Child Neuropsychology 2004, Vol. 10, No. 4, pp. 262–279
Turner Syndrome: A Review of Genetic and Hormonal Influences on Neuropsychological Functioning Joanne Rovet Department of Pediatrics and Psychology, University of Toronto, Toronto, Ont., Canada
ABSTRACT Turner syndrome (TS) is a gene tic disorder affecting mainly females that arises from a loss of X chromosome material, most usually one of the two X chromosomes. TS is associated with a number of characteristic physical features such as short stature and absent ovaries as well as a set of common neuropsychological deficits and social and behavioral features. This paper will serve to review the cognitive, social, and psychoeducational abilities of individuals with TS as well as neuroimaging findings. Several putative genetic mechanisms contributing to their particular neurocognitive deficits will also be described including candidate genes. In addition, the available evidence on how hormones affect specific abilities in TS will be reviewed. It will be concluded that the TS neurobehavioral profile arises from an atypical cerebral organization caused by the complex interplay of insufficient expression of certain (unknown) genes on the X chromosome and by abnormal hormonal levels; however, it is still not clear exactly how the specific genes affect broader cognitive abilities. Future research needs to identify the elemental processes that are disturbed in TS and map these both to events in early brain development and subsequent brain function and to specific gene and hormonal contributions.
Turner syndrome (TS) is a genetic disorder that affects approximately 1/2500 females due to the loss of some X chromosome material, most often one of the two X chromosomes. TS is associated with a number of characteristic physical features, as well as a common set of neurocognitive deficits, which include weak visuospatial skills and poor math ability. Individuals with TS also often display atypical social and behavioral characteristics. Because both the genetic mechanisms contributing to their particular physical and psychological features and the neuroanatomic manifestations of their neurocognitive deficits can now be identified, this condition offers a unique model for understanding complex
issues in brain development. Also, because sex steroid hormone production is abnormal in TS, this condition serves as a model to study the impact of hormonal deviations on selective aspects of neurobehavioral functioning. The present review will emphasize some of the factors that influence variability in the TS population and the different genetic and hormonal mechanisms that contribute to their particular profile of deficits. Examined will be their neuropsychological characteristics in several of the major functional domains, neuroanatomic findings, and recent attempts at identifying the specific genetic mechanisms influencing outcome in this population.
Address correspondence to: Joanne Rovet, Ph.D., Brain and Behaviour Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ont., Canada M5G1X8. Tel.: þ1-416-813-8283. Fax: þ1-416-813-8839. E-mail:
[email protected] Accepted for publication: July 11, 2003. 0929-7049/04/1004-262$16.00 # Taylor & Francis Ltd. DOI: 10.1080/09297040490909297
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BACKGROUND AND ETIOLOGY The first TS report dates back to 1805, when Dr. Charles Pears of England described a 29year-old female patient with short stature, absent secondary sexual characteristics and unusual behavioral characteristics and he queried if these were in any way linked (Pears, 1805). In 1930, Ullrich from Germany described a group of female patients who had a cluster of physical abnormalities that included short stature, lack of ovaries, and infantilism (Ullrich, 1930). Then in 1938, Dr. Henry Turner from Oklahoma, whose name became eponymous with the syndrome, reported on five women who presented with sexual infantilism, short stature, an abnormality of elbow formation, and webbing of the neck (Turner, 1938). Later, Polani, Lessoff, and Bishop (1956) suggested that TS might be caused by a single X-chromosome complement since affected individuals showed an increased incidence of color blindness and shortly thereafter, Ford, Jones, and Polani (1959) proved this was the case. As shown in Table 1, approximately 50% of individuals with TS are missing an entire X chromosome and among these individuals, 2/3 have a maternal X chromosome (designated as Xm) while the remaining 1/3 has only a paternal X chromosome or Xp (Jacobs et al., 1997). The monosomy-X etiology occurs during the stage of meiosis when the duplicate DNA strands divide and separate providing each ovum or sperm with a single set of chromosomal strands. TS arises when one strand from an X chromosome becomes lost
