Turner syndrome (TS) was first described in the 1930s. The condition was initially described by Uhlrich, a German physician, but is named after Henry Turner who, several years later, described a series of women with the now classical Turner phenotype. 

The incidence of Turner syndrome is approximately 1:2,500 live female births. However, it is estimated that up to 10% of all foetal spontaneous abortions are due to underlying Turner syndrome and also that only a small fraction of Turner embryos survive to birth. 

Interestingly, Turner syndrome does not appear to be associated with increasing age of the mother. In those females born with TS, there is an increased mortality comparable to the general population with this being attributed to cardiovascular risk.

Genetics

Turner syndrome is due to either complete loss of an X chromosome (monosomy X), which is seen in approximately 50% of TS girls, or else an abnormality of one of the X chromosomes (eg. ring chromosome, isochromosome). Less evident phenotypes may be seen with mosaic Turner where only a percentage of the cell lines are affected. 

A small percentage of women with mosaic Turner syndrome can have presence of Y chromosome material, which necessitates removal of their gonads due to tumour risk (gonadoblastoma transformation). In this latter group there is a significantly increased tumour risk with increasing age.

Diagnosis

Turner syndrome girls can be diagnosed at various ages with the average age of diagnosis occurring at around three to four years. Antenatal ultrasound may point toward a diagnosis if lymphoedema is seen. In the neonatal period, an experienced neonatologist may consider the diagnosis if a baby has puffy hands and/or feet. This again is a consequence of lymphoedema, due to the abnormal lymphatics seen in these girls. 

A smaller number in the newborn period will present via the cardiology department with coarctation of the aorta, at which point a karyotype may be sent to exclude Turner syndrome.

Later in childhood, a girl may be referred for assessment of short stature and Turner syndrome should always be a consideration in this group, especially if the child is growing at a slow height velocity and is outside of their genetic target centile as based on mid-parental height. Other phenotypic features which may be helpful in terms of diagnosis include the presence of low set ears, micrognathia and cubitus valgus. 

The short stature seen in Turner syndrome is thought to be skeletal in aetiology with haploinsufficiency of the short stature homeobox (SHOX) gene on the short arm of the X chromosome being accountable for this to a degree. Variations within the individual chromosomal make-up can account for some of the variations seen in phenotypic features but are not predictive of outcome. However, the presence of ring abnormality on the X chromosome, as seen in some Turner girls, is associated with an increase in significant learning difficulties. 

Ovarian dysgenesis or ‘streak ovaries’ is part of the TS complex, again due to abnormalities of the ovarian determining areas of the X chromosome. This results in either primary or secondary amenorrhoea. Some girls will not be diagnosed with Turner syndrome until puberty due to failure of pubertal development with a background of short stature.

A percentage of girls may show early features of puberty with early breast development, but will then fail to progress through puberty, while a smaller percentage will have spontaneous menarche.

Management

At initial diagnosis, all Turner girls are screened for associated risks, including coarctation of the aorta and are referred for echocardiography. In most cases these girls will have scheduled repeat echocardiographs every five to seven years or so. 

A renal ultrasound is also part of routine investigations due to the increased presence of renal anomalies such as horseshoe kidneys.

Growth hormone therapy

Girls with Turner syndrome invariably are treated with growth hormone during childhood. The average time for starting growth hormone is four to five years of age which is often associated with the slowing in growth velocity seen in this group. 

Untreated Turner girls will be on average 20cm shorter at final height than the average female. The dose of growth hormone used in TS is actually double the dose used in children with diagnosed growth hormone deficiency, in an attempt essentially to overcome the skeletal resistance seen in patients. The potential height gain in treated girls is up to 10cm compared to untreated girls, bringing them into the normal height range. 

From an economic perspective it is worth bearing in mind that the cost of growth hormone use per year averages at about e15,000 per patient. 

The use of growth hormone has been shown to be safe in this particular group.

Oestrogen levels

Primary gonadal failure will be evident clinically due to lack of pubertal development and in particular breast development with subsequent primary amenorrhoea. Some girls will enter puberty spontaneously (approximately 1:10) and go on to achieve the menarche. However, a significant proportion of these will have a very early menopause. 

