Turner syndrome – The clinical spectrum and management dilemmas

Abstract

Introduction

Turner syndrome (TS) is a common sex chromosome disorder, with a varied clinical spectrum and prognosis. It may range from the complete phenotype of TS characterised by short stature, ovarian failure, cardiac and renal abnormalities, with milder variants often associated with mosaic TS.

Materials and Methods

We describe five cases of TS.

Results

In case 1, complete TS was identified by first‐trimester screening with a grossly oedematous fetus at 11 weeks of gestation and underwent medical termination of pregnancy due to the dismal prognosis. In case 2, a hydropic fetus and large cystic hygromas were identified at routine second‐trimester morphology scan. Intra‐uterine fetal death was identified at 22 weeks of gestation and formal karyotype confirmed complete TS. Case 3 demonstrates the potential for a successful live birth of mosaic TS with mild neurocognitive and renal abnormalities. Case 4 demonstrates the ability for TS to go undetected until adolescence where the patient was diagnosed at 15 years of age during investigations for severe anaemia, identified as secondary to critical aortic stenosis and Heyde's syndrome. Case 5 highlights the potential for patients with TS to reproduce with assisted reproductive technology.

Discussion

These cases explore the prognostic spectrum of TS and highlight that they have a potential to lead productive and fulfilling lives.

Conclusion

Consequently, a multimodal risk stratification approach to prognostic counselling should be under‐taken with consideration of pertinent history, major sonographic abnormalities, maternal serum testing and invasive testing.

Introduction

Turner syndrome (TS) is the commonest sex chromosome abnormality in females, affecting approximately 3% of all females conceived. Lower prevalence of live‐born infants with TS is attributed to high rates of spontaneous miscarriage in up to 15%, with only 1% of complete TS 45,XO surviving to term.1, 2, 3, 4

The genetic disorder is characterised by short stature, premature ovarian failure and cardiac abnormalities.1 While signs are less frequent and often milder in the mosaic subtype, which occurs in up to 91.7% of ultrasound (US) positive TS diagnosis, mortality increases threefold compared to the general population and requires close monitoring and management of multi‐organ complications.2 Both complete and mosaic karyotypes have the potential for normal intellect and have a large spectrum of functionality, presenting a management dilemma in antenatal diagnosis.1 Although most women are infertile, assisted reproductive techniques with oocyte donation have shown 30–46% successful pregnancies from embryo transfers, with surrogacy, adoption and rare cases of spontaneous pregnancy as other options.5

Antenatal diagnosis is often made through identification of typical features and/or soft markers such as echogenic bowel and increased nuchal translucency identified on US.6 This case series aimed to explore five cases of TS and outline the diagnostic and management decision‐making response.

Case series

Case 1: first‐trimester diagnosis (Medical TOP)

The patient was a 16‐year‐old nulliparous Caucasian woman who was referred for further investigation as a diffusely oedematous fetus was identified on a first‐trimester scan performed for early pregnancy bleeding in an otherwise uncomplicated pregnancy. At thirteen weeks, serial scans identified a nuchal translucency of 8.9 mm, the development of bilateral pleural effusions and ascites. Chorionic villus sampling (CVS) identified a karyotype of complete TS (45,XO). A repeat tertiary US at 14 weeks demonstrated ongoing fetal heart activity, symmetrical fetal growth and normal AFI, but increasingly severe anasarca with large bilateral cystic hygromas. Counselling was provided, and parents were advised on the high likelihood of intra‐uterine fetal demise (IUFD) and termination of pregnancy was recommended (Figure 1).

Figure 1.

(a) US Image Showing an Increased Nuchal Thickness of 8.93 mm at 13 weeks of Gestation. (b) US Image Demonstrating Large Cystic Hygroma at 13 weeks of Gestation in Grossly Oedematous Fetus with Fetal Hydrops. (c) US Image Showing Generalised Oedema of Fetal Hydrops with Ascites at 13 weeks. (d) US Image Demonstrating Pleural Effusion at 13 weeks of Gestation in Grossly Oedematous Fetus with Fetal Hydrops.