such that on fertilization, the resulting embryo has the normal complement of 22 autosome pairs, but only one X chromosome. This chromosome can come from either the mother or father depending on whose gonad contained the normal egg or sperm. Recently, reasons as to why the paternal sex chromosome is twice as likely to become lost (e.g., alcoholism) have been investigated (Kagan-Krieger, Selby, Vohra, & Koren, 2002). Although the 45,X condition is mainly seen in females, there are very rare instances of males with this karyotype. These individuals have lost all of the paternal Y except for the small testisdetermining region of the Y chromosome containing the SRY gene (Lahn & Page, 1999), which was translocated to an autosome (e.g., Da´ valos et al., 2002) and so was sufficient for male differentiation during embryogenesis. Like females, these boys are infertile and have a similar set of physical features as that seen in females with TS. Among the remaining 50% of individuals with TS, most (30% of the TS population) present with a mosaic karyotype, the most common of which contains both a normal 46,XX and an abnormal 45,X cell line. Mosaicism occurs after fertilization has taken place, typically during an early stage of mitotic cell division. At this time, the dividing cell loses an X chromosome and passes on this single X complement to all future cells in the same cell line. Other mosaic combinations include combinations of three cell lines (one normal and two abnormal) as well as cell lines involving a 47,XXX karyotype (Ferna´ ndez, Me´ ndez, & Pa´ saro, 1996). In a small proportion of
Table 1. Characterization of Turner Syndrome Etiologies. Karyotype Monosomy X
45,X
Mosaicism
45,X/46,XX or 45,X/46,XY 46,isoXm or 46,isoXp
Isochromosome
Deletions, rearrangements, and translocations Ring X
Frequency (%)
Description
45–50
2/3 maternally derived; occurs during meiosis Occurs early in mitotic cell division; almost all are female Occurs during anaphase when chromosome strand divides in transverse direction, not axially Abnormality during meiotic division
30 10
10 2–5
Loss of centromere causing ring to form
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cases, mosaicism can also involve a normal male chromosome complement (XY) and a missing X, referred to as 45,X/46,XY, and it is seen mostly in females. In these females, the 45,X cell line was probably expressed during the stage of sexual differentiation, whereas in males with this karyotype, it was the 46,XY cell line that was expressed during sexual differentiation. The remaining 20% of individuals with TS include those with an ‘‘isochromosome’’, a ring chromosome, or a deleted, rearranged, or translocated region of one of the two X chromosomes. An isochromosome, which contains two long or two short arms (as opposed to one long and one short arm), occurs during the anaphase lag stage of meiosis and results when instead of a chromosome dividing in a transverse direction, it divides
axially so as to contribute two short arms or two long arms. A ring-X chromosome occurs when the centromere region of the X is missing resulting in a ring formation (Abd et al., 1997; Migeon et al., 2000). Deletions, rearrangements, and translocations represent abnormalities of meiotic division.
PHYSICAL PHENOTYPE The TS physical phenotype is characterized by abnormalities in three basic systems: the skeletal, the lymphatic, and the reproductive systems. Skeletal defects include short stature, cubitus valgus or an unusual carrying angle of the elbows and arms (see Fig. 1), as well as a short 4th-digit
Fig. 1. Cases with Turner syndrome. Variation in presentation. Photographs provided by courtesy of Judy Ross. Permission granted for all cases.
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metacarpal, micrognathia, and a high arched palate. Until recently, females with TS were typically more than 2 standard deviations below peers in height and would achieve a final height of about 40 –700 . However, since the advent of growth hormone therapy, as well as other hormones to augment growth, they now achieve heights within the bottom end of the normal range. The high arched palate, can give rise to initial feeding difficulties and later articulation problems. Because their facial abnormalities can cause an abnormal orientation of the ear canal, children with TS are at high risk of ear infections (Stenberg, Nyle´ n, Windh, & Hultcrantz, 1998). The lymphatic system defect occurs from abnormal lymphatic clearance and this can give rise to a brain hygroma in utero. While permanent neck webbing can result after the hygroma recedes, in many cases the hygroma is so severe as to cause fetal demise. Many neonates present with severe edema, which is often the reason for the diagnosis of TS. Regarding reproductive-system defects, most females with TS have ovarian dysgenesis due to streak ovaries containing no ova. As a result, they lack endogenous estrogen and have reduced androgen production (Gravholt, Svenstrup, Bennett, & Christiansen, 1999). Unless they receive hormonal replacement therapy during adolescence, they remain sexually infantile throughout life. Although the majority of females with TS are infertile, a few individuals do spontaneously produce estrogen and undergo normal pubertal development (Pasquino, Passeri, Pucarelli, Segni, & Municchi, 1997). There are also a handful of women with karyotypes other than 45,X who have successfully reproduced. In addition, individuals with TS are at risk for cardiac abnormalities due to coarctation of the aorta and renal abnormalities from horseshoe kidneys. Most have multiple pigmented nevi and nail dysplasia. Despite the consistency of these physical features, there is wide variability among affected individuals and few if any have every abnormality. Generally, a more severe presentation is associated with a complete loss of a single X chromosome or the ring X condition while the least severe presentation is associated with a
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mosaic karyotype involving a normal 46XX cell line. Deletions, rearrangements, or translocations of the X chromosome represent intermediary conditions. The treatment of TS entails biosynthetic recombinant human growth hormone to increase height, estrogen to initiate puberty and maintain normal female functioning, and androgens to advance linear bone growth.