Hormonal evaluation demonstrates very elevated basal gonadotrophins with low oestrogen levels. Pelvis ultrasonography will show a small pre-pubertal uterus with immature streak ovaries. 

There is considerable debate regarding the right time to institute oestrogen replacement therapy, especially between paediatric and adult endocrinologists. As oestrogen is the most potent hormone in causing epiphyseal fusion and growth cessation, there was a tendency to delay oestrogen therapy until 14 years of age so as to maximise final height. 

However, there is now an increasing tendency to start oestrogen replacement at 12 years of age to aid breast and uterine development.  The debate centres around potential reduction in final adult height with earlier introduction versus smaller breast and uterine size seen with a later introduction. 

The dose of oestrogen is initially started low and then gradually increased over two and a half years to ensure a normal timed progression through puberty, at which point progestogen is added or the girl is switched to the oral contraceptive pill (OCP). At this point, withdrawal periods will occur on a timed monthly basis. It is important for periods to occur to maintain the health of the womb and reduce the risk of endometrial cancer. 

Some centres advocate the use of the continuous OCP with defined withdrawal periods perhaps three to four times per year to reduce the time of oestrogen deficiency which would otherwise occur for seven days of every month and for which some women are symptomatic.

From a fertility perspective, apart from the very occasional spontaneous conception, this can only be achieved in almost all cases through egg donation and IVF. There is, however, a high foetal loss in the subsequent pregnancy which is partly explained by the small uterine size in TS adults. 

TS women are also at risk of cardiovascular events in pregnancy and need to be closely monitored from this perspective. Psychological counselling may be required in some adult TS women for this reason.

Cardiovascular risks

From a cardiovascular perspective, congenital heart problems include coarctation of the aorta and bicuspid aortic valve with an increased risk of aortic root dissection and sudden death. There is also an increased risk of hypertension in both TS girls and adults.

While it is acknowledged that the likely main cause for the short stature in these girls is bone-related, other bone-related features include wide-carrying angle (cubitus valgus) and Madelung (bowing) deformity of the wrist and lower radius, which is often noted radiologically.

Osteoporosis is also a recognised feature of Turner girls and as part of their evaluation they should have a DXA scan to assess this, especially prior to transitioning to adult services. Potential explanations for the osteoporosis include whether it is a true finding of under-mineralisation or representative of delayed puberty, along with the fact that TS girls have smaller bones in general and therefore lower BMD scores. 

However, some studies do suggest an increased fracture risk in adults with TS compared with controls, and therefore this should be assessed and potential treatment considered. The use of growth hormone and possibly an earlier introduction of oestrogen-replacement is associated with improved BMD scores, but an intrinsic bone defect remains a likely explanation for the osteoporosis risk in this group. 

From an academic perspective, the majority of TS girls are of normal intelligence. However, there is an increased risk of deficits in visual-spatial and motor co-ordination. This may be evident in areas of mathematics and some TS girls struggle with aspects of this in their education. 

In the specific genetic sub-set of Turner girls with ring chromosome abnormality, there can be significant developmental delay. In Ireland, girls with TS and their families can be directed to a Turner support group (www.tcgi.ie) which provides educational resources along with general support. Literature on Turner syndrome is freely available and provided to TS girls and their families in clinics.

Other issues which are fairly commonly seen include recurrent otitis media in the first few years of life which may impact hearing and speech if not adequately managed. Older females with TS are also at risk of sensorineural hearing deficit in adult years. Nail problems are also notable and some parents will complain of problems with ill-fitting shoes and difficulty in cutting nails of the younger child with TS. 

While renal abnormalities, eg. horseshoe kidney, are relatively common in TS, kidney function is mostly unaffected. Thyroid abnormalities also occur and should be screened for in the child and adult with TS. There is also a significantly increased risk of both Crohn’s disease and ulcerative colitis.

In conclusion, females with Turner syndrome need multidisciplinary input from childhood, principally in terms of their growth and puberty management. Other systems need to be carefully assessed and a careful and co-ordinated transition to adult services needs to be properly managed. Support groups and services along with provision of educational material is essential.

References

1. Elsheikh M, Dunger D, Conway G, Wass JA. Turner Syndrome in Adulthood. Endocrine reviews 2002.29(1):120-140

2. Sybert VP, McCauley E. Turners syndrome. N Engl J Med 204;351:1227-38