Case 2: second‐trimester diagnosis (IUFD)

The patient was a 27‐year‐old Caucasian primi gravid woman who was referred as her routine morphology scan revealed large cystic hygromas, fetal hydrops, oligohydramnios and asymmetrical intra‐uterine growth restriction (IUGR) with fetal heart activity at 20 weeks of gestation. Other than maternal obesity with a BMI of 30 and heterozygous status for factor V Leiden, the pregnancy was uncomplicated with no history of chromosomal abnormalities, maternal infections, adverse antenatal events or teratogen exposure. Amniocentesis revealed a karyotype of complete TS (45,XO) and parents opted for conservative management with IUFD at 22 weeks of gestation (Figure 2).

Figure 2.

(a) US Image Showing Bilateral Cystic Hygromas and a Well‐defined Ligamentum Nuchae at 20 weeks Gestation. (b) US Image Showing Significant Fetal Hydrops and Ascites at 20 weeks.

Case 3: mosaic TS live birth

A 34‐year‐old woman successfully gave birth to a neonate with mosaic TS at 39 weeks of gestation after an uncomplicated pregnancy and normal routine antenatal imaging. Diagnosis was based upon positive first‐trimester screening results and subsequent amniocentesis, which identified the mosaic TS karyotype (45,XO/47,XXX). Postnatal analysis confirmed Monosomy X constituting 7.14% on BACs‐on‐Beads™ (BoBs™) karyotyping and 8.5% on FISH analysis. We describe her pre‐pubertal appearance as a phenotypically normal 8‐year‐old girl. Her growth parameters lie within the normal range, with appropriate linear growth between the 10th and 25th percentile. She has no dysmorphic features and has healthy skin with no cutaneous markers commonly associated with TS.

However, she was born with a duplex kidney undetected on antenatal US, requiring an excision of the ureterocele at 3 months after signs of renal obstruction. As follow‐up, a repeat US at age 4 has revealed a small right kidney at 6.1 cm and a normal left kidney of 7.2 cm. The patient also has a history of recurrent urinary tract infections with cultures growing Escherichia coli as the causal organism. She has been treated with prophylactic and treatment courses of antibiotics with good effect. No hormonal therapies have yet been indicated but will have to be considered as her development progresses.

Psychosocially, she is able to maintain friendships at school and has normal social and emotional development. She attends primary school and has been noted to have difficulties with maintaining attention, completing tasks and academic progress. She has been diagnosed with ADHD and is being treated with Ritalin. There has been an ongoing issue with toileting, which is perpetuating her chronic constipation and enuresis (Figure 3).

Figure 3.

(a) Neonatal US at Age of 1 week Demonstrating Duplex Kidney. (b) Neonatal US with Trans‐abdominal Colour Doppler US Image at Age of 1 week Dual Blood Supply for Duplex Kidneys. (c) Antenatal Morphology US Showing Coronal View of Normal Kidneys at 19 weeks.

Case 4: atypical mosaic TS with late diagnosis

The patient is a fifteen‐year‐old girl who has had an incidental diagnosis of mosaic TS. Antenatally, no first trimester screen was performed and the US findings were unremarkable. She required no paediatric input until she was diagnosed with severe iron deficiency anaemia at fifteen years of age with a haemoglobin of 50 and mean cell volume of 55, requiring blood and iron transfusions. With no definitive cause for her anaemia and a background of dysmenorrhoea, investigations revealed a karyotype of Mosaic TS (45,XO/47,XXX) with Monosomy X for 2.9% on BoBs™ karyotyping, but 36% on FISH analysis. It was incidentally noted that she had short stature and her growth was along the 10th centile. A critical supravalvular aortic stenosis was identified and the cause of her anaemia attributed to a secondary Heyde's syndrome. She is otherwise well with no renal abnormalities and normal neurocognitive and psychological development (Figure 4).

Figure 4.

(a) Cardiac MRI Identifying Critical Supravalvular Aortic Stenosis in Fifteen‐Year‐Old Girl in Coronal View. (b) Cardiac MRI Identifying Critical Supravalvular Aortic Stenosis in Fifteen‐Year‐Old Girl in Sagittal View.