THE TS PSYCHOLOGICAL PHENOTYPE Intelligence and Cognitive Functioning An intellectual deficit in TS was first reported more than 50 years ago (Haddad & Wilkins, 1959) while subsequently it was acknowledged that their lower IQs reflected a significant reduction in Performance IQ, whereas Verbal IQ was normally distributed (Garron, 1977; Money & Alexander, 1966; Schaffer, 1962). Accordingly, Money coined the term ‘‘space-form blindness’’ to describe their particular pattern of difficulty and to this day, their visuospatial problems represent their cardinal cognitive deficit (Money, 1963). However, selective deficits in attention, memory, and executive processing are also seen. Although their verbal abilities are for the most part spared, individuals with TS may show reduced fluency, poor articulation, and difficulty processing syntactic structures (Inozemtseva, Mtute, Zarabozo, & Ramirez-Duenas, 2002; Temple, 2002). A large number of individuals with TS demonstrate excellent musical aptitude. On testing with the Wechsler scales, individuals with TS display subnormal Full Scale IQs with Performance IQs 12–15 points below Verbal IQ (Rovet, 1990). They typically score below population norms on Arithmetic, Digit Span, Picture Completion, Coding, and Object Assembly subtests (McGlone, 1985; Ross, Roeltgen, & Cutler, 1995; Silbert, Wolff, & Lilienthal, 1977). There are inconsistencies in the literature as to Block Design (Lahood & Bacon, 1985; Waber, 1979) with most researchers claiming performance on this task to be weak (e.g., Rovet, 1990). Results from visuospatial processing testing (see Table 2) reveal the TS group attains significantly lower scores than controls on measures of visual construction (Murphy et al., 1994), design
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Table 2. Neurocognitive Deficits in Turner Syndrome. Domain Spatial ability Visualization Visuomotor Memory Attention Executive function Language
Affected areas
Not affected areas
Block construction, puzzle assembly, mazes, directional sense, mental rotation Part-whole perception, rod and frame, visual discrimination, visual imagery Design copying, visual sequencing, visuomotor integration Visual memory, short-term recall, working memory Inhibitory control, auditory attention Planning, fluent production Verbal fluency, articulation, complex syntactic knowledge
copying (Waber, 1979), directional sense (Alexander, Walker, & Money, 1964), extrapersonal space perception (Alexander & Money, 1966), mazes (Nielsen, Nyborg, & Dahl, 1977), mental rotation (Berch & Kirkendall, 1986; Rovet & Netley, 1982), part-whole perception (Silbert et al., 1977), rod and frame (Nyborg, 1990), spatial and visual reasoning (Money & Alexander, 1966; Murphy et al., 1994), visual discrimination (Silbert et al., 1977), visual imagery (Downey et al., 1991), visual memory (Murphy et al., 1994; Ross et al., 1995), visual sequencing (Robinson et al., 1986) and visualmotor integration (Lewandowski, Costenbader, & Richman, 1985). Ross (1996) reported they had greater difficulty in determining how things went together and with spatial location and orientation than with identifying objects. In addition to visuospatial problems, girls with TS also exhibit motor clumsiness and problems with selective aspects of attention, executive function, and memory deficits (Cornoldi, Marconi, & Vecchi, 2001; Romans, Roeltgen, Kushner, & Ross, 1997; Ross et al., 1995; Temple, Carney, & Mullarkey, 1996; Williams, Richman, & Yarbrough, 1991). Attention test findings reveal difficulties with inhibitory control but not sustaining or focusing attention (Romans et al., 1997; Ross, Zinn, & McCauley, 2000) while executive function testing indicates difficulties with distraction, planning, and fluent production but not set shifting (Romans et al., 1997; Temple
Verbal memory, rote memory Sustained attention, focusing Shifting set Word knowledge, expressive abilities, pragmatics, receptive abilities
et al., 1996). Regarding memory, problems include difficulties with short-term recall as well as poor visual working memory (Buchanan, Pavlovic, & Rovet, 1998). In a study attempting to identify the most strongly affected of the neuropsychological abilities, Ross, Kushner, and Zinn (1997) used discriminant function analysis (DFA) and showed that weaknesses in auditory attention, visual discrimination and perception, abstract figure drawing, and word reading most strongly differentiated individuals with TS from controls. Hepworth and Rovet (2001) reported that the defect underlying poor visuospatial processing in TS seemed to be more general than previously thought. The findings from a single child showed a primary deficit in ‘‘global’’ or configural processing but intact ‘‘local’’ or featural processing ability. For example, while the child could copy the Rey figure (albeit poorly), she lost the figure’s configuration totally in both the immediate and the delayed recall conditions. Even more striking was the observation that her global deficit extended to other aspects of cognitive functioning, including her language, which was primarily feature-based and lacked any gestalt or integrative quality. For example, when shown a playground scene, she described all of the individual items in the picture but could not relay what the picture was about. Recent studies of women with Turner syndrome have also focused on their face processing
