Turner syndrome is the clinical picture caused by one missing X chromosome in a girl or a woman.
The karyotype is 45,X. The syndrome may be mosaic, i.e. only some of the patient's cells are affected, or one X chromosome may be structurally aberrant.
The incidence of Turner syndrome is estimated at about 1/2 200-1/2 500 newborn girls.
It usually causes short stature, ovarian dysfunction and a variety of other symptoms.
Certain increased risks of disease must be considered when following up on the patients' health, also in adulthood.
Aetiology
In most cases, the syndrome is not hereditary but an incidental chromosomal aberration usually occurring due to disturbed gamete division or at an early stage of embryogenesis.
In 45,X mosaicism, the clinical picture may be milder.
The syndrome may also be due to structural aberration of the X chromosome, such as a ring chromosome or deletion in one X chromosome. In such cases, the clinical picture varies and may be milder.
Some patients also have a cell line including the Y chromosome, in which case the risk of gonadoblastoma is increased.
Diagnosis
A 45,X set of chromosomes may cause severe foetal oedema. This can be found in a chromosome study during pregnancy that is either done for this reason or, if done for another reason, sometimes as a random finding.
The chromosomal aberration may be detected in childhood when investigating small size or sometimes oedema. There may be few other symptoms, and a chromosome study should form a part of the basic studies of any girl examined for slow linear growth Normal and Abnormal Growth in Childhood.
Turner syndrome is usually diagnosed when examining delayed puberty in adolescence, at the latest.
It can be found by chromosome analysis in blood (or other tissue, such as the placenta or amniotic fluid), i.e. a karyotype test, or ordinary chromosome test (the possibility of mosaicism should be considered); in most cases, it can also be detected by molecular karyotyping (array comparative genomic hybridization, arrayCGH).
A diagnosis made during pregnancy should be confirmed by chromosome analysis of a blood sample after birth.
With advancing age, it is normal for 45,X mosaicism to be found in chromosome analysis of a blood sample in a small share of a woman's cells. This is a normal phenomenon related to ageing and does not always require further investigations (< 5% mosaicism in a woman over 50). When interpreting the result of chromosome analysis, the degree of mosaicism, the woman's age and health should be considered.
Signs and symptoms
In the foetal period
A 45,X set of chromosomes may be associated with severe foetal oedema, involving a high risk of miscarriage.
In babyhood
Symptoms are often absent or only mild.
There may be oedema of the hands and metatarsi due to lymph vessel failure, an extra skin fold in the neck, and size at birth may be smallish.
A congenital heart defect is found in 15-50% of babies (such as coarctation of the aorta or a bicuspid aortic valve).
In childhood and school age
Usually causes short stature; linear growth in middle childhood is 2-3 SD less than expected Normal and Abnormal Growth in Childhood. The mid parental height influences the child's height, and some girls grow along the normal curves for the population.
Other features may include a short neck, neck skin folds, low hairline, or rather wide chest, for example. The external features are often mild or absent.
Recurrent otitis media is common, and there is also a risk of sensorineural hearing loss.
About 25% of patients have a structural renal or urinary tract anomaly (such as horseshoe kidney or renal agenesis). These may be asymptomatic or predispose the patient to recurrent UTIs.
The risk of autoimmune thyroiditis and resulting hypothyroidism is increased.
A squint and scoliosis occur slightly more often than average.
The syndrome does not involve intellectual disability but there may be learning difficulties (such as problems with abstract or mathematical perception) and challenges associated with social relationships.
In puberty and adolescence
Due to an insufficient number of egg cells or ovarian dysfunction, puberty may not begin at all or not proceed normally. There will be no growth spurt or development of secondary sex characteristics, and menstrual cycles will not begin. Hormone therapy to initiate puberty is used to ensure both the development of external signs of puberty and psychosocial development in pace with the peers.
In some girls, puberty begins spontaneously, and about one in five have spontaneous menarche (more often those with mosaicism or structurally aberrant X chromosome). Yet, ovarian function often ceases quickly, leading to climacterium praecox.
As the pubertal growth spurt does not occur, short stature may be emphasized.
In adulthood
The syndrome usually involves infertility. Spontaneous pregnancies occur in about 5-8% of women with Turner syndrome, usually those with mosaicism or structurally aberrant X chromosome.
The average adult height without growth hormone therapy is 147 cm.
There may be multiple pigmented naevi and a tendency to develop keloids.
The syndrome involves a tendency to hypertension, hypercholesterolaemia and overweight. The risks of coronary artery disease, stroke and diabetes are increased.
The risk of dilated aortic root is increased even if no congenital cardiac anomaly has been detected and blood pressure levels are normal.
Slightly increased aminotransferase levels are common. Sufficient oestrogen doses may correct this to some extent. The cause of hepatic dysfunction is unclear. Hepatic dysfunction rarely becomes severe.
Sensorineural hearing loss may develop in adulthood.
The risk of autoimmune diseases (such as hypothyroidism, coeliac disease, type 1 diabetes, inflammatory bowel diseases) is increased.
There is a risk of osteoporosis in patients not receiving sufficient hormone replacement therapy.
Mental symptoms, such as anxiety and challenges associated with social relationships, occur in some women with Turner syndrome.
The risk of developing breast cancer is lower than on population level.
Age-related mortality is increased mainly due to cardiovascular diseases.
