Turner syndrome: What GPs need to know

Turner syndrome

Prof Amanda Vincent: Welcome to this session which is for GPs. So I’m going to provide an overview of Turner syndrome and then I’ll be followed by Dr. Esther Davis who will provide an update regarding cardiology and Professor Beverley Vollenhovan who will talk about fertility issues.

These are my disclosures. So this is an outline of my presentation today. I’ll start with an introduction. I’ll talk about what the role of the GP is, and this is a really key role partnering with patients and also with specialists in the management of individuals with Turner syndrome. I’ll use a case to illustrate the different steps involved, including making the diagnosis and management.

So Turner syndrome affects about one in 2000 live female births, and it’s really complete or partial X chromosome monosomy in a female. The characteristic features are short stature and hypergonadotrophic hypogonadism, and we know that Turner syndrome is associated with multi-morbidity and decreased survival.

Turner syndrome has a variable genotype, and the different types of genotypes are shown here, and their frequency as well. The most common karyotype is the 45,X karyotype, which occurs in about 40 to 50% of patients. And that is really the classic Turner syndrome karyotype, which was initially described. But as you can see there are multiple other karyotypes as well, including those which are involved with mosaicism. So some cells having the 46,XX, which is the normal female karyotype, which is mosaic with other cells containing the 45,X karyotype.

So we’re getting greater understanding about the genotype phenotype. And the bottom line is it’s complicated and we don’t know the details. So what this slide shows, if you look at A, you can see the X chromosome there with all the individual genes and associating with the specific features of the phenotype. But what we do know is in those women who have a mosaic Turner syndrome, then there’ll be some tissues which have the 45,X and there’ll be others which have a 46,XX karyotype, and that produces changes in the phenotype and the level of health issues or comorbidities that are associated or that express in the individual.

But what we are now finding out is, shown in the panel C, is that it’s not only just what is occurring on the X chromosome with the genes. Downstream of the genotype itself, there’s also changes in transcription, epigenetic processing, splicing and translation, so that you get changes in expression of genes and also the proteins produced which are contributing to the phenotype. As part of epigenetic processing, and also there’s hypomethylation in a lot of the genes associated with Turner syndrome, and that again can change gene expression and contribute to the phenotype that we observe.

And finally, if you look at E, what happens is that there seems to be an interaction between both the X chromosome, so you’ve got one X chromosome lacking, so you’ve got haplo insufficiency of certain X-linked genes, but then that is combined with a variation on an autosome. So another chromosome completely. And here we’ve got the example of TIMP1 haploinsufficiency on the X chromosome combined with a second hit on chromosome 22 affecting the TIMP3 gene. And what results from that is contributing to aortopathy and dilated aorta.

We need, as well as these genetic sort of changes going on, we also need to think about other issues which may affect the phenotype, including oestrogen therapy, lifestyle such as smoking, the influence of the gut microbiome, environment, impact of other health issues, and then of course ageing related changes as women age.

So these are a summary of the clinical features associated with Turner syndrome, and as you can see really all organ systems are affected. The characteristic findings, as I said before, is short stature, and then hypergonadotrophic hypogonadism. So primary amenorrhea or secondary amenorrhea and premature ovarian insufficiency affect almost all patients with Turner syndrome at some stage. The highest prevalence of comorbidity is with the 45,X karyotype and those with a mosaic Turner syndrome karyotype have a milder phenotype. Most women with Turner syndrome have intellectual abilities within the normal range of the general community, apart from those with a ring chromosome, and that chromosome karyotype is associated with intellectual disability. And finally, there seems to be a lower prevalence of the bicuspid aortic valve with the isochrone XQ and ring X karyotypes as well.

We know that Turner syndrome does have a three to fourfold increase in mortality and this is predominantly due to cardiovascular disease, shown in the centre panel here. And if you look at the cumulative risk of death across time and age, all-cause in the general community is shown by the dotted lines, whereas that in a Turner syndrome cohort is shown by the solid lines. And you can really see the increase in all-cause mortality above that of the general population and as well as that from circulatory diseases. And finally, we know that people with, women with Turner syndrome are more likely to have cardiovascular disease, endocrine disease and gastrointestinal disease, less likely to have motherhood and cohabitation.

So what’s the role of the GP? And I’ve summarised this here. And the role, the GP really plays a key role often partnering with both the patient and also with the multidisciplinary hospital or specialist team that will be involved in the care of these patients. And really it can be summarised as early identification, helping to confirm a diagnosis, potentially initial management, being a pathway for referral, and assisting with long-term follow-up. And the arrows represented each time point when a GP might consider referring to a specialist care or into a multidisciplinary hospital service. So that may be at the time of diagnosis or to confirm a diagnosis. It might be referring for initial management and also it might be in assisting with long-term follow-up. But really the GP retains a intrinsic role within the management of women with Turner syndrome.

