As indicated previously, one of the most common clinical features among individuals with TS is short stature which can affect peer relationships and social adjustment. Growth hormone (GH) is typically prescribed to children with TS in order to increase final height. Girls with TS who were treated with GH for one year were significantly taller than those who did not receive GH [94
]. Studies suggest that GH treatment can result in achievement of normal adult height, and starting GH at an early age (4–6 years) appears to be a factor in the success of the treatment [1
]. The effects of GH on height can diminish after the first 1–2 years of administration and therefore an escalating dosage schedule is often required, with higher doses in adolescence [1
Some clinicians have expressed concerns that GH treatment may result in undesirable changes to body proportions such as enlarged feet and hands in adolescents [1
]. Further research is needed in this area. Researchers also warn treatment providers to be wary of psychosocial problems related to weight management issues in TS [98
]. However, GH treatment may result in increased lean body mass and decreased body fat thus improving physical health associated with body composition [94
GH does not affect bone mineral density [94
] but may increase the risk of otitis media and certain joint disorders [1
]. There also some concerns regarding increased risk of colon and lymphatic cancers [97
]. GH decreases insulin sensitivity which, in combination with a tendency towards greater adiposity in TS, may contribute to development of type 2 diabetes [99
]. However, insulin resistance tends to decrease after approximately 7–8 years of GH therapy and returns to normal after GH therapy is discontinued [100
It is unclear whether or not GH therapy affects cognitive function in girls with TS. Very few studies examining this relationship have been conducted. One small (N = 20) but very well designed study indicated no influence of GH on cognitive function in females with TS. [101
]. A follow-up study employing an expanded cognitive testing battery confirmed these findings [14
Estrogen Replacement Therapy
One of the key features of TS is estrogen deficiency [102
] that occurs secondary to ovarian dysgenesis or degeneration associated with early follicular apoptosis [1
]. Despite ovarian abnormality being one of the most common features of TS [1
], approximately 5–10% of females with TS demonstrate some degree of spontaneous puberty and 2–7% experience spontaneous pregnancy [103
]. These pregnancies tend to be at high risk for miscarriages, genetic abnormalities, stillbirths and malformations [103
] However, there have been some rare reports of successful, uneventful pregnancies in women with TS [103
Estrogen replacement therapy (ERT) is currently the standard treatment for estrogen deficiency/insufficiency. ERT should ideally be started around the age of 12 or at an age consistent with pubertal development in the patient’s peers to decrease psychosocial distress [1
] ERT should be initiated also with consideration of GH therapy. Some reports have indicated that ERT can reduce final adult height in patients being treated with GH [105
] However, more recent studies indicate that the use of transdermal or intramuscular estradiol administration [106
] and/or initial use of a low-dose parenteral estradiol with an increasing dosage schedule [91
] may reduce ERT’s affect on height attainment.
It has been suggested that some features of cognitive impairment associated with TS may be related to estrogen function [101
]. Certain cognitive deficits such as motor speed, nonverbal processing time, verbal and nonverbal memory may improve following ERT [62
]. Many other areas of cognitive function, particularly those associated with visual-spatial and visual-motor processing as well as attention, seem to persist despite ERT [35
]. ERT has been shown to have several beneficial effects including age-appropriate development of secondary sexual characteristics, improved psychosocial functioning, increased bone mineral density and better uterine development [111
Girls with TS also demonstrate androgen deficiency [102
]. Androgens are believed to have a significant role in cognitive function, potentially enhancing cognitive performance and emotional state [112
] One study showed that oxandrolone (synthesized testosterone) may help improve certain cognitive functions such as working memory performance in girls with TS [40
]. Further studies are required to determine if androgen replacement is an efficacious treatment for cognitive impairments associated with TS.
There have been very limited studies of psychosocial treatment efficacy in TS. Existing studies are outdated and tend to involve case studies rather than randomized clinical trials or other more robust methods [113
]. The paucity of literature in this area reflects our currently limited understanding of psychiatric functioning in TS. Emotional difficulties may stem primarily from chronic medical problems and social isolation rather than X-monosomy.
It is hoped that continuing to more precisely define the cognitive, psychosocial, neurobiologic, endocrinological, genetic and other relevant aspects of TS will aid in developing more syndrome-specific psychosocial interventions. Based on our understanding of TS thus far, such interventions should ideally include a combination of the following, based on individual strengths and weaknesses: 1) general coping and adaptive skills training as well as a specific focus on dealing with chronic medical problems such as cardiovascular disease, hearing impairment and infertility; 2) social skills training including self-monitoring, social perspective taking, facial affect and body language recognition and interpretation as well as group social skills therapy; 3) stress management training to help prevent and treat anxiety and mood disturbances; 4) emphasis on improving self-esteem and self-perception; and 5) internal and external strategies to compensate for cognitive weaknesses such as using self-talk to pay attention and remain on task, focusing on doing one task correctly, rather than doing several things at once and paraphrasing what others have said to ensure comprehension.
Treatment plans should consider the individual’s cognitive profile. Neuropsychological assessments can be vitally helpful in informing education and special education services as well as psychotherapy parameters. For example, a girl with TS who has executive function deficits such as abstract reasoning or attention impairments is more likely to benefit from concrete, behaviorally oriented therapies rather than psychoanalytic ones.
Summary and Future Directions
Significant progress has been made in describing the cognitive-behavioral, neurobiologic, endocrinologic, physical and genetic factors associated with Turner syndrome. However, many questions remain. Existing studies have typically involved relatively small sample sizes, large age ranges and mixed genotypes. Smaller sample sizes obviously present potential difficulties in terms of power and generalizability. Large age ranges limit the ability to determine how hormone replacement therapies, particularly estrogen treatments, impact outcome in TS. Additionally, there have been no studies on gene expression patterns of girls with X monosomy and TS. Studies involving genetic analyses such as microarray technology will be necessary to examine gene expression profiles in girls with TS and identify potential candidate genes underlying the cognitive-behavioral impairments associated with TS. Continued studies of X-linked genes that escape inactivation and have Y chromosome homologues also will be essential in identifying candidate genes involved in the cognitive-behavioral and physical phenotypes of TS.
Genetic profiles of participants, including genotype, karyotype and genomic parental origin are of particular interest for future studies of TS. Because individuals with the maternal X chromosome outnumber those with the paternal X by approximately 2:1 [116
], further studies are required that oversample for participants with Xp
Also, many studies tend to include only females with a monosomic 45,X genotype (non-mosaic). To date, there has not been a comprehensive study of the cognitive-behavioral features associated with various karyotypes in TS. The analyses involved in interpreting cognitive-behavioral outcome associated with cytogenetic variants are quite complex due to the large number of variants that exist. However, these studies would offer a unique opportunity to investigate the relationship between X chromosome gene function and cognitive-behavioral phenotype. Future studies could begin including individuals with mosaic TS genotypes and compare their outcome to those with a non-mosaic genotype.
Finally, cross-modal, longitudinal, randomized clinical trial and other such comprehensive study designs are needed to start examining the relationships between aspects of TS such as neurodevelopment, endocrine function, medical status and cognitive outcome. These studies will hopefully aid us in developing syndrome specific interventions that will improve functioning and quality of life in individuals with TS.