Case 5: successful pregnancy in maternal complete TS

The patient is a 26‐year‐old female with complete TS referred for the management of her successful pregnancy with a donor egg and the use of assisted reproductive technology. She displays significant phenotypic features of TS with typical facies, webbed necking, abnormal toes, short stature and premature ovarian failure. Despite orthopaedic surgery for the correction of her bony abnormalities of her feet, she has had no severe cardiac or renal complications of TS and has normal neurocognitive and psychological development. She consequently had an uncomplicated pregnancy with spontaneous vaginal delivery at 38 weeks of gestation. She had no psychological concerns indicative of postnatal depression and developed good bonding with the baby.

Discussion

Turner syndrome exists with various karyotype and phenotypic variation in 1:2500 live female births. More common features include short stature and gonadal dysgenesis, with 15‐50% exhibiting associated cardiac malformations, namely coarctation of the aorta and ventricular septal defects. Oedema of the hands and feet is a common finding in newborns, with renal abnormalities such as horseshoe kidney and agenesis found in a third of females with TS. Intelligence is usually normal; however, intelligence quotient is usually 10–15 points lower than siblings. Mild speech and language delays, psychosocial difficulties consistent with autism spectrum disorder, difficulties with spatial perpetual, vision‐motor integration and social adjustment are commonly reported, and are associated with haploinsufficiency for sex chromosome genes.1, 3, 4, 7

Most women with TS are infertile but live independent lives with the necessary cardiologist, endocrinologist and paediatrician involvement, and ongoing psychological support with potential roles for growth hormone treatment and educational assistance. While ovarian failure is a typical feature in TS, reproductive options include adoption or surrogacy, and assisted reproductive techniques (ART). While these are the only options for complete TS due to streak gonads, rare cases of spontaneous pregnancy are demonstrated in mosaic TS with Doger et al. demonstrating rates of spontaneous pregnancy in 5% at 6 months, and 8% at 2 years in mosaic TS.8, 9, 10, 11 These small proportions of mosaic TS conceiving in the first 2 years where pregnancies are complicated by high rates of miscarriage at 67.3% indicate that intervention should still be considered early within this period and at a much younger age if possible with take home baby rates with ART at 5.7% per IVF cycle.11 For those who have undergone ovarian failure, hormone replacement therapy is necessary to achieve the development of normal female sexual characteristics and to prevent cardiovascular complications and osteoporosis.

Ultrasound findings

Major US abnormalities are detected in 13.4% of TS and 30% within the first trimester from presence of phenotypic signs.4, 7, 12 Papp et al. has identified hygromas colli, tri‐lobed septation of a cystic mass and fetal hydrops to be the most common sonographic findings and increased nuchal fold to be the most predictive marker for all major aneuploidies with greater than 90% detection rates.4, 13, 14, 15 Cystic hygromas are identified as a high‐risk feature for adverse fetal outcome with normal phenotype reported in less than 10% of cases, and 20% of affected cases associated with cardiac abnormalities.16, 17, 18, 19, 20 While the presence of cystic hygromas are pathognomonic for TS, various studies identify cystic hygromas to occur in a various other aneuploidy disorders such as Down's syndrome and Noonan's syndrome, indicating the need for definitive diagnosis with cytogenic studies to confirm TS.18, 21

Other significant findings on US include renal, left‐sided cardiac defects, ventriculomegaly and echogenic bowel.3, 4 Associated cardiac abnormalities include coarctation of the aorta, hypoplastic left heart syndrome and myocardial hypoplasia. The finding of low heart weight is less commonly seen in other aetiology, and thus, it can be hypothesised that myocardial hypoplasia is a primary defect of TS and a point for diagnostic differentiation and a contributor to mid‐gestational death.22 While US positive cases of TS have higher rates of spontaneous foetal loss and medical termination, US remains a key tool for prognostication and it is important that clinicians are aware of the multifaceted risk stratification process.3, 4, 12, 23

Serum screening levels

Like ultrasonography, maternal serum testing provides another minimally invasive screening tool, which is able to identify fetuses at high risk of aneuploidy. An accurate triple test is able to differentiate high‐risk aneuploidy, with its value determined by laboratory, accuracy of gestational age and structural abnormalities on US.24 The relevance of this test to TS is validated with a rate of detection greater than 90% in the combined first‐trimester screening which combines nuchal translucency and serum biochemical markers (Free beta‐hCG and PaPP‐A).15, 25