So let’s start with our case. This is a 36-year-old woman with secondary amenorrhea, and she comes to you with eight months of amenorrhea following cessation of her oral contraceptive pill. She’s had mild vasomotor symptoms. She’s a G2P2 two with spontaneous conception, and no pregnancy complications, with two children, age eight and six years. And she’d commenced the oral contraceptive pill about 10 years ago following the birth of her last child, ah sorry, stopped it for her children and then recommenced it. She has a family history of dyslipidaemia but none of early menopause. Significantly, on examination, she was quite short with a height of 138.5 centimetres. Normal weight with A BMI of 23. She was normotensive and the rest of her examination was unremarkable.

So the important thing is to consider the diagnosis. And these are recommendations from the 2024 Turner syndrome guideline about those things to, clinical features which may prompt you to consider genetic testing for a diagnosis of Turner syndrome. In our Turner syndrome clinic, the oldest age at diagnosis was 65, so patients are never too old to think about the diagnosis, if they have some of these characteristic clinical features. The case I’ve just showed you has short stature and also secondary amenorrhea. But as you can see there’s quite a number of different clinical features which may prompt consideration of a diagnosis of Turner syndrome.

So when we think about premature ovarian insufficiency, we need to think about that in any woman under the age of 40 who presents with more than four months of oligo amenorrhea, may or may not have symptoms of oestrogen deficiency, they may be presenting with infertility, or they may have symptoms or signs of a potential cause. And the short stature of this patient is a clue that there might be POI and what might be the cause of her POI. So the key test for determining whether or not someone has premature ovarian insufficiency is to check the follicle stimulating hormone level. Obviously you will have done a pregnancy test as any workup of secondary amenorrhea, but it is the FSH level which is the key investigation.

Both serum oestradiols and pelvic ultrasounds are helpful but not essential for diagnosis. And the current criteria, and this is from the 2024 POI international guideline, is that a combination of an FSH level greater than 25 plus oligo amenorrhea for at least four months, can consider a diagnosis of POI. If the diagnosis is not confirmed on the first FSH test, then repeat it after four to six weeks, and you could also at that point check an AMH level to help confirm the diagnosis.

Once you’ve made a diagnosis of POI, and this algorithm is again taken from the new international POI guideline, then the next step is looking at assessing cause. And as you can see here, genetic testing with a chromosomal analysis is one of the key steps in identifying a cause for POI and one in which we can actually identify a cause.

So if we think back to our case, so she had an FSH level which was grossly elevated at 129 international units per litre, low-ish oestradiol, and the vaginal ultrasound here, which showed an incidental finding of a horseshoe kidney. Her karyotype was 45,X/47,XXX and thus a diagnosis of POI due to mosaic Turner syndrome was made. She was sensitively informed of the diagnosis of Turner syndrome and POI. And it’s really important to be very empathic and sensitively inform women of the diagnosis. It can be quite a distressing diagnosis for women. She was then referred for genetic counselling and to our Turner syndrome clinic at Monash Health for further management.

So the median age of diagnosis of Turner syndrome is around about 15 years old, although most are diagnosed at birth and childhood, but there are a proportion who are diagnosed in adulthood. And really when children come to attention because they may have growth failure and short stature or around the time when they fail to start puberty or do not commence menstrual periods. There is some suggestion that there’s a significant proportion of women who may not be diagnosed, and that’s on the basis of looking at what the gene frequency is and then the number of diagnoses. But there has been increased detection, particularly around that perinatal period, with the use of non-invasive prenatal testing and new genomic techniques. But these are still being developed and their specificity and sensitivity being worked out.

There are challenges associated with a late diagnosis. They can have reduced final height, reduced bone density, reduced uterine size, and that graph just shows you that early initiation of hormone replacement therapy results in a bone density which is very similar to similar aged menstruating controls, but those with a late initiation have a reduced bone density. Late diagnosis also has adverse effects on both psychosocial and psychosexual development. And then there’s also the problem of unrecognised comorbidities and potentially decreased quality of life.

So management involves screening for comorbidities, attention to psychological health, lifestyle management, hormone fertility, advice regarding fertility, and education and counselling. And this is really, a GP is involved in all of these aspects of care. This is the algorithm or the checklist that we use in the Monash Health Turner syndrome clinic for screening both at the initial diagnosis and then at our annual reviews and subsequent two-yearly DEXA scans and echocardiograms, and then certainly the pre-pregnancy things. And as you can see there really is a significant screening to look at all the potential comorbidities that may occur in these patients so that we can intervene to prevent complications from occurring or getting worse.

