Turner Syndrome

Turner syndrome is a congenital genetic syndrome caused by a numerical or structural alteration of the X sex chromosome. This syndrome occurs in approximately 1 in 2000/2500 live births, although true prevalence is still difficult to ascertain since milder cases may escape diagnosis.
People with this Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) e may present a wide variety of signs and symptoms, the most frequent being a low growth rate as from 5 to 6 years of age, resulting in a short stature. They can be born with congenital lymphoedema (swelling) of the hands and feet, a broad chest, a low hairline and low implanted ears. Other features are a shield-like chest with widely spaced nipples, the so-called 'pterygium colli' (i.e. webbed neck), cubitus valgus (outward deviation of the forearm), micrognathia and retrognathia (small, backward jaw), arched palate, palpebral ptosis (drooping eyelids), epicanthus (presence of a skin fold that originates from the upper eyelid and reaches to cover the inner corner of the eye), hypertelorism (eyes widely spaced apart).
People with Turner syndrome have an increased risk of autoimmune diseases (Hashimoto's thyroiditis, coeliac disease), defects of the cardiovascular system (especially bicuspid aorta and/or high blood pressure), urinary and skeletal defects. Hearing loss and impaired liver function may occur on aging.
Turner syndrome is one of the most common causes of premature ovarian failure, due to the acceleration of the normal process of ovarian follicle degeneration. Most of those affected do not have mammary development and have primary amenorrhea (no onset of menarche, the first menstrual cycle). In approximately 15-30% of cases, either there is an initial breast development which stops at puberty, or there is complete puberty, but with subsequent onset of secondary amenorrhea and premature ovarian failure. A small percentage of persons with Turner syndrome, however, have normal pubertal development and regular menses.
The cognitive functions of people with Turner syndrome are usually normal, but they may present specific neurocognitive deficits with difficulties in attention and space-time orientation.

Genetic traits
Most people have a genetic makeup of 23 pairs of chromosomes, one of which is the sex chromosome (XX or XY).  Turner syndrome is characterised by a numerical or structural alteration of the X sex chromosome.  In 45% of cases, it is  a monosomy X, i.e. there is only a single X chromosome in all cells of the body. About half the people with Turner syndrome exhibit a 'mosaic' chromosome set: some body cells have only one X chromosome, while others may have a second X or Y chromosome. In the remaining cases, different abnormalities may be found on the X chromosome responsible for the syndrome, with or without mosaicism. The various forms of chromosome abnormalities are responsible for the variability of clinical pictures. 
Turner syndrome is not hereditary, and the chromosome alterations described above are caused either by errors during the gamete formation process (oocytes and spermatozoa) the union of which results in an individual affected by the syndrome, or by errors occurring during the early cell divisions after fertilisation.

Identification
Turner syndrome is occasionally diagnosed during prenatal tests (amniocentesis, CVS, fetal DNA). More commonly, it is suspected after birth upon the presence of characteristic clinical signs (lymphoedema during infancy, short stature during childhood and adolescence, incomplete or no breast development), unexplained growth delay, delayed puberty, primary or secondary amenorrhoea. 
Diagnosis is confirmed by karyotype analysis (a test that assesses the number and structure of a person's chromosomes). An early diagnosis is important to manage comorbidities, including possible successful treatment of short stature.

Medical options
Considering the countless aspects to be dealt with, the management of subjects with Turner syndrome calls for a multidisciplinary approach involving various specialists (pediatrician, endocrinologist, obstetrician-gynecologist specialising in reproductive medicine, cardiologist). The person also needs to count with adequate psychological support. Treatment and management may vary from person to person, depending on how complex the manifestation of the syndrome is.
In light of the various comorbidities of Turner syndrome, close monitoring through periodic clinical checks is necessary to prevent/manage possible complications in a timely manner.
From a gynecological perspective, hormone therapy plays a key role for those with primary or secondary amenorrhoea, both for the induction of puberty (increasing doses of estradiol and then progesterone) and for the subsequent maintenance of secondary sexual characteristics, bone health, adequate uterine growth, and the prevention of cardiovascular risks. Hormone replacement therapy should continue until menopause, i.e. on average until 50–51 years of age.
Regarding fertility, the probability of spontaneous conception declines rapidly with age, and the timing of ovarian exhaustion is unpredictable. That is why careful counseling about various fertility and oocyte preservation options should be considered as early as possible. 
Cryopreservation of ovarian tissue and/or oocytes of preadolescent or adolescent persons with Turner syndrome is being studied as a technique that could allow reproduction at a later age. Cryopreservation of oocytes is an established fertility technique, but its use in the presence of Turner syndrome is limited to individuals with mosaicism whose ovarian function persists after puberty. Recently, a pregnancy from thawed oocytes was reported in a woman with Turner syndrome. Cryopreservation of ovarian tissue and subsequent maturation of oocytes in vitro is still an experimental technique, but could be applied in the case of pre-pubertal subjects with a high probability of ovarian depletion before puberty.
In any case, it should be noted that pregnancy is usually discouraged because of the excess mortality risk attributed to the numerous comorbidities the person may have. Some cardiac pathologies are, indeed, among the absolute or relative contraindications to pregnancy. In patients with Turner syndrome, pregnancy is classified as high risk and often requires the supervision of a multidisciplinary team comprising not only a gynecologist but also a cardiologist, endocrinologist and other specialists. 
Among the risks pregnant women may face are gestational hypertension, preeclampsia, gestational diabetes, worsening of congenital heart disease, heart failure, aortic dissection and maternal death. As for fetal risks, there is a 30% risk of miscarriage, 20-30% risk of a small fetus for gestational age, 10% risk of prematurity, and 2% risk of fetal death. Appropriate counselling on possible pregnancy-related complications is therefore a must. 
 

Bibliography
Bouet PE et al. Fertility and Pregnancy in Turner Syndrome [Abstract] . Journal of obstetrics and gynaecology Canada. 2016 Aug;38(8):712-8
ESHRE Guideline Group on Female Fertility Preservation et  al. ESHRE guideline: female fertility preservation. Human reproduction open. 2020 Nov 14;2020(4):hoaa052
International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. European journal of endocrinology. 2017 Sep;177(3):G1-G70
European Society of Human Reproduction and Embryology. Guideline on the management of premature ovarian insufficiency
Steiner M, Saenger P. Turner Syndrome: An Update [Abstract] . Advances in pediatrics. 2022 Aug;69(1):177-202
Strypstein L et al. First live birth after fertility preservation using vitrification of oocytes in a woman with mosaic Turner syndrome. Journal of assisted reproduction and genetics. 2022 Feb;39(2):543-549
European Society for Human Reproduction and Embryology (ESHRE) Guideline Group on POI et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Human reproduction. 2016 May;31(5):926-37

Link
Ospedale pediatrico Bambino Gesù. Sindrome di Turner
NHS. Turner syndrome