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capabilities. Elgar and colleagues, for example, reported that persons with TS performed more poorly than controls on tasks of face recognition, emotion processing, and familiar face recognition (Elgar, Campbell, & Skuse, 2002; Elgar, Kuntsi, Coleman, Campbell, & Skuse, 2003). Unlike nonTS females, who typically find it harder to recognize inverted than upright faces, women with TS found both formats equally difficult. This finding suggests they may have been processing the individual facial features, not the configurations. Furthermore, these women also exhibited greater than normal difficulty processing anger and fear as well as understanding the gaze of others, especially ascribing social intention to gaze (Elgar et al., 2002). Most of the observations seen in children with TS have been found to persist into adulthood (Downey et al., 1991; Ross et al., 2002), particularly their visuospatial and visual memory deficits. However, some abilities do show improvements with age (Romans, Stefanatos, Roeltgen, Kushner, & Ross, 1998). For example, weaknesses in perceptual judgment seem to catch up in late adolescence, signifying a developmental lag in this ability. Motor planning skills also appear to improve from childhood in adults with TS (Romans et al., 1998). Psychoeducational Abilities and Vocational Status On tests of academic achievement, individuals with TS demonstrate considerable difficulty with arithmetic (Schaffer, 1962) but perform at par for age in terms of their reading and spelling and they are often described as avid readers. They typically score several grades below current grade level in arithmetic and show difficulty in most aspects of arithmetic processing. Analyses of their math errors suggested problems in fact learning as well as selective operational/procedural difficulties (Rovet, Szekely, & Hockenberry, 1994; Temple & Marriott, 1998). They also made more alignment errors than controls (Mazzocco, 1998). At school, many ‘‘individuals with TS’’ are identified as having a non-verbal learning disability (Rovet, 1995) and have increased need for special education (Rovet, 1993). A substantial proportion also experiences grade retention. The
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majority of individuals with TS hold clerical or semi-professional positions (i.e., teaching, nursing, early childhood education) and they tend to be over-represented in child-care positions. Fewer than 5% achieve higher professions, although a few individuals with TS hold graduate degrees and have become physicians or lawyers. There is a high incidence of dependence with many living at home with parents as adults (Ross, Zinn, & McCauley, 2000) while issues with autonomy are also reported (Kagan-Krieger, 1998). Psychosocial and Behavioral Characteristics Psychosocially, females with TS show a definite female gender identity, assume a typical female gender role (Pavlidis, McCauley, & Sybert, 1993), and reportedly display exaggerated female play behavior. The one boy with TS I have seen has a definite male gender identity and is typically boyish in his behavior (Rovet, unpublished data). Social immaturity is often described in individuals with TS and their social relations are often difficult, particularly during adolescence when they are maturationally ‘‘out of synch’’ with their peers (McCauley, Feuillan, Kushner, & Ross, 2001; McCauley, Kay, Ito, & Treder, 1987). The majority have few friends (McCauley et al., 1987) and they often experience significant teasing and sometimes bullying. As adults, difficulties with relationships and coping with TS are commonly reported (Kagan-Krieger, 1998). Due to their particular set of physical stigmata, they generally have a poor body image and low self esteem (McCauley, Sybert, & Ehrhardt, 1986). In childhood, a significant proportion tends to be hyperactive (Mazzocco, Baumgardner, Freund, & Reiss, 1998; McCauley, Ito, & Kay, 1986; Rovet & Ireland, 1994) while up to 10% have ADHD at adolescence (McCauley et al., 2001). However, many others are extremely inhibited and shy, especially in adolescence, which is a particularly unhappy time for teenagers with TS (Mambelli, Perulli, Casella, et al., 1995). Although anxiety is commonly described, a recent study of girls and adolescents with TS failed to show differences from controls on standardized questionnaires or observed hand and face movements
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other than fewer facial movements (LesniakKarpiak, Mazzocco, & Ross, 2003). Difficulties with social cognition are frequently seen, particularly as they often fail to respect interpersonal boundaries and property, intrude on the physical space of others, and have difficulty with face processing (Elgar et al., 2002; McCauley et al., 1987).