Back to our case. So when we did her investigations, she’s got a slightly elevated TSH and normal Free T4 with positive thyroid antibodies, indicative of subclinical hypothyroidism. Lowish vitamin D, you can see normal lipid profile and euglycemia, normal liver function, urinary function, negative celiac antibodies, normal bone density. She had evidence of a high frequency hearing loss, and cardiology investigations were normal.

We know that Turner syndrome is associated with a specific neurocognitive phenotype, and there are also other psychological impacts which really have bi-directional interactions. These patients often have problems with learning difficulties, particularly in relation to mathematics. They can have attentional problems and there is an increased risk of ADHD in these patients. There is difficulties with social cognition, so recognising social cues, recognising facial impacts can be a problem, and this can contribute to feelings of isolation, can contribute to anxiety and depression. There’s also problems with relation to coordination and motor function as well as executive functioning problems such as planning. And so it’s recommended that all patients with Turner syndrome be assessed for both their psychological, cognitive and neuropsychological evaluation and the appropriate interventions, be it counselling, behavioural, social, be undertaken to assist and support women with these issues.

HRT is beneficial and it should be instituted promptly when there’s evidence of ovarian insufficiency, whether that be with primary amenorrhea or the subsequent development of POI. And continued adherence is important as we know that non-adherence is associated with bone loss. HRT should be continued until at least the usual age of menopause and then reassessment at that time can occur for continuing HRT after that time. As you can see, there are multiple beneficial effects of HRT on a variety of organ systems, both cardiovascular, weight and metabolic changes, musculoskeletal system, urogenital system, sexual function and cognitive function. And importantly, there is no increased risk of breast cancer with HRT in these patients.

The choice of HRT involves consideration of the patient’s age. Is there a need for pubertal induction or growth hormone? What symptoms may be present? Are there any contraindications to HRT? Whether or not she has a uterus, is there a need for contraception? The presence of different comorbidities, and patient preference. So it’s really important that we have shared decision making and individualise the therapy for that patient.

This is a management algorithm for POI, which is from the POI guideline, and it basically follows that for women, postmenopausal women at an older age, looking at whether or not it’s contraindicated, the presence of hysterectomy in which case oestrogen-only therapy is needed, and whether contraception is required. And at that point, a combined oral contraceptive pill with continuous use, or the use of the Mirena if the uterine size is sufficient, plus additional oestrogen is useful. Otherwise using HRT either continuous, combined or sequential is important. Remembering that HRT is not contraceptive.

There are different comorbidities which will influence your choice of hormone therapy. If the patient has malabsorption, then obviously it’s more important to use transdermal. In the setting of migraine with aura, hypertension, obesity or prior VTE or abnormal liver function tests, then transdermal therapy is preferred. And if a patient has a history of breast cancer or known cardiovascular coronary heart disease, then hormone therapy is relatively contraindicated.

These are recommendations from the 2024 Turner syndrome guideline, and they give preferences for using oestradiol. Transdermal is preferred, probably over oral, and over ethanol oestradiol, but some oestrogen is better than no oestrogen. These younger women often need combined sequential therapy but could have a combined continuous regimen. It depends on patient preference. And these doses also, women as you can see also tend to require higher doses than what we would use in older postmenopausal women, so at least two milligrams of oral oestradiol, two Sandrena patches for example, or three to four pumps of EstroGel per day. And the AMS Australasian Menopause Society has really useful guides to using hormone replacement therapy and MHT, which I’ve shown here.

As with, if you’re using a higher dose of oestrogen, then you need to have a higher dose of progestogen, and these are some examples of doses of progestogen that you would use in combination with the higher doses of oestrogen. Sometimes you might need to combine preparations. So Bijuva is a one milligram oestradiol plus a hundred milligrams of micronized progesterone in a single capsule. To get an adequate dose in a woman with POI including Turner syndrome, you would need to use two of those per day. One milligram of oestradiol is not going to be sufficient for these women’s needs.

So back to our case. So we discussed the hormone replacement therapy options with her. She was sexually active and she’d previously used the contraceptive pill without any problems, so she was happy to recommence that, and she was advised to take it continuously. We increased her vitamin D dose, we provided lifestyle advice for chronic disease risk reduction, and monitored her thyroid function test for management of the subclinical hypothyroidism. We offered her referral to a psychologist as she was somewhat distressed by the diagnosis of Turner syndrome and what that might mean, and referred her to a Turner syndrome support group. And this was a plan for a yearly clinical review and subsequent investigations as you can see here.