Treatment and follow-up
In childhood and adolescence
In specialized care, a paediatric endocrinologist is usually responsible for the treatment and, from around puberty onward, also a(n) (adolescent) gynaecologist.
Risk of congenital structural anomaly
Echocardiography and ultrasonography of the urinary tract
Due to the risk of aortic dilatation, echocardiography about every 5 years is recommended even if nothing abnormal has been found in previous examinations.
Any structural abnormality of the heart should be treated normally.
Prophylaxis for UTI should be started, as necessary. Surgical treatment of vesicoureteral reflux is sometimes necessary.
As puberty age approaches, the timing of hormone therapy to start puberty should be considered. If gonadotropin levels are at normal prepubertal level, spontaneous onset of puberty can usually be awaited.
The need for contraception should be discussed with adolescents with menstrual cycles (even if irregular).
The girl or young adult, at the latest, should be provided with age-appropriate counselling on issues and treatment possibilities related to fertility.
The situation should be followed up as required by any growth hormone therapy or hormone therapy to start puberty. Monitoring of thyroid levels is usually also recommended in childhood, already, of blood glucose and liver values annually, and of 25(OH)D values about every 3-5 years from about the age of 10 years.
Coeliac screens from the age of 2 years about every 2 years
Hearing tests about every 3 years
Annual skin checkups
Learning difficulties should be assessed and supportive measures planned without hesitation.
Attention should be paid to weight management particularly after the end of linear growth.
The girl and her family should be offered genetic counselling.
When follow-up by a paediatric endocrinology unit and possibly by an adolescent gynaecology unit ends, it is important to refer the patient for any follow-up in adulthood that may be needed. The transition stage carries a risk of falling out of follow-up.
In adulthood
Any woman with Turner syndrome should have a designated doctor responsible for her follow-up. In many cases, this is a gynaecologist, but it may also be a physician in primary health care or some of the monitoring may be done in primary health care.
Treatment and examinations for infertility or impaired fertility should be done in specialized care in a unit with expertise in the treatment of childlessness. In some cases, it may be possible for pregnancy to begin without treatment and, in others, donated egg cells may make it possible.
Pregnancy in a woman with Turner syndrome is a high-risk pregnancy and should be followed at least by a perinatologist familiar with the syndrome and by a cardiologist. Pregnancy carries an increased risk of miscarriage, aortic rupture or dissection, and a higher than normal risk of hypertension and pre-eclampsia.
If a woman with Turner syndrome does not wish to get pregnant, she will need hormone replacement therapy in sufficient doses until the average menopause age and thereafter according to individual assessment. This should be planned by a gynaecologist.
As the risk of aortic dilatation and dissection is increased, echocardiography and, as necessary, MRI of the heart should be performed regularly, normally every 5-10 years, even if the cardiac findings are normal and no hypertension has been detected. Such monitoring should be done by a cardiologist.
Antihypertensive medication should be started without hesitation if blood pressure levels exceed 130/80 or at levels of 140/90 mmHg, at the latest. If a heart defect or aortic dilatation has been diagnosed, treatment should be started earlier. Treatment with a beta-blocker and/or an ATR blocker is recommended.
Lifestyle guidance and lifestyle treatment concerning cardiovascular diseases should be provided.
Assessment of any need for support due to mental symptoms
Other health monitoring (can usually be done in primary health care)
ALT, ALP, HbA1c, fasting blood glucose, TSH, free T4 should be tested every year, as well as lipids, if there is even one cardiovascular risk factor
Weight and blood pressure at every visit
Annual skin checkups (pigmented naevi)
25(OH)D every 3-5 years
Hearing test every 5 years
Bone densitometry every 5 years
Coeliac screen as necessary depending on the symptoms
References
Guttenbach M, Koschorz B, Bernthaler U et al. Sex chromosome loss and aging: in situ hybridization studies on human interphase nuclei. Am J Hum Genet 1995;57(5):1143-50. [PubMed]
Gravholt CH, Andersen NH, Conway GS et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;177(3):G1-G70. [PubMed]
Cui X, Cui Y, Shi L et al. A basic understanding of Turner syndrome: Incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res 2018;7(4):223-228. [PubMed]
Snyder EA, San Roman AK, Piña-Aguilar RE et al. Genetic counseling for women with 45,X/46,XX mosaicism: Towards more personalized management. Eur J Med Genet 2021;64(3):104140. [PubMed]
Folsom LJ, Slaven JE, Nabhan ZM et al. CHARACTERIZATION OF SPONTANEOUS AND INDUCED PUBERTY IN GIRLS WITH TURNER SYNDROME. Endocr Pract 2017;23(7):768-774. [PubMed]
Viuff MH, Berglund A, Juul S et al. Sex Hormone Replacement Therapy in Turner Syndrome: Impact on Morbidity and Mortality. J Clin Endocrinol Metab 2020;105(2):. [PubMed]
Noordman ID, Fejzic Z, Bos M et al. Cardiac abnormalities in girls with Turner syndrome: ECG abnormalities, myocardial strain imaging, and karyotype-phenotype associations. Am J Med Genet A 2021;185(8):2399-2408. [PubMed]
De Sanctis V, Khater D. Autoimmune diseases in Turner syndrome: an overview. Acta Biomed 2019;90(3):341-344. [PubMed]