ± 20.4 ||
 * //SHOX// point mutations || 7 || 42.7 ± 20.2 || -2.7 ± 1.6 || 67.0 ± 11.5 ||
 * Table 2** Mean age, height standard deviation, TSCS score of subject grouped

//STS,// or the steroid sufatase gene, encodes proteins that convert sulfated steroid precursors into estrogen during pregnancy (12). Mutations in this gene are known as X-linked ichthyosis and are reported to have reduced visuo-spatial attention in mice (13) and possible analogous neurocognitive deficits in humans with Turners.

//NLGN4X//, also in this region, encodes a neural cell adhesion molecule that serves as organizing and remodelling the central nervous system synapses (14). Mutations in this gene are linked to autism spectrum disorders, but recent evidence suggests no link between autistic features and Turner’s. Earlier studies report that it may be because of the increased risk of social problems that cause the cognitive impairments in Turner’s individuals (14).

//SHOX ,//known as the short stature homeobox, was recently identified as a non-growth hormone gene causing short stature (15). Since //SHOX is// expressed in the middle protion of the limb, knee and elbow, mutation or absence in this gene on the X chromosome is shown to produce the characteristic short arms and lower legs reported in Turners. The authors also suggested the lack of expression of //SHOX// in the 1nd and 2rd pharyngeal arches forming the external auditory meatus to produce early hearing loss observed in individuals with Turners.

Recent evidence also reported that visuo-perceptual impairments of Turners may be influenced by genetic imprinting (16). The authors reported those with defects in Xmat chromosome scored lower on the **Perceptual Reasoning Index** than the Xpat chromosome. This study was small however and did not yield sufficient results to draw a generalized conclusion.

Investigation into the genetic mechanism of TS identifies new ways to counteract effects of the disease pathways, enhance health-promoting pathways and to better understand the mechanisms of Turners so that new treatment approaches and preventative measures can be proposed. 

Brain Anatomical Differences


After years of research, characteristic Turners cognitive impairments such as visuo-spatial skills, executive function and higher-order functioning are thought to be linked to the morphological differences in brain structure (17-19). Changes in parietal lobe, amygdala and hippocampus are only a few structures in which consequences of Turner’s characteristics areseen. Using univariate whole brain MRI, studies displayed significant reduction in grey matter volume of parietal lobules, pre-central gyrus, post-central gyrus and temporal region and of TS individuals when compared to controls (**Figure 5**) as shown by Marzelli et. al. Parietal regions are associated with visuospatial attention as well as visual memory (20) and reduction in the parietal lobules gives evidence of deficits in these regions seen in TS individuals. Additional neuroimaging studies also suggest that impairments in executive function are also related to frontal-parietal region (3). The grey matter volume reductions in the two gyri, which are responsible for motor and sensory inputs (21), may correlate to the motor and sensory impairments in TS. The morphological changes in the temporal region provide further evidence of reduced spatial ability of TS. Reduced spatiotemporal resolution also suggested deficits in higher-order functioning such as arithmetic (22). Morphological differences have also been prevalent with psychological impairments in TS. Emotion recognition and gaze perception are also thought to be impaired in Turner Syndrome. Amygdala, the structure responsible for conditioned emotional responses and perception of emotion expressions especially fear, is another structure to focus in TS. The neuroanatomical abnormalities of amygdala indicate a psychological dysfunction in emotional regulation and face recognition especially fear (23, 24). Since individuals with Turners have also been identified as having more social anxiety than controls (25), studies suggest bilateral amygdala lesions in monkeys cause inability of emotional responses to previously feared stimuli, indicating that an enlarged or hyperactive amygdala may lead to social anxiety (26,27).

Significantly reduced grey and white matter volumes in the hippocampus also contributed to memory and spatial deficits of TS individuals (27). The hippocampus is a structure responsible for consolidation of memory, as well as recognizing spatial patterns as seen through the Morris Water Maze and Radial Arm Maze. The reduced hippocampal size is observed in the majority of TS individuals when compared with controls (**Table 3**). Because direct projections travel from the primate amygdala to the ipsilateral hippocampus (28), there may be an influence of the amygdala on the hippocampus. The enlarged left amygdala may affect the ipsilateral, left hippocampus and together construct the cognitive and psychosocial profile of Turner Syndrome.

Ultimately, understanding brain structure, anatomy and function will lead to better treatment approaches for TS.

= 347) //P// = 0.18 || gray and white matter volumes of HIP is seen in the TS individuals.
 * >  ||> TS ||> CON ||> Wilks’ lambda ||> Omnibus //P//-value ||> ANOVA //P//-value ||
 * > Total cerebral tissue ||> 1036 (96) ||> 1077 (83) ||>  ||>   ||> (//U//
 * > Total amygdala & hippocampal tissue ||>  ||>   ||> 0.65 ||> 0.000 ||>   ||
 * > Amygdala & hippocampal tissue specific (gray/white) ||>  ||>   ||> 0.74 ||> 0.003 ||>   ||
 * > Left AMYG ||> 2.4 (0.48) ||> 2.1 (0.34) ||>  ||>   ||> 0.001 ||
 * > Gray ||> 2.2 (0.44) ||> 1.9 (0.32) ||>  ||>   ||> 0.000 ||
 * > White ||> 0.23 (0.09) ||> 0.20 (0.08) ||>  ||>   ||> 0.24 ||
 * > Right AMYG ||> 2.3 (0.70) ||> 2.1 (0.51) ||>  ||>   ||> 0.17 ||
 * > Gray ||> 2.1 (0.63) ||> 1.8 (0.47) ||>  ||>   ||> 0.15 ||
 * > White ||> 0.24 (0.14) ||> 0.23 (0.09) ||>  ||>   ||> 0.71 ||
 * > ** Left HIP ** ||> ** 2.7 (0.52) ** ||> ** 2.9 (0.56) ** ||>  ||>   ||> ** 0.22 ** ||
 * > ** Gray ** ||> ** 2.4 (0.46) ** ||> ** 2.6 (0.47) ** ||>  ||>   ||> ** 0.27 ** ||
 * > ** White ** ||> ** 0.29 (0.13) ** ||> ** 0.32 (0.11) ** ||>  ||>   ||> ** 0.26 ** ||
 * > ** Right HIP ** ||> ** 2.7 (0.50) ** ||> ** 3.1 (0.54) ** ||>  ||>   ||> ** 0.008 ** ||
 * > ** Gray ** ||> ** 2.5 (0.46) ** ||> ** 2.8 (0.45) ** ||>  ||>   ||> ** 0.01 ** ||
 * > ** White ** ||> ** 0.28 (0.11) ** ||> ** 0.36 (0.13) ** ||>  ||>   ||> ** 0.02 ** ||
 * Table 3** Hippocampal volumes (HIP) of TS individuals is compared to controls (CON) and a reduction in both