It’s really important to provide women with Turner syndrome with education and support, and there are excellent support organisations, both the USA, the UK and the Turner Syndrome Association of Australia, and they have really excellent websites with lots of useful information on them. We’ve also created an app called Ask Early Menopause, which has information that is around POI, which encompasses Turner syndrome, which can also be helpful. So I would suggest that, I would encourage you to refer these support groups and websites to your patients.

Back to our case. 24 months later at her regular review, she’s had a weight gain of three kilos, no menopausal symptoms. She continues to take her ethanol oestradiol contraceptive pill continuously as was commented upon, but her blood pressure was noted to have increased. It’s now 140 on 90. Her thyroid function tests remain unchanged. Her lipids, full blood examination and HBA1C and liver function tests are all normal. So at that point it was thought that we should cease her ethanol oestradiol combined pill because it could be contributing to her elevated blood pressure.

And so the question is what is her hormone replacement therapy options at that time? And I’ve just given three here that could be potentially discussed with her. If she needs contraception, then using the Mirena plus transdermal oestradiol, she could try an oestradiol-containing combined pill such as Zoely or Qlaira, or she could try Slinda plus a 50 microgram patch, although that may not be enough oestradiol for her. Otherwise, if she does not need contraception, then transdermal oestrogen plus prometrium would be a reasonable suggestion. Obviously lifestyle advice for her blood pressure and weight management, she may require home blood pressure monitoring or ambulatory blood pressure monitoring, and if her blood pressure does not improve, then we need to start an anti-hypertensive. And Esther will go through a little bit more about this in detail. We may need to consider doing her echo a little bit earlier than we would usually plan to.

So my take home messages are for GPS to consider the diagnosis of Turner syndrome in the young woman with oligo amenorrhea or characteristic clinical features, or the younger adolescent who does not enter puberty or has primary amenorrhea. The diagnosis is based on a karyotype, and needs to be informed in a sensitive manner. Provide education and psychological support. Assess, monitor and manage comorbidities. Individualise HRT and continue that until at least the age of 51 years. And the GP plays a key role as part of the specialist healthcare team, both as part of for early identification, diagnosis, but then for initial and ongoing management. Thank you very much.

Dr Esther Davis: So it’s my pleasure to speak a bit on the unique cardiac aspects of Turner syndrome and some of the things that differ, as well as some of the things that are the same from our standard treatment of a patient at higher cardiovascular risk. This is the overview of what I’ll be discussing today. We will briefly look at the issues that are unique to Turner syndrome, recommendations for screening for cardiac disease in Turner syndrome. Predominantly adult, but I will briefly touch on paediatric recommendations. Congenital heart disease and Turner syndrome. Aortic dilation and aortic dissection, which is obviously one of the more feared potential complications of the aortopathy that can be seen in Turner syndrome. Hypertension and hypercholesterolemia. And then touch briefly on cardiac disease and pregnancy planning for Turner syndrome patients.

Turner syndrome patients have a lifelong significant burden of both congenital and acquired cardiovascular disease, and cardiac disease is primarily responsible for the early morbidity and mortality that we see in adults with Turner syndrome. It is important to note that the prevalence of congenital heart disease is markedly increased compared to the general population, with the prevalence of up to 60% in some studies. This is particularly left-sided obstructive lesions, so coarctations, bicuspid aortic valves. Aortopathy is prevalent, the risk of aortic dissection is higher than in the general community, and dissections occur at smaller absolute aortic dimensions than are seen in the general population.

Women with Turner syndrome are also at risk of premature acquired coronary disease, which is probably actually where the vast majority of the increased morbidity and mortality comes from, and this is exacerbated by the high risk of premature onset hypertension and predisposition to metabolic abnormalities.

The recommendations for cardiac screening and cardiology involvement in women with Turner syndrome really depend on when the diagnosis is made. If the diagnosis is made prenatally, foetal echo can be helpful, with paediatric cardiology consultation at that time. Regardless of the age that the diagnosis is made, an echo is the primary initial investigation to look for things like bicuspid aortic valve, coarctation, anomalous venous return, coronary anomalies and hyperplastic left heart syndrome. If congenital heart disease is detected, then the management will be determined by the type and severity of the underlying lesion.

There is then ongoing monitoring through childhood, particularly with early consideration of elevated blood pressure, and then follow-up is often determined by the presence or absence of aortic dilation As we get towards growth completion, it is important that cross-sectional imaging is undertaken, generally with CMR, although CT can be considered in some contexts, to determine absolute aortic dimensions, which can be underestimated on echocardiogram. Some of the anomalies also seen, particularly pulmonary venous return and things of that nature, will not necessarily be detected on echocardiography. So cross-sectional imaging is necessary.

