Turner Syndrome

Introduction

Turner syndrome is a chromosomal disorder affecting females. It has a wide phenotypic manifestation, including short stature and underdeveloped ovaries.

Females with Turner syndrome are born with only one X chromosome instead of the usual two X chromosomes. Turner syndrome occurs in 1 in 2000 baby girls.¹

Aetiology

The X and Y chromosomes are the sex chromosomes, with females having XX sex chromosomes and males having XY sex chromosomes.

In Turner syndrome, one X chromosome is missing, so the genotype is referred to as 45XO or monosomy X. This is most commonly caused by a non-disjunction mutation when a pair of chromosomes fail to separate during meiosis. It is a sporadic mutation meaning it isn’t inherited, and there are no known risk factors.¹

Up to 50% of patients with Turner syndrome have mosaic Turner syndrome meaning some cell lines have the 45XO genotype and some have the normal 46XX genotype. This means patients with mosaic Turner syndrome will have some but not all phenotypic features, so their management needs to be considered individually.¹

It is important to note that Turner syndrome affects many more pregnancies (it is estimated that up to 1% of conceptions are affected), but only 1% survive to term.¹

Clinical features

A diagnosis of Turner syndrome should be suspected in any girl with short stature or delayed puberty.²

Short stature

Women with Turner syndrome reach approximately 20cm less than average female height without treatment during childhood.

It is important to note that growth may be normal until three years old, as growth in this stage of development is driven primarily by nutrition. During childhood, the growth rate may slow and short stature becomes very apparent during puberty when they fail to undergo normal pubertal growth spurts. This is a result of hormone insufficiency secondary to ovarian dysgenesis.¹

Delayed puberty

Girls with Turner syndrome are commonly identified when they present concerned they haven’t undergone menarche like their peers. Amenorrhoea and infertility in Turner syndrome are caused by primary hypogonadism due to ovarian dysgenesis.

The degree of ovarian dysfunction is variable, particularly with mosaic Turner syndrome, and therefore, some girls with Turner syndrome may undergo normal menarche and adrenarche.¹

Systemic manifestations

Systemic manifestations of Turner syndrome include:³

• Renal tract abnormalities: the most pathognomonic being a horseshoe kidney (when the kidneys remain fused at the inferior pole and fail to ascend)
• Cardiac abnormalities: most commonly bicuspid aortic valve or aortic coarctation (narrowing of the aorta)
• Recurrent otitis media and conductive hearing loss
• Autoimmune disease: hypothyroidism, type one diabetes mellitus, coeliac disease

Clinical examination

In the context of suspected Turner syndrome, a thorough examination is required. This includes a full cardiovascular examination and growth assessment.

On general examination, peripheral stigmata of Turner syndrome include:³

• Webbed neck (Figure 2)
• Cubitus valgus (a wide carrying angle)
• Broad chest with widely spaced nipples
• Short 4^th digit
• Scoliosis
• Low set ears
• Low posterior hairline
• High arch palate
• Increased number of melanocytic naevi

On cardiovascular examination, findings may indicate aortic coarctation:³

• Radio-femoral delay
• Blood pressure: hypertension with a gradient between the upper limb and lower limb blood pressure
• Murmur: ejection systolic murmur heard loudest on the back at the inferior tip of the left scapula

Clinical features of Turner syndrome which may be seen in the neonatal period include:^1,4

• Neonatal peripheral lymphedema: can cause short and curved nails
• Cystic hygroma
• Stigmata of Turner syndrome (webbed neck, cubitus valgus and low-set ears) may be identified on the newborn physical examination (NIPE)

Differential diagnoses

Noonan syndrome is the main differential diagnosis to consider in the context of suspected Turner syndrome. This genetic disorder also presents with short stature, wide neck and associated cardiovascular defects.

However, Noonan syndrome is caused by an autosomal dominant mutation of the PTPN11 gene, and it can affect males or females.⁵

Other important differential diagnoses in the context of short stature and delayed puberty include:⁶

• Other causes of primary ovarian failure: chemotherapy or autoimmune ovarian failure
• Gonadotropin deficiency: secondary to pituitary diseases such as craniopharyngiomas (benign brain tumour which grows near the pituitary) or Kallmann syndrome (syndrome pathognomonic of delayed puberty and impaired sense of smell)
• Functional gonadotropin deficiency: secondary to malnutrition, over-exercise or chronic disease

Investigations

Bedside investigations

Relevant bedside investigations include:^1,3

• Blood pressure: there may be hypertension secondary to cardiovascular or renal disease
• Growth assessment: height and weight should be plotted on a growth chart so the response to growth hormone therapy can be monitored over time
• Urine dip: assesses for complications of renal tract abnormalities such as a urinary tract infection (raised leukocyte esterase and nitrites will be seen)

Laboratory investigations

Relevant laboratory investigations include:^1,3

• Karyotyping: chromosomal analysis will identify the 45XO mutation
• Blood tests to screen for autoimmune complications: thyroid function tests (hypothyroidism), blood sugar (type one diabetes), anti-TTG and IgA to screen (coeliac disease)
• Hormone tests: FSH, LH and oestrogen to identify primary hypogonadism secondary to ovarian dysgenesis (high FSH and LH and low oestrogen will be seen)
• Metabolic profile: fasting glucose and cholesterol to screen for type two diabetes and hypercholesterolemia, which are more common in adults with Turner syndrome

Imaging

 Relevant imaging investigations include:^1.3

• Echocardiogram: screen for bicuspid aortic valve and aortic coarctation. Further imaging including cardiac MRI may be required
• Renal tract ultrasound: identify structural abnormalities of the renal tract
• Pelvic ultrasound: used to check for the presence of the uterus which will affect decisions regarding pregnancy in the future
• DEXA scan: to identify osteoporosis

Other investigations

 Other relevant investigations include: ^1.3

• Pure tone audiometry: screen for a conductive hearing loss

Diagnosis

Turner Syndrome is diagnosed via karyotyping, which shows a missing X chromosome.

