I. Introduction
Turner syndrome (TS) is one of the most common genetic disorders associated with X chromosome abnormalities, occurring in approximately 50 cases per 100,000 live births in girls. 45XO haplotype karyotype is the most common form (up to 60%), but other karyotypes are possible, including chimerism. Many abnormalities have been found to be associated with TS, most of which arise from genetic haploinsufficiency, the normal expression of both X chromosomes. the typical features of TS are short stature and ovarian failure. Healthcare has consequently been focused on early and prenatal diagnosis and the development of pediatric management guidelines for growth hormone and pubertal therapy.
There is now growing evidence that patients with TS are vulnerable to a number of diseases that begin or progress in adulthood, such as osteoporosis, hypothyroidism, diabetes mellitus, dyslipidemia, and non-congenital cardiac and renal-urinary changes. Morbidity and mortality are increased and life expectancy is reduced by up to 13 years, mainly due to cardiovascular disease. Special care during adulthood is necessary.
In addition, guidelines are required for the management of sensory neurological and endocrine disorders associated with TS; associated malformations; and reproductive and sexual health counseling. In this article, we describe the management of adult patients with TS.
II. Abnormal skeletal development and subsequent bone disease
Short stature and ovarian failure caused by gonadal hypoplasia, with or without other malformations secondary to lymphedema, are the main clinical features. The association between karyotype and phenotype is well established, but it is not predictable. In addition, isobaric chromosomes are associated with sensory neurological and immunological disorders without congenital malformations. Short stature is an almost invariant finding in TS patients whose mean final adult height is close to 150 cm. Major bone defects associated with SHOX and PHOG genes on the distal short arms of the X and Y chromosomes (Xp11-22 and Yp11) and partial insensitivity to growth hormone (GH) have been shown to be the main cause of short stature in TS patients. In one study, TS patients treated with GH were on average 7 cm taller than those who did not receive treatment. GH therapy is recommended to be initiated 4 years prior to estrogen supplementation. increased use of oxandrolone (GH) appears to increase height benefit and slow breast development without affecting BMI. Mutations in the SHOX and PHOG genes may also explain some of the skeletal abnormalities in TS, such as elbow Haploinsufficiency in SHOX expression could explain other features such as chronic otitis media, ear protrusion, and problems learning how to suck, blow, eat, and express. Lymphedema is caused by absent or underdeveloped lymphatic vessels and is usually found at birth but improves with time. Other external physical disorders associated with TS are entropion, malformed auricles, micrognathia, cleft palate, short neck, short limbs, and ectropion. It is hypothesized that osteoporosis and short stature may be due to defects in bone formation caused by SHOX and PHOG, and that other genes located on the X chromosome are associated with connective tissue alterations. Peak bone mass is reduced by 25% in TS patients and the incidence of fractures is 3 times higher in girls and women with TS than in normal controls. GH treatment for at least one year, combined with estrogen replacement therapy started before the age of 12 years improves BMD and reduces the risk of fractures.
III. Ovarian hypoplasia and reproductive problems
After the third month of gestation, TS fetuses have accelerated oocyte depletion and increased interstitial fibrosis of the ovaries. As a result, ovarian failure occurs in most patients within a few months or years after birth. Although primary amenorrhea is common in TS, the incidence of spontaneous puberty is 8% in patients with the 45X0 karyotype and up to 40% in chimeric patients.
After induction of puberty with estrogen, most patients with TS require long-term estrogen replacement therapy to prevent osteoporosis, reduce atherosclerotic risk factors and improve cognitive function. The use of natural estrogens, either oral or transdermal, is recommended for hormone therapy, as ethinyl estradiol used in birth control pills has been shown to be associated with liver enzymes, lipid metabolism and blood pressure side effects in patients with TS karyotype. In women with TS, replacement therapy improves some cognitive deficits (reaction time, non-verbal processing speed and short-term memory). Therefore, estrogen replacement in physiologic doses should be maintained until the expected age of menopause.
Spontaneous pregnancy occurs in less than 5% of TS patients with an increased risk of congenital malformations or chromosomal abnormalities. Egg donation and in vitro fertilization should be recommended. Nevertheless, there is a higher risk of early pregnancy miscarriage, which may be due to uterine dysplasia and uterine ischemia during gestation.
IV. Congenital cardiovascular defects and diseases in adulthood
Cardiovascular complications are the main cause of death in TS. The main ones are aortic root dilatation and hypertension. cardiovascular complications in TS are mainly associated with hypogonadism, but differences in X chromosome gene expression may also be responsible.
Other abnormalities, such as localized abnormal venous drainage and mitral valve prolapse, are more common in women with TS, and left-sided cardiac abnormalities associated with endocarditis mean that preoperative prophylactic antibiotics are essential. However, the main risk for patients with TS is aortic coarctation, which can occur at any age and lead to sudden death.
Finally, it is crucial that since TS is associated with many cardiovascular diseases, a cardiac evaluation, including echocardiography and strict blood pressure monitoring, is recommended before assisted reproduction and before pregnancy.
V. Metabolic and endocrine disorders
Many women with TS have associated metabolic risk factors such as dyslipidemia and diabetes mellitus. Type 2 diabetes is elevated up to 4-fold due to insulin resistance and hyperinsulinemia. Hypertriglyceridemia and hypercholesterolemia are also common in patients with TS.
Hypothyroidism affects more than 70% of TS patients and is usually autoimmune in origin; therefore, thyroid function should be checked annually for early diagnosis of hypothyroidism.
In conclusion, close control of blood pressure and annual measurement of lipids, carbohydrates, liver and thyroid function should be included in the evaluation of adult women with TS.
Summary
In conclusion, women with TS are at high risk of developing the disease from birth to adulthood. Once diagnosed, these patients should be monitored by a multidisciplinary team to detect and treat associated comorbidities. The first step is for a specialized pediatrician to screen for congenital anomalies and initiate growth hormone and estrogen replacement therapy to ensure sexual development. Afterwards, endocrine-gynecologists diagnose complications starting in adulthood, especially metabolic, immunological and neurological disorders, and refer patients to other specialties (cardiovascular medicine, ENT, gastroenterology and dermatology) when indicated.