Copyright 2004. Kesler, S.R. et. al. Amygdala and hippocampal volumes in Turner syndrome: a high-resolution MRI study of X-monosomy. //Neuropsychologia// **42 (14)**, 1971-1978 (2004).

Diagnosis
Because Turner Syndrome is presented with certain characteristic features, diagnosis of the condition can be observed easily. The diagnosis can then be confirmed using standard karyotpying (29). Standard karyotyping allows for chromosomal analysis of 30 peripheral lymphocytes, and those with Turner syndrome will present with a missing X chromosome in all cells (45, X) or a combination of cells (45, X/46,XX; mosaic Turner syndrome) (**Figure 6** ) as shown by Morgan. In standard karyotpying, a sample of the whole blood is attained and subsequent steps allow it to be stained and observe the chromosomes. This method is recommended for girls with unexplained short stature (more than two standard deviations lower than the mean height for that age) (30, 31). Along with an abnormal or missing X chromosome, standard karyotyping has also identified mosaicism of normal or abnormal Y chromosome in 6%-11% patients with TS (32). The presence of Y chromosome in females with Turner syndrome is important because of the risk of gonadoblastoma (33). A gonadoblastoma-suscepbitility locus has been proposed in the Y chromosome which can progress to dysgerminoma with metastatic potential. Thus, early detection of this condition is necessary for a good prognosis

Despite excellent prenatal diagnosis, 99% of Turner-syndrome conceptions are thought to end in still-birth or spontaneous abortion (34). Specific ultrasound signs like nuchal translucency, cystic hygroma, coarctation of the aorta and/or other left-sided heart defects, brachycephaly, renal anomalies, polyhydramnios, oligohydramnios, and growth retardation are seen in fetuses with Turner Syndrome. Abnormal prenatal serum marker screening results with elevated levels of human chorionic gonadotropin and inhibin and slightly decreased levels of alpha fetoprotein and unconjugated estriol are associated with an increased likelihood of a Turner syndrome diagnosis (32) (**Figure 7**). Prenatal testing is then followed by standard karytoype to confirm TS. If blood karytoyping fails to confirm presence of TS, analysis buccal or skin cells can be conducted.

During pregnancy, amniocentesis or chronic villi sampling can also be used to diagnose TS (35).

media type="youtube" key="bZcGpjyOXt0" width="235" height="221"Amniocentesis is a common procedure conducted to diagnose many chromosomal disorders including Down’s syndrome, [|Edward’s Syndrome] and Turner Syndrome. It is carried out through the insertion of a needle into the amniotic sac of the mother and extraction of amniotic fluid, guided by ultrasound. The fetal cells are then extracted from the sample, cultured, grown and stained and observed for chromosomal abnormalities. media type="youtube" key="goEZ7feoZVk" height="129" align="right" width="305"

Chronic villi sampling is carried out the same way but takes place earlier than amniocentesis with sample extracted from the chronic villus (placental tissue) and tested for chromosomalabnormalities.

Diagnosis can be performed at various stages in individuals with TS, but most diagnoses follow puberty when the female fails to develop properly. ==

Treatment
As a chromosomal condition, there is no cure of Turner syndrome but certain measures can be taken to minimize the symptoms (similar to Neimann-Pick Disease). Growth hormone treatment is often given to improve growth with the safest and most influenced dose given in the first year (36). Earlier, growth hormone was extracted from human pituitary glands from where the hormone is normally secreted, but presently DNA recombinant technology is used to produce GH. In addition to TS, [|Prader-Willi syndrome]also uses growth hormone therapy for improved weight management, body composition, improved strength and agility and height that are all impaired in the syndrome. Neurodegenerative disorders like Alzheimer’s are also seen linked to decline in growth hormones levels and authors suggest using growth hormone therapeutic techniques can be a future antineurodegenerative strategy (37, 38). Other genetic diseases such as Creutzfeld-Jakob disease also receive this treatment which leads to a later onset of a variant Creutzfeld-Jakob disease (vCJD).

A very common thereapeutic approach used for individuals with TS is estrogen replacement therapy. One of the key features of a Turner Syndrome individual is gonadal dysgenesis leading to infertility with the absence or aberration of the X chromosome to promote premature ovarian failure. Sex hormone inefficiency is also involved with increased heart risk, insulin resisitance, increased risk of autoimmunity and several physical abnormalities. Thus, proper sex hormone replacement therapy must be ensured. Low dose of estrogen replacement therapy is given to Turner’s individuals that allows for early initiation of estrogen replacement (39). Estrogen replacement therapy has been used for several years and many different drugs are available.