Testing cell‐free DNA (cfDNA) is being clinically applied as another non‐invasive fetal screening test to identify the most common chromosomal aneuploidies. While some recent studies have proposed the introduction of cfDNA testing in routine clinical practice emphasising its high sensitivity and specificity, reports demonstrate inconsistencies between cfDNA analysis and subsequent karyotype.26 This can be attributed to the majority of cfDNA in the maternal plasma being derived from trophoblastic tissue and that placental mosaicism occurs in between 0.8 and >2% of viable fetuses and can give discordant and thus invalid results. Consequently, the joint American College of Obstetrics and Gynecology (ACOG) and The Society of Maternal‐Fetal Medicine (SMFM) Committee have concluded ‘a negative cfDNA test result does not ensure an unaffected pregnancy. A patient with a positive result should be referred for genetic counselling and should be offered invasive prenatal diagnosis’ as CVS and amniocentesis represent the only forms of prenatal diagnostic tests (Table 1).26

Table 1.

Marker pattern in multiple of median and detection rates in aneuploidies 1

Aneuploidy	NT	Free beta‐hCG	PAPP‐A	Detection rate (%)
45,XO	4.76 MOM	1.11 MOM	0.49 MOM	>90
Trisomy 21	2.67 MOM	2.15 MOM	0.15 MOM	90

MOM, multiple of median; beta‐hCG, beta human chorionic gonadotropin; NT, nuchal translucency; PAPP‐A, pregnancy‐associated plasma protein‐A.

Invasive testing

While ultrasonography soft markers and positive maternal serum screening are risk factors for fetal disease, they are screening tools and should not be considered diagnostic of TS. They should rather facilitate invasive testing by chorionic villus sampling (CVS) or amniocentesis for determining formal karyotype.4 Amniocentesis is the most common means of fetal chromosome analysis and can be performed from 15 weeks onwards. Alternatively, CVS is performed between 11 and 14 weeks of gestation and has the benefit of an earlier diagnosis and higher positive predictive value of 67% compared to 21%. CVS is however associated with an increased risk of antepartum bleeds, spontaneous miscarriage, placental abruptions and incorrect diagnosis due to confined placental mosaicism, especially in individuals with high incidence of monosomy X.27

The issues with invasive testing are highlighted in a study conducted on prenatal and postnatal TS which identifies the relative risk of diagnosis to be 5.68 on amniocentesis and 13.3 on CVS, but a positive predictive value between 21% and 67%.28 This level of uncertainty causes stress in management decisions once a positive invasive test is achieved and highlights the importance of timely and comprehensive genetic counselling.

Cytogenetic results are available within a few hours with rapid aneuploidy tests (RATs) for common aneuploidies with methods such as quantitative fluorescence polymerase chain reaction (QF‐PCR) and more commonly used bacterial artificial chromosomes (BACs)‐on‐Beads (BoBs™) technology with a superiority of being able to detect specific microdeletion syndromes.29 While both these tests have a diagnostic accuracy of between 97.5% and 99.8%, they are performed on cultured cells and are subject to culture bias.29 The performance of fluorescence in situ hybridisation (FISH) as a complementary test on uncultured cells is able to provide a quick confirmation of karyotyping results and also obtain information about the extent of mosaic chromosomal abnormalities. These results are not subject to culture bias described by Sheng‐Yuan et al. which are demonstrated by discrepant results between the tests as seen in case 4 with Monosomy X demonstrated in only 2.9% on BoBs™ and 36% on FISH analysis. Here, the latter is more consistent with the significant phenotype seen in the patient and is less likely to have been affected by cultural bias, increasing information available at the time of parental counselling in considering possible phenotype of an antenatally diagnosed TS.30, 31, 32

Management plan

The question to terminate a prenatally diagnosed TS is challenging, with risk stratification and comprehensive genetic counselling as key determinants to an informed final decision. Multidisciplinary input is imperitive as Grunchy et al. demonstrating the successes of this with a significant decrease in rates of termination of affected fetuses, notably those with numerous good prognostic features of mosaicism, incidental and/or later diagnosis, and unremarkable US.33 This highlights the combined role of sonographers, specialist obstetricians, maternal‐fetal medicine specialists, geneticists, social workers and support groups for parents.