And then after transition to adult care, ongoing management with transthoracic echoes and other cross-sectional imaging will continue to be necessary. Generally, there is a lower index for involvement of cardiology in Turner syndrome patients compared to the average adult population. Certainly there is involvement of our paediatric cardiology colleagues throughout childhood, but it’s also important that a cardiologist is involved around the time of planned pregnancy, because there are very specific risks in this population that need to be discussed.

Certainly as with any patient, if there are any new or potentially unexplained cardiac symptoms, where there is the development of hypertension, to ensure that there has been a robust screen for secondary causes. And if there is abnormalities on the ECG, because these are somewhat more prevalent in Turner syndrome population. It’s also important to consider that if any new medications are being given that may cause cardiovascular side effects or precipitate hypertension, that there may be a need for cardiology involvement at that point for these patients.

Depending on the age of the patient and the imaging technique used, congenital heart disease may impact 40 to 60% of patients with Turner syndrome. Some of this will simply reflect the fact that we do do more aggressive cross-sectional imaging and therefore lesions that may otherwise be silent are detected in these women. However, there is no doubt that there is a large increase in risk compared to the general population. Left-sided obstructive lesions are the most common and the rates are highest in the 45,X karyotype and lower in patients with mosaicism.

Many of these lesions will not be detected without advanced cardiac imaging, particularly cardiac MRI. And that’s why it’s important that these patients have a comprehensive screening. This looks at how common individual lesions are actually for patients with Turner syndrome. So you can see that it is up to 60 times more likely to have congenital issues compared to the regular population. Bicuspid aortic valve, 40 to 50 times more likely, coarctation, somewhere between 12 and 44 times more likely.

A bovine aortic arch, where the left common carotid arises from the brachiocephalic, at least twice as likely. An aberrant right subclavian artery, where the right subclavian arises as a fourth branch of the arch, up to 16 times more likely. Persistent left-sided SVC, which drains into the coronary sinus rather than regressing, more than 26 times more likely. And partial anomalous pulmonary venous return more than 40 times more likely. There’s also a markedly increased risk of hyperplastic left heart, but this is almost inevitably diagnosed in childhood and requires complex congenital repair, so not something you’re likely to see in an adult population.

The bicuspid aortic valve is present in up to 40% of women with Turner syndrome and is commonly associated with thoracic aortic dilation, coronary anomalies, coarctation, and other left-sided cardiac lesions. Although it is a common feature of Turner syndrome, it’s important to recognise that bicuspid valves are common in the general population and can be seen in one to 2% of patients. Therefore, the diagnosis of a bicuspid valve does not necessitate genetic evaluation unless there are other features of Turner syndrome present.

Echocardiography in bicuspid valves should be performed at intervals depending on the severity of stenosis or regurgitation and the presence or absence of aortic dilation. Generally with mild lesions, either stenosis or regurgitation, echoes are undertaken every three to five years, and with moderate lesions, echoes are taken between every one and two years. As both stenotic and regurgitant lesions move into the more severe category, echos are taken more frequently, up to every six months, and certainly cardiology should be involved in patients with more than moderate stenosis regurgitation.

Coarctation of the aorta is a narrowing of the descending aorta, typically located just distal to the left subclavian at the site of the insertion of the ductus in utero. About 30% of patients will have another associated congenital abnormality and approximately five to 15% of girls with coarctation have Turner syndrome. Therefore, genetic testing for Turner syndrome may be considered in patients who are found to a coarct. Clinical manifestations vary with age, and very severe lesions are almost inevitably picked up in childhood with presentations with heart failure. However, in older children and adults, premature onset hypertension is classic.

They can be treated either percutaneously or surgically, depending on the age of the patient and anatomy, although there is some concern in a Turner’s population specifically that there may be a higher risk of dissection with percutaneous treatment. It’s important to note that hypertension can and does persist after treatment of coarctation. and recoarctation rates after treatment, depending on technique, can be as high as 15%. So these patients are monitored throughout their lifetime. These patients are generally maintained under the care of a hypertension expert or an adult congenital cardiologist throughout their life.

The most feared association with Turner syndrome is aortic dissection, and the incidence of aortic dissection is much higher in Turner syndrome compared to the underlying population at 164 per hundred thousand patient years versus six in the general population. So a very marked increase. Similar to other genetic aortopathies, Marfan’s et cetera, we see dissection at a young age with an average age of 30 to 35. The risk factors that predispose to dissection are the presence of bicuspid valve, coarctation, rates are higher during pregnancy and the peripartum period. Patients who are hypertensive will experience higher rates of dissection. Where there’s a rapid increase in aortic dimension, which is defined as more than three millimetres a year, and absolute size is a key determinant. The greatest risk is where the aortic height index is more than 23 millimetres or the score is 3.5.