NEUROANATOMIC AND NEUROIMAGING FINDINGS In early studies, EEG abnormalities were frequently reported although there was no consistency as to wave-form abnormality, severity, locus, or extent of localization (Palm, Pfeiffer, Ammermann, & Schulte, 1973; Poenaru, Stanesco, Poenaru, & Stoian, 1970; Tsuboi & Nielsen, 1976). Palm et al. (1973) reported an over-representation of low amplitude and a diffuse beta and alpha–beta mixture while Tsuboi and Nielsen (1976) found EEG abnormalities in 60% of cases reflecting increased beta waves, diffuse abnormalities, or frontal dominant abnormalities. Epilepsy is rarely seen rare this population. Autopsy studies revealed different developmental abnormalities ranging from a migration defect to localized changes in the posterior right hemisphere, to the absence of abnormality (Brun & Skold, 1968; Reske-Nielsen, Christensen, & Nielsen, 1982). Early studies using lateralization techniques showed that TS individuals had atypical hemispheric specialization. For example, Netley and Rovet (1982) reported the TS group was less likely than controls to process verbal information in the left hemisphere and more likely to engage their left hemispheres in the processing of music and visual information than controls. Studies using event-related potentials have found that females with TS show functional differences in brain organization. For example, Schucard, Schucard, Clopper, and Schachter (1992) reported a deficit in the ability to use right hemisphere resources for non-verbal skills. Johnson (1995) similarly found significantly delayed event-related potential latencies during visuospatial processing tasks suggesting that
females with TS may be using different strategies and neural resources to process this kind of information. A recent MRI report of a woman with a 45,X/ 47,XXX karyotype who had seizures and mental retardation indicated bilateral brain dysgenesis including an asymmetric irregularity in the gyral pattern with uneven thickness of the cortex and absence of gyri in the left frontal lobe (Tereo, Hashimoto, Nukina, Mannen, & Shinohara, 1996). Table 3 summarizes the findings from three volumetric MRI studies and from two PET studies on adults (Murphy et al., 1993) and children with TS (Brown et al., 2002; Reiss, Eliez, Schmitt, Patwardhan, & Haberecht, 2000; Reiss et al., 1993). In comparison to age-matched female controls, patients with TS show smaller sized posterior cortical structures (occipital or parietal) as well as reduced caudate, thalamic, and hippocampal volumes (Murphy et al., 1993). Larger volumes were seen in the medial temporal lobes (Reiss, Mazzocco, Greenlaw, Freund, & Ross, 1995) as well as cerebellar gray matter (Brown et al., 2002) and amygdala (not shown in Table 3, reported in Elgar et al., 2003). The study by Reiss et al. (1993), which compared brain volumes in a set of 10-year-old twins discordant for TS, showed the child with TS had smaller occipital, parietal, and frontal volumes as well as increased sulcal widths and increased CSF volumes compared to her unaffected co-twin. The two PET studies on women with TS reported reduced posterior activation during rest (Clarke, Klonoff, & Hayden, 1990) as well as decreased activation in the insula, superior temporal cortex, left inferior frontal lobe (Murphy et al., 1997). Two studies have used fMRI to understand the neural correlates of information processing in individuals with TS. In the first, Haber Echt et al. (2001) compared 12 children with Turner syndrome to normal controls on a spatial ‘‘n-back’’ task in which they had to determine whether the position of an object on the screen matched that of the one immediately preceding it (the 1-back condition) or two back from it with one stimulus intervening (the 2-back condition). Compared to controls, the group with TS showed increased activation in bilateral parietal regions (suggesting more effort) in the 1-back condition while in the
Table 3. Neuroimaging Findings in TS. Study
Age
Occ
Pariet
Temp
Front
Caud
Lent
30 10.9
TS < C TS < C
TS ¼ C TS < C
TS ¼ C
TS ¼ C TS < C
TS < C
TS < C
Reiss et al. (1995) Brown et al. (2002)a
18 2 (twins) 30 26
6–17 13.2
TS < Cb TS C
TS < C TS < C TS ¼ C
TS > C TS ¼ C TS ¼ C
TS ¼ C TS ¼ C
PET studies Clarke et al. (1990) Murphy et al. (1997)
5 10
27.8 28
TS < C TS < C
TS < C TS < C
TS < C
TS < C
Volumetric MRI Murphy et al. (1993) Reiss et al. (1993)
Insula
Thal
Put
Amygd
Hipp
Cereb
TS ¼ C TS ¼ C
TS < C
TSC
TS ¼ C
TS < C
TS ¼ C TS C TS ¼ C
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N
TS < C
Note. aUpper line for gray matter; lower for white matter. b Trend only.
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2-back condition, they were less likely to engage the frontal lobes, premotor cortex, and caudate. The authors interpreted these findings to mean the TS group exhibited greater effort than controls in the 1-back condition and less engagement (leading to poorer performance) in the 2-back. More recently, Tamm, Menon, and Reiss (2003) gave 11 adolescents with TS monosomy age-matched controls a ‘‘go-no-go’’ paradigm in the scanner. Results indicated the TS group activated a more extensive functional network, which was thought to signify the TS group was compensating for their executive dysfunction by recruiting additional prefrontal cortical regions.