Karyotyping is usually performed after a detailed history and examination. Most commonly, Turner syndrome is diagnosed in late childhood, but Turner syndrome may be suspected on prenatal ultrasound scans when the following are seen:¹

• Horseshoe kidney
• Aortic coarctation
• Fetal lymphedema

If Turner Syndrome is suspected in-utero, amniocentesis or chorionic villus sampling can be performed to allow for karyotyping of the fetal chromosomes.¹

Management

Hormone replacement therapy is the mainstay of management for Turner syndrome.²

Hormone replacement therapy

Oestrogen

Oestrogen replacement therapy is started at age 11, and the dose is increased slowly to mimic the normal physiological process of puberty. Oestrogen can be given as a gel, tablet or patch.

The role of oestrogen is to:

• Trigger breast development
• Maintain uterus health
• Maintain bone mineral density to prevent osteoporosis

Progesterone

Progesterone replacement therapy is started after oestrogen replacement therapy.  It can also be given as a tablet or patch. The role of progesterone is to trigger menarche and maintain a normal menstrual cycle.

Both oestrogen and progesterone are given until around age 50 when sex hormones naturally decrease when a woman enters the menopause. Hormone replacement can continue beyond 50 after considering the risks and benefits. 

Growth hormone

Growth hormone is given as a daily injection from age 5-16 to help trigger growth. On average, patients with Turner syndrome undergoing growth hormone replacement therapy grow 5cm taller than those without.

Multidisciplinary management

A multidisciplinary management approach is required in Turner syndrome:²

• Geneticist: involved in the diagnosis of Turner syndrome
• Endocrinologist: manage hormone replacement therapy and autoimmune disease
• Nephrologist: monitor blood pressure and manage any complications of renal tract abnormalities
• Cardiologist: monitor and treat cardiovascular abnormalities
• ENT: monitor and treat otitis media and conductive hearing loss
• Obstetrician: in vitro fertilisation and close monitoring during pregnancy
• Psychologist: support with behavioural problems and the mental health consequences of having a chronic condition that affects growth, fertility and appearance.
• General practitioner: often the first medical professional to suspect a diagnosis of Turner syndrome when patients present with short stature or delayed puberty.

Complications

Complications of Turner syndrome include:^1,2

• Autoimmune diseases: hypothyroidism, type one diabetes mellitus and coeliac disease
• Recurrent otitis media and glue ear: may lead to a conductive hearing loss
• Increased risk of urinary tract infection: due to structural abnormalities of the urinary tract
• Osteoporosis secondary to low oestrogen: oestrogen promotes osteoblastic activity required to produce bone
• Hypertension secondary to renal and cardiac abnormalities: hypertension must be managed effectively to reduce the risk of cardiovascular complications in later life (e.g. stroke or aortic dissection)
• Higher rates of type two diabetes mellitus and hyperlipidaemia. This is reflected in the mortality rates of Turner syndrome, for which the most common cause of death is non-congenital cardiovascular disease, including coronary artery disease and stroke.

Key points

• Turner syndrome is a chromosomal disorder affecting females where one X chromosome is missing
• The classical features of Turner syndrome are short stature and delayed puberty
• Turner syndrome has systemic manifestations in the renal tract (e.g. horseshoe kidney) and the cardiovascular system (e.g. aortic coarctation)
• The classical stigmata of Turner syndrome are a webbed neck, wide space nipples and a wide carrying angle
• Turner syndrome is diagnosed with karyotyping to identify the missing chromosome
• Growth hormone, oestrogen and progesterone replacement therapy is the mainstay of management in Turner syndrome

Reviewer

Dr Kayleigh Weedon

General Practitioner

Honorary Associate Professor | University of East Anglia

Editor

Dr Chris Jefferies

References

1. UpToDate. Clinical manifestations and diagnosis of Turner syndrome. Published in 2022. Available from: [LINK]
2. Patient.info. Turner syndrome. Published 2021. Available from: [LINK]
3. BMJ Best Practice. Turner’s syndrome. Published 2021. Available from: [LINK]
4. NHS Health. Turner syndrome. Published 2021. Available from: [LINK]
5. Patient.info. Noonan syndrome. Published in 2016. Available from: [LINK]
6. GP notebook. Delayed puberty. Published in 2021. Available from: [LINK]

Image references

• Figure 1. Unknown author. 45,X. License: [Public domain]
• Figure 2. Imen Mehri Turki.Preoperative webbed neck in Turner syndrome. License: [CC BY]