There are a number of ways that this is measured in adults and there’s not great consensus on which is the most appropriate way of indexing aortic measurements in women with Turner’s syndrome because of their short stature. Generally, there is an index for either height or body surface area, but there can be issues when indexing for body surface area, if the BSA is artificially inflated due to an increased BMI. I generally tend to use indexing for height in that situation. We do use echo as the mainstay of monitoring, but CT and MRI are more accurate. We will certainly ensure all women with dilation have at least one formal cross-sectional imaging. And then we will repeat this at times where they’re either planning for pregnancy or are approaching surgical cutoffs.

These are the guidelines for screening for aortic dilation in Turner syndrome below the age of 15. It is based on Z scores, paediatric Z scores, and depending on size, screening is more or less frequent. Over the age of 15, decisions are based on the presence or absence of risk enhancers. So bicuspid valve, hypertension or coarctation. And then absolute aortic size, with low risk patients being screened every five to 10 years, and high risk patients being screened up to every six months.

The interventional thresholds for aortic dilation in Turner syndrome are very different than in the general population. The most recent ESC guidelines on aortopathy would suggest that we intervene on most sporadic aortic dilations at somewhere in the vicinity of 50 to 52 millimetres. Whereas for Turner syndrome patients, it is based on indexed dilation, which will lead to us intervening at relatively small absolute dimensions, even down as low as four centimetres. You’ll see these women being sent and considered for surgery. Surgery can be high risk, given the comorbidities that these women experience. So it is an individualised decision as to exactly what aortic dimension to intervene.

In terms of exercise and activity with aortic dilation overall, generally the cardiovascular and metabolic effects of exercise benefits outweigh, vastly, the very small risk of exercise-associated dissection in these patients. And so we recommend the standard cardiac recommendations of 150 minutes of moderate physical activity for adults, and 60 minutes daily activity for children. But it is important to ensure that patients are evaluated from a cardiac point of view before beginning an exercise program. Generally where aortic size is normal, there is no restriction, but with mild to moderately dilated aortas, intense weightlifting activities are generally advised against. And when an aorta is moderate to severely dilated, competitive sport, intense weightlifting, and activities with high risk of contact injury are generally recommended against.

Hypertension is two to three times, sorry, three to four times more prevalent in Turner syndrome compared to the baseline population and affects up to 40% of children and 60% of adults. So the presentation is early and severity often progresses throughout life. Although it can be associated with coarctation or renal anomalies, a lot of it is sporadic and so patients should be seen annually and diagnosis should be confirmed, whether they’re home monitoring or 24-hour BP monitoring. It is important to note that 24-hour BP monitoring is only funded once a year, and for patients who are not on antihypertensive therapy. So your patients may experience a cost if they have already been commenced on medications.

Treatment depends on the presence or absence of aortic dilation. If aortic disease is present, there is a preference towards ARB and beta blockers. If there is not, it is simply guideline directed anti-hypertensive therapy. In keeping with the most recent European society guidelines, I aim for a blood pressure of one 20 to 129 on 70 to 79 in patients with no aortic disease. But I do aim more strictly if aortic dilation is present and aim to get the systolic blood pressure below 120 if tolerated.

Hypercholesterolemia is also highly prevalent, influenced by obesity, metabolic syndrome and diabetes. And there is some suggestion that Turner syndrome patients may have higher cholesterol compared to controls, impacting all aspects of the lipid panel. Where an elevated cholesterol is found, it’s important to exclude secondary causes, most notably hypothyroidism. And diet and lifestyle changes are the backbone of therapy for these patients. Statin therapy when needed is to standard primary and secondary prevention guidelines.

Ischemic heart disease is a major cause of morbidity, mortality, due to their multiple premature risk factors, particularly hypertension, diabetes, and metabolic syndrome. But there are no specific guidelines for routine coronary artery screening in Turner syndrome outside of standard preventative healthcare screening recommendations

Finally and briefly, cardiovascular disease and pregnancy are of particular note and importance in Turner syndrome patients, as pregnancy is a high risk window for aortic dissection. Women with Turner syndrome are also at increased risk of hypertensive disorders of pregnancy. Women therefore should have full cardiovascular imaging, ideally with CMR, within two years of a planned pregnancy. The majority of women tolerate pregnancy well, but severe valvular lesions and significant aortic is a very high risk situation and therefore patients need to be seen by a cardiologist with experience in cardio obstetrics as part of a multidisciplinary team, including maternal foetal medicine when pregnancy is planned.