GENETIC-NEUROBEHAVIORAL CORRELATIONS The Role of Karyotype As described previously, TS can be caused by various abnormalities of X chromosome complement including a missing entire X chromosome, a ring X chromosome, a deletion or rearrangement of the X chromosome, an isochromosome or various forms of mosaicism. Generally, the ring X karyotype is associated with the most severe deficits, mental retardation, absence of the corpus callosum, and extremely large ventricles (Abd, Turk, & Hill, 1995; Kuntsi, Skuse, Elgan, Morris, & Turner, 2000). Studies comparing individuals with TS by karyotype have found much lower WISC Performance IQs in the 45,X group than groups with other karyotypes. For example, Temple and Carney (1995) in comparing children with (i) a pure 45,X chromosome condition, (ii) an isochromosome, and (iii) a mixed condition involving a deletion or rearrangement reported the 45,X group had significantly lower Performance IQs than the other groups but there were no differences in Verbal IQ. Ross, Kusher, and Zinn (1997) compared the discriminant function analysis (DFA) scores (see above) of adults with TS by karyotype and found lower scores in the 45,X, ring X, and isochromosome karyotype groups than the mosaic group, who scored comparably to controls. O’Neill, Ghelani, Rovet, and Chitayat (2000) studied the neuropsychological abilities of pre-
school children identified on amniocentesis with 45,X/46,XX. As shown in Figure 2, these children scored above the mean of test norms on most indices except NEPSY Narrative Memory and they were significantly higher than the norms on Memory for Faces. Several of these children were also quite tall and few showed any of the characteristic physical features of TS. Rovet and Ireland (1994) compared the sociobehavioral features of children with TS participating in a national clinical trial of growth hormone by karyotype. Results from the Child Behavior Checklist completed by parents at the trial’s baseline session revealed the children with rearrangements and isochromosomes had the poorest social skills followed by those with a 45,X karyotype while those with mosaic conditions, deletions, and the presence of a Y chromosome showed normal social skills. In contrast, children with rearrangements or deletions were more likely to exhibit significant behavior problems than the others, while those with (a) a Y chromosome were moderately affected, (b) 45,X or isochromosome karyotype were minimally affected, and (c) mosaicism scored above normal. These findings suggest that children with rearranged X chromosomes are at the greatest risk for both social and behavior problems while children with isochromosomes are at risk for social problems and those with deletions for behavior problems. Children with mosaicism are the least affected. Imprinting Effects One genetic mechanism that has received considerable attention recently is the phenomenon known as genomic-imprinting (Hall, 1997) or the parent from whom the child originally received her X chromosome (Barlow, 1995). It appears that there is differential expression of certain genes depending on the parent of origin as seen for example in Prader-Willi and Angelman syndromes. These are two very different disorders that emanate from the same gene defect on chromosome 15 but Prader-Willi is paternal in origin while Angelman’s is maternal in origin. The mechanism in genomic-imprinting is thought to reflect different methylation from the two parents with one (usually the mother) preferentially
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Fig. 2. Neuropsychological test results of children with Turner syndrome diagnosed with a 45,X/45,XX karyotype prenatally. Results are presented as difference scores from test norms expressed in standard deviation (z-score) units. Striped bars represent NEPSY subtest scores, stipled bars represent the Wide Range Assessment of Visuomotor Abilities results, and the horizontal striped bar represents the Beery Test of Visuomotor Integration.
silencing a particular gene. This means that if a gene on the maternal chromosome is inactivated, then females with TS who inherit their single X chromosome from the father will still be able to express the gene, whereas those who inherit it from the mother will be deficient in that gene (Brown et al., 2002). In a study comparing 55 females with maternally derived X-monosomy and 25 with paternally derived X-monosomy to chromosomally normal males and females in terms of outcome and selective abilities, Skuse et al. (1997) showed the maternally derived monosomy X group was more likely than the paternally derived group to need special education, have low IQs and social difficulties, and be disinhibited on cognitive tasks. In contrast, the paternally derived group had scores that were almost identical to chromosomally normal subjects. Bishop et al. similarly studying Ximprinting effects on memory performance, showed material specific differences (Bishop et al., 2000). As seen in Figure 3, the paternally derived X chromosome (Xp) group did poorly on tests of verbal retention but were similar to controls on tests of visual retention. In contrast, those
Fig. 3. Effect of imprinting on memory test performance for visual and verbal information. Turner syndrome groups are shown with solid lines and filled symbols. The maternally derived X group is represented by circles, paternally derived X group by squares. Normal controls are shown with broken lines and unfilled circles (females) or squares (males). This work is adapted from Bishop et al. (2000). Reprinted with permission from Pergamon press.
with a maternally derived X chromosome (Xm) showed deficits on tests of visual retention but performed comparably to controls on verbal
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memory tests. In other words, having only a paternally derived X chromosome impairs verbal memory performance but spares visual memory, whereas having only a maternally derived X chromosome impairs visual but not verbal memory. It is interesting to note that the Xm group showed a similar, albeit lower, profile as normal boys, who also only get their X chromosome from their mother. Neuroimaging findings also reveal that the Xm group is more aberrant bilaterally than the Xp group and also has a larger than normal right superior temporal gyrus (Elgar, Lawrence, Kuntsi, Coleman, Campbell, & Skuse, in press). Haploinsufficiency Effects It has been posited that one of the two X chromosomes in females is normally inactivated and gene expression is randomly maternal or paternal in origin, a theory known as the Lyon Hypothesis (1962). However, because this theory cannot account for the situation in the Turner syndrome monosomy group (who should be just like normal males who also have a single X chromosome), it was proposed that some genes within specific regions of the X chromosome behave like autosomes (pseudoautosomes), such that one needs both copies of these genes to express a trait properly. These genes have homologous regions on the X and Y chromosomes. In females with TS who have only one gene copy, there will be a reduced gene dosage or a haploinsufficiency leading to reduced production of certain critical proteins, namely those required for growth or certain aspects of brain development (Zinn & Ross, 1998). To identify these ‘‘pseudoautosomal’’ regions, researchers have studied the rare cases with partial X deletions or rearrangements. In one such study, Zinn et al. (1998) found evidence of pseudoautosomes in several loci on the short arm of the X chromosome (designated as Xp in contrast to the long arm designated as Xq) in the region from Xp11.2 to Xp22.1. Patients missing this region had high arched palates and ovarian dysgenesis, whereas those who had this region but were missing another did not show these characteristics. For example, Zinn’s study contained two mother–daughter pairs (or triplets meaning a