A systematic approach to risk stratification should be taken through a detailed history, consideration of differential diagnosis and the spectrum of disease, maternal serum markers, US findings and karyotyping. The use of a multifactorial risk stratification system is reinforced by the pitfalls of karyotyping. While karyotyping is definitive in most cases, the detection of mosaicism depends on the proportion of cells present from the additional cell lineages. Routine testing karyotyping is able to detect mosaicism at a level of about five per cent, but the presence and degree of mosaicism may differ between different tissues with high frequency of tissue‐specific mosaicism.34, 35, 36 Studies demonstrate the severity of the syndrome to be directly proportionate to the magnitude of abnormal cell populations and significant phenotypic changes occurring from 6% aneuploidy.37

Parents should be counselled on termination options, alternative choices and their associated risks and benefits. Risk stratification can be summarised in the compilation of positive and negative prognostic factors, and with appropriate parent counselling to ensure informed decisions are being made about terminations after understanding the viability of TS in adult life (Table 2).

Table 2.

Prognostication features

	Better prognosis	Worse prognosis
Diagnosis method	(Incidental) Amniocentesis	Ultrasound features identified
Karyotype	Mosaic	Complete 45,XO
Degree of mosaicism	Less than 6% aneuploidy	6% Aneuploidy and above2
Gestation	Late diagnosis	Early diagnosis
USS findings	Nil	Abnormal growth and/or structural defects
Triple test	Negative	Positive
Maternal serum beta‐hCG	Normal (1 MOM)	Increased (1.11 MOM) 1
Maternal serum PAPP‐A	Normal (1 MOM)	Decreased (0.49 MOM) 1
Nuchal translucency	Normal (1 MOM)	Increased (4.76 MOM) 1
Cardiac defects	Absent	Present
Other anomalies	Absent	Present
AFI	Normal	Oligohydramnios
Cystic hygromas	Transient	Persistent
Septations of CH	Absent	Present

These prognostic findings can be applied to the cases discussed, where cases 1 and 2 both reflect poorer prognostic features. Case 1 is confirmed as complete TS on CVS, with preceding positive first‐trimester screening and positive findings on first‐trimester US with pleural effusions, ascites, and persistent, septated cystic hygromas. Case 2 is identified as complete TS on amniocentesis, with second‐trimester US findings of oligohydramnios and growth restriction., septated cystic hygromas and fetal hydrops. Case 3 contrasts these cases with persistently normal US findings with an incidental finding of a positive first‐trimester screen which consequently identified mosaic TS diagnosis on amniocentesis. The case has no other complicating factors and has lead to a successful live birth with mild renal abnormalities causing recurrent UTIs and behavioural issues, in an otherwise functional and fulfilling life. This outcome is reinforced by case 5 where ART is used for successful procreation in the setting of streak gonads of complete TS. Case 4 emphasises the need for first‐trimester serum screening and invasive testing as stigmata of aneuploidy was missed on US in an atypical case of mosaic TS. This was despite the presence of gross cardiac abnormalities and the diagnosis was eventually made at fifteen years of age.

Conclusion

While karyotyping provides guidance in confirmation of diagnosis and the distinction between mosaic and complete TS, the evidence of multi‐organ involvement is a significant prognostic indicator. Consequently, the irreversible decision to terminate a TS pregnancy should be made after multidisciplinary and comprehensive maternal counselling with discussion of prognostic factors for poor fetal outcome as they have the potential to lead functional and productive lives.7, 14

Consent

Verbal consent was obtained from the patients for use of any de‐identified ultrasound images as well as the publication of this case report.

Competing interests

The authors declare that they have no competing interests.

Authorship declaration

The authorship listing conforms with the journal's authorship policy, and all the authors are in agreement with the content of the submitted manuscript.

Disclosure statement

Cases included in this review were from Redcliffe Hospital, Queensland. The authors acted as a consultant and resident medical officers at this hospital during the period that the research was designed and conducted over the period of 2011 to 2018.

Author's contributions

AK contributed to the performance and interpretation of ultrasound scans. AK, KT and KC completed the final manuscript and compiled the ultrasound images.