I will refer you to the modified WHO 2.0 risk classifications for cardiac disease in pregnancy, which were recently announced in September at the European Society of Cardiology. Particularly these classify women into four risk categories, where a WHO category 4 is a very high risk pregnancy with a significant risk of maternal morbidity and mortality. In here, the relevant lesions for Turner syndrome patients are severe symptomatic aortic stenosis, which can be intervened on prior to pregnancy, but also aortopathy with an ASI of greater than 25 mls per metre squared in Turner’s syndrome. Risk counselling and generally recommendations against pregnancy are often considered in this case. Thank you.

Prof Beverley Vollenhoven: This is a subject that is pretty close to my heart, given I have a number of patients with Turner syndrome who have been successful in becoming pregnant. So as Amanda has alluded already, the majority of women with Turner syndrome are infertile. However, there are some women with Turner syndrome, and the classic Turner syndrome, who are XO who actually do become pregnant. And this is because they are XO in their peripheral blood, but they’re XX in their ovaries, and that’s where the eggs are going to be coming from. So I’ve had two patients like this who’ve been XO, and both of whom have become spontaneously pregnant, one after at the age of 14 freezing eggs, and she never actually used her eggs because she became spontaneously pregnant. So it’s quite important to understand that.

So the causes of early menopause or POI, that there’s a variant failure due to either absent or damaged ovarian follicles or an accelerated depletion of oocytes. So as we know, ovarian reserve declines in all women. That’s why women go through menopause. But the decline in someone with Turner syndrome is much faster. It may, in fact, a woman with Turner syndrome may never go through puberty, or they’ll become menopausal earlier if they have been having periods. And that’s compared to someone with a typical ovarian reserve.

So what can we do in the area of fertility preservation? And this encompasses three things, either oocyte cryopreservation, embryo cryopreservation, or ovarian tissue cryopreservation. The important thing to understand is that the fertility window is quite narrow. So if someone is having periods, their chances of pregnancy are going to be quite low. If a young woman, so teenager, let’s say, has gone through the process of puberty and has started to have periods, then oocyte cryopreservation may actually be a very good option for this young woman.

So to have oocyte cryopreservation, you need to have gone through puberty, and therefore be having periods, and there needs to be detectable ovarian function. So by detectable ovarian function, I mean not just having periods, but the FSH is not extremely elevated and the AMH is usually low, but hopefully not really very low. To have oocyte cryopreservation, it does require an IVF cycle. And that may be an issue for a lot of teenagers, though I must say I have a lot of young girls with POI, not necessarily Turner syndrome, who will have a go at an IVF cycle.

The other option is embryo cryopreservation. The issue with this is that it requires a partner, because we are actually going to be making embryos, not just freezing eggs. So this is not going to be an option in a young teenager. So then the third option is ovarian tissue freezing. And there are many pros and cons to this, and in someone who is to have chemotherapy, I think it’s now well established, if there is no time to freeze eggs or embryos, that freezing tissue is of value. In someone with Turner syndrome, it’s not as clear, because in someone who has Turner syndrome, their ovarian function is already reduced. And if you start slicing bits of ovary away, or as some have advocated actually removing one ovary itself, whatever ovarian function that is there will have disappeared. And so ovarian tissue cryopreservation may be something that’s used in young women who are prepubertal, but that is really still in the research realm. We don’t know how, if we take a tissue and freeze it, in a prepubertal girl, how that tissue is going to behave, or can we make that tissue behave like adult tissue with age.

So as I said, we are looking at removing, so slices done laparoscopically, slices of ovarian tissue are removed, or as I said, there’s a unilateral oophorectomy. So variant tissue cryopreservation is accepted as a standard, but that’s really in women who are undergoing chemotherapy. Not as much of a standard in young women with Turner syndrome, particularly if the tissue is to be removed prepubertally.

So these are the outcomes after tissue freezing in the general population. And these are, as I said, the women having had chemotherapy versus Turner syndrome. So what are the other fertility options? And in the end, egg donation is probably one of the best options for these women. And so obviously that means eggs from someone else. That person has an IVF cycle, donates the egg to the couple, donates the eggs to the couple, embryos are made, and then the embryo is transferred back to the patient with Turner syndrome.