mother and her two daughters) all of whom were missing a region quite high up on the X chromosome but had an intact region from p11.2 to p22.1. Since these mothers were obviously fertile, whereas individuals missing the region below this had ovarian dysgenesis, it was posited that genes involved in ovarian production must be located within the former region. Short stature was localized to a much smaller region midway within that general area. Are genes in this region also responsible for the cognitive phenotype in TS? Ross, Roeltgen, Kushner, Wei, and Zinn (2000) compared visuospatial abilities in 34 children and adults with partial Xp (i.e., short arm) monosomy. Cases were stratified according to whether their discriminant function analysis (DFA) scores were negative (meaning poor visuospatial ability) or positive (meaning adequate visuospatial ability). Since all individuals with negative DFA scores were missing the part of the X chromosome within pseudoautosomal region (Xp22.3) known to escape X inactivation, this signifies that both copies of genes in this region must be present to express this trait properly. The task now is to identify which of the seven known genes in this region cause the spatial deficit and how exactly this occurs. Candidate Genes The earliest gene to be identified in TS was the SHOX or short homeobox gene (Rao et al., 1997). This gene, which is located at Xp22 or Yp11.3, is important for growth and if missing or abnormal, causes growth failure and idiopathic short stature. SHOX was first discovered in the condition Le´ ri-Weill dyschondrosteosis (LWD), which is a dysplastic condition involving short stature, short arms and legs, and the ‘‘Madeline deformity’’ or an unusual carrying angle of the elbows and a short fourth metacarpal (Ross et al., 2001) much like that seen in TS. SHOX mutations or deletions are also seen in about 5% of children with idiopathic short stature (Binder, Schwarze, & Ranke, 2000). Within the TS population, SHOX deletions are found to be associated with skeletal abnormalities (ClementJones et al., 2000; Kosho et al., 1999) while TS cases with rearrangements involving three SHOX copies (e.g., due to a short arm isochromosome)
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had tall stature (Binder, Eggermann, Enders, Ranke, & Dufke, 2001). Although no studies have as yet linked SHOX to the neurocognitive deficits in TS, Ross et al. (2000) showed that individuals the lowest DFA scores (a marker of visuospatial abilities, see above) were missing a region 15–30 kilobases from the centromere (which contains SHOX). A different region of the X chromosome may be responsible for some of the social adjustment difficulties in TS. Skuse, Good, Elgar, Thomas, and Morris (2001) similarly examined partial-X monosomies and found a region at Xp11.3 (which is closer to the centromere than SHOX) was associated with these types of difficulties. Individuals who lacked this region of the X chromosome had difficulties processing fear emotions in faces, poor social adjustment, and limbic system abnormalities in their neuroimaging scans (Elgar et al., 2003).
THE ROLE OF HORMONES ON OUTCOME Individuals with TS lack endogenous estrogen production and also have reduced androgen production. Thus, they are exposed to insufficient levels of both hormones until replacement therapy is provided. While estrogen therapy is commonly given in adolescence to bring on puberty and sustain normal menstrual functioning, androgen
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therapy is given only to augment growth. In addition, most children are now treated with biosynthetic growth hormone to increase final height. The findings from a number of studies to determine how variations in their hormone levels affect cognitive and behavioral functioning are summarized in Table 4. Estrogen Effects Although the majority of females with TS lack normal estrogen production, there are exceptional cases with estrogen production. These individuals are diagnosed with TS because of the other physical features. One of the first studies to link estrogen levels to specific aspects of cognitive processing examined event-related potentials (ERPs) in response to different kinds of information (Johnson, Rohrbaugh, & Ross, 1993). Prior to puberty, there were few differences between the children with TS and normal controls in ERP parameters, whereas by late adolescence, controls showed the developmental phenomenon known as the O-wave, which appears in the frontal region but adolescents with TS did not, unless they were receiving estrogen therapy or had endogenous estrogen production. Recent studies of women with TS taking estrogen exogenously showed no effects of estrogen on visuospatial task performance, regardless of whether they were taking estrogen or not (Ross et al., 2002). By contrast, visual perceptual and motor planning skills seem
Table 4. Effect of Hormones on Selective Neurobehavioral Functions. Hormone
Positive effects
Lack of effect
Estrogen
ERP O-wave Perceptual abilities Motor Planning skills Motor speed Memory
Spatial abilities
Androgen
Verbal working memory
Verbal abilities Spatial abilities Executive function
Growth hormone
Psychological functioning Internalizing behaviors Arithmetic
Cognitive abilities
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to be improved with exogenous estrogen therapy (Roman et al., 1998; Ross et al., 2000). In a randomized controlled study of estrogen treatment, Ross, Roeltgen, Feuillan, Kushner, and Cutler (1998) found the estrogen-treated group had superior speeded motor performance and faster cognitive processing speeds than the non-treated groups. However, groups did not differ in their visuospatial abilities. Similarly studies with children show those receiving low dose estrogen replacement therapy had better memory functioning than those not receiving estrogen (Ross et al., 2000). Androgen Effects In contrast to estrogen, androgens used to facilitate growth may positively affect selective aspects of memory functioning in TS, particularly skills implicating the hippocampus (Murphy et al., 1994). In a recent treatment study involving oxandrolone, Ross and colleagues reported a positive effect of oxandrolone on verbal working memory but not on verbal abilities, spatial cognition, and executive function (Ross et al., 2003). Growth Hormone Effects Young girls with TS are not truly growth-hormone deficient, although abnormalities are seen after age 9 (Ross, Long, Loriaux, & Cutler, 1985). Regardless, studies providing growth hormone replacement therapy to children and adolescents with TS show improved height on average with little effect on cognitive abilities (Ross, Feuillan, Kushner, Roeltgen, & Cutler, 1997). In contrast, growth hormone therapy is associated with improved psychological well-being, fewer internalizing emotional problems, and slightly better arithmetic abilities than seen in individuals not receiving this therapy (Siegel, Clopper, & Stabler, 1998). Although Stabler (1995) reported a very modest (non-significant) gain in IQ after 2 years of growth hormone therapy, the effects of growth hormone on overall neuropsychological functioning have not been adequately studied.