An egg donation is obviously quite possible, and the main issue is that the donor should be young. So under the age of 35. And whose fertility is proved to be okay and whose ovarian reserve is normal. So in the end, this often is the most successful option, and we know that the chance that pregnancy with donor eggs can be 50%, which is very, very high compared to someone with low ovarian reserve. whose chances of pregnancy may be less than 1%. So pregnancy is possible, provided the uterus is functional, and I’ll talk about that in a second. So surrogacy is also an option, particularly if there’s a high cardiac risk, as Esther’s talked about. And then child-free living or adoption. So, as Esther’s also talked about pregnancy planning is one of the most important things in patients with Turner syndrome who are wanting to become pregnant. And these are important that, it’s elective pregnancy if you like.

And the reason that pregnancy planning is so important is because of the high risk of aortic dissection and maternal mortality. And there’s also not just that increase, but the increased risk of hypertension, diabetes, and then in pregnancy, preeclampsia, which is much higher if someone is already hypertensive before the pregnancy occurs. So it’s really important that they have good cardiovascular monitoring or are seen by cardiologists. And certainly all of my patients with Turner syndrome who are contemplating pregnancy, we’ll see a cardiologist prior to looking at getting pregnant, because it’s really important to know that they’ll try and achieve a pregnancy safely.

Endocrine evaluation is also very important, because these women may have impaired glucose tolerance, they may have thyroid issues, as Amanda has spoken about, with positive thyroid antibodies, liver abnormalities and their liver function can be affected. So it’s really important that, you want to optimise all of these things before a pregnancy is actually contemplated.

And a lot of these women are already on HRT, so because they’re on HRT, they would continue on that until they were ready to conceive. And then when they’re ready to conceive, the HRT would just change. If a woman is postmenopausal for whatever reason, we can always make the uterus functional, provided the uterus is a normal size. The uterus becoming functional just involves looking at the combination of oestrogen and then the progestogen that we would use in pregnancy.

So in times past, a lot of young women with Turner syndrome were not treated with HRT early, and so their uteruses never had the chance of growing. And we know that if a uterus is not a good size, you’re actually not going to get pregnant. So now that we do start HRT early, this is not as big a problem. It’s also important in a teenager to, and I’m not talking about pregnancy planning now, obviously, but it is also important in a teenager to look at using HRT early because as you know, young teenage girls can be really mean. And so if your friend doesn’t look like you in terms of there’s no breast development, et cetera, there can be quite a lot of bullying that occurs. So that’s why it’s also really important to look at hormones very early on so that everyone looks the same.

So in pregnancy, as Esther has said, there’s a risk of aortic dissection, et cetera. So it’s really important that this care occurs in a multidisciplinary team. So someone with Turner syndrome should not be delivering in a small country hospital. They should be in a tertiary centre. And there’s joint care with maternal foetal medicine specialists, cardiologist, and potentially endocrinologists, especially if the woman has diabetes. So blood pressure control is really, really important.

So postpartum, you don’t just say, “Bye, you’ve had your baby, now go away.” It’s also important that their heart is reassessed. They have ongoing endocrine follow up, particularly if they had subclinical hypothyroidism, and their thyroid function becomes normal post-pregnancy. And also it’s important for contraception counselling. So we know that in all women, there should be at least a nine month gap between pregnancies, and that decreases the risk of having a preterm birth in the next pregnancy.

If someone’s had a caesarean section, and these women with Turner syndrome are more likely to have a caesarean section, it’s important that they have between nine and 12 months between pregnancies. So if a spontaneous pregnancy has occurred, then some sort of contraception discussion is very important. And then obviously there’s a lot of psychological support. Amanda talked about the psychological support that occurs around diagnosis. But it is also important that there’s psychological support in pregnancy, because these are high risk pregnancies and often these women are terrified of what may happen. And so psychological support at that time is very important.

And as Esther has talked about, there are pregnancy contraindications. So this would be discussed between the cardiologist and the fertility specialist. And in someone like this, then surrogacy with the patient’s own eggs or with donor eggs is the option. And this is just some Monash health data that we collected now some time ago, looking at our patients with pure Turner syndrome, so 45,X XO and mosaicism. And we saw that, not surprisingly, the number of pregnancies were higher in the mosaic population, and they also had a greater number of live births. And as you can see in both groups, there wasn’t any cardiac, there weren’t any cardiac problems.

So Turner syndrome often leads to infertility, but it’s important to make sure that the patient understands that there are options. And often if a young girl comes to me, like at the age of 10 from a paediatric endocrinologist, and we are going to be talking about breast development, et cetera, I will start talking about fertility, because it’s important that they understand that they don’t have to necessarily remain childless because they’ve got this condition. It’s really important that that’s spelt out early. So early detection and intervention is critical, as I’ve said, not just for uterine size, but to make everyone look the same, which is important in the teenage years. And with proper care, there’s a possibility of pregnancy, and safe pregnancy. Thank you.

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