SUMMARY AND CONCLUSIONS To summarize, TS represents a genetic disorder that affects females primarily although very rare
cases of males with TS have been described. TS is associated with a characteristic set of physical stigmata and psychological features. In particular, individuals with TS show a specific cognitive deficit affecting primarily their visuospatial abilities while dysfunction in attention, executive function, memory areas and math processing areas are also frequently seen. Deficits in social cognition and difficulty with selective aspects of face processing have additionally been reported. Many children with TS also exhibit a non-verbal learning disability and need special education at school. Neuroimaging studies reveal abnormalities in structural brain development reflecting reduced volumes in posterior cortical and subcortical structures as well as increased size of the medial temporal lobe, cerebellum, and amygdala. Neuropsychological studies point to abnormal hemispheric lateralization suggesting a unique cerebral architecture. Recent functional neuroimaging studies support this view showing that different brain substrates are recruited during different information processing tasks thereby suggesting atypical cerebral networks. Certain fundamental processes such as integrating information into meaningful units or configurations may be particularly disturbed in TS as has been shown in other disorders. These elemental problems may be contributing to both the cognitive and psychoeducational profiles seen in TS. There is marked variability in presentation of the individual features among individuals with TS and these variations reflect both genetic and hormonal factors. Genetic factors include the child’s particular karyotype and genomic-imprinting and gene dosage effects. Regarding hormones, TS is associated with a hormonal imbalance in estrogen, androgen, and growth hormone supplies and these different hormonal abnormalities may also contribute to different aspects of cognitive dysfunction. Studies of hormonal therapies have shown that treatment with estrogen improves attention and executive function skills and with androgens (to enhance growth), verbal working memory. While growth hormone therapy has little effect on cognitive skills per se, it is associated with improved behavior and arithmetic. These findings have implications for treating patients
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with TS and for the choices in selecting particular hormone replacement therapies. In addition, these findings are important for furthering our general knowledge regarding the role of hormones in brain development and later brain functioning since TS offers a unique experiment of nature to study these effects. While the particular findings on TS have implications for designing remedial strategies for them, further work is clearly needed to understand for example why their math deficits are so prominent when they first appear and how they may be initially rectified. It is important to determine what their basic visual defect is and how and why this impacts on visual special functioning as well as math concepts. Clearly more studies of young children with TS are needed to answer these questions. Regarding the genetic studies, recent research is making headway as to candidate genes and underlying genetic mechanisms contributing to the particular profile in TS. However, further studies in this area are definitely warranted. The recent genetic studies identifying restricted chromosomal regions contributing to different phenotypic characteristics promises to be fruitful in discovering the particular genes that contribute to specific cognitive functions. Furthermore, this approach may also advance our knowledge of sex differences in behavior. As more rare cases with deletions become identified, it is important to examine their particular abilities and neuroimaging status. However, because these cases are so rare, large-scale international studies are recommended. Future research also needs to identify the elemental processes that are particularly disturbed in TS and link these to specific alterations in brain formation. One area of research on TS that has been particularly limited is the study of their development longitudinally and in particular examining how different genetic and hormonal mechanisms impact on these children at different stages of development. Only once the research on this disorder is conducted at this elemental level and over time will the identification of what the genes on the X chromosome do be possible, as in conditions such as Williams syndrome (Donnai & Karmiloff-Smith, 2000; Paul, Stiles, Passarotti, Bavar, & Bellugi, 2002) and fragile X syndrome
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(Loesch, Huggins, Bui, Taylor, & Hagerman, 2003).
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