Provocări terapeutice la o pacientă cu sindrom Turner și sarcină obținută prin FIV – prezentare de caz

Introduction

Turner syndrome (TS) was first described by He­nry Turner in 1938, after he identified short stature, webbed neck, cubitus valgus and sexual infantilism in seven patients⁽¹⁾. TS is a rare genetic disorder characterized by the complete or partial absence of the second X sex chromosome (45,X). TS afflicts 25-50 per 100,000 women, and can present multiple organ and system abnormalities. A multidisciplinary approach is necessary in such cases⁽²⁾. Turner syndrome is one of the most common chromosomal abnormalities in women, and it can present several karyotypic variants: 45,X (40-50%), mosaic 45,X/46,XX (15-25%), or isochromosomal (20%). The clinical phenotype greatly varies depending on the karyotype. The least severe phenotypic changes are observed in mosaic karyotype⁽³⁾.

Clinically, numerous signs and abnormalities determined by this genetic anomaly can be observed: short stature, cardiovascular, renal, endocrine and autoimmune disorders, neurological deficits, or reproductive system abnormalities⁽⁴⁾. Turner syndrome has been associated with numerous autoimmune diseases, the most common being autoimmune thyroiditis, but type 1 diabetes, colitis, celiac disease and psoriasis have also been reported. Cardiovascular events have an increased incidence in patients with TS, and congenital cardiac anomalies are more common than in the normal population. Cardiac valvular anomalies have an increased prevalence, especially aortic bicuspid deformity. Other anomalies associated with TS include skeletal anomalies, osteoporosis, broad chest, short neck, nail dysplasia and genu valgum⁽⁵⁾. Women with Turner syndrome may have neurological developmental disorders associated, with impaired memory, attention and social cognition, and their visuospatial reasoning and executive functioning may be affected. These patients are at an increased risk of autism spectrum disorders, anxiety, depression, concentration and memory issues⁽⁶⁾.

The median age of diagnosis of Turner syndrome is approximately 15 years old, and there are three important periods in which this syndrome can be suspected: intrauterine, by the presence of abnormalities on fetal ultrasound scan, in adolescence, by oligo- or amenorrhea, delayed puberty and short stature, or in adulthood, in case of infertility. When there are signs and symptoms that raise the suspicion of Turner syndrome, genetic testing is indicated⁽⁷⁾.

The presence of streak gonads in TS patients causes delayed puberty, and may require puberty induction therapy and hormone replacement therapy⁽⁸⁾. Women with Turner syndrome present premature ovarian failure due to gonadal dysgenesis which causes hypergonadotropic hypogonadism and infertility. These infertility problems have a significant negative impact on the quality of life of these patients⁽⁹⁾. People with Turner syndrome should be counseled, because their likelihood of conceiving decreases rapidly with age. A significant number of patients with TS experience menopause much earlier than normal women. Only a small proportion of women with Turner syndrome achieve spontaneous pregnancy with their own oocytes. The spontaneous pregnancy rate in these patients is low, and it has been reported to be between 4.8% and 7.6%. The spontaneous abortion rate after a spontaneous pregnancy in patients with Turner syndrome is high, and ranges between 30.8% and 45.1%^(10,11). The live birth rate is reduced in these patients. In addition to the increased possibility of abortion, most spontaneous pregnancies result in stillbirth or newborns with congenital anomalies. Given that the spontaneous pregnancy rate in TS patients is low, alternative methods for these patients to become mothers are important. Among the solutions used in these cases are assisted reproduction techniques (ART), such as oocyte donation (OD), embryo donation, in vitro fertilization or insemination. Oocyte donation is the most used method in TS patients. The live birth rate is considerably higher after OD than in the case of waiting for a spontaneous pregnancy, but even so, the live birth rate is lower than in normal women who benefit from oocyte donation. This is due to multiple causes of infertility in TS patients, beyond ovarian failure: autoimmune diseases, uterine changes, or an increased risk of chromosomal abnormalities⁽¹²⁾.

Case report

We present the case of a 34-year-old patient known with Turner syndrome who achieved a pregnancy after oocyte donation. This was the first pregnancy of the patient; she had no previous births or miscarriages. In childhood, the patient presented growth disorders, webbed and short neck, and the diagnosis of proportionate dwarfism was established. The diagnosis of Turner syndrome was established by genetic testing which confirmed the presence of karyotype 45,X. The patient was diagnosed with ventricular septal defect, horseshoe kidney, bilateral auricular dysfunction and autoimmune thyroiditis with euthyroidism. The patient did not have spontaneous menstrual cycle. She underwent estrogen-progestin treatment, with the onset of menstruation at the age of 18. The patient underwent hormonal treatment for two years, after which she decided to discontinue it on her own initiative.

More than 10 years after stopping hormonal treatment, the patient presented, at the age of 33, for a gynecological consultation in order to achieve a pregnancy. At that time, transvaginal ultrasound scan revealed the presence of a 15/7 mm uterus, homogeneous myometrium, atrophic endometrium, and the ovaries were not visualized. The patient received hormonal treatment for 10 months with estradiol valerate 2 mg and norgestrel 0.5 mg tablets in a 21-day on – 7-day off regimen. After hormonal treatment, ultrasound scan revealed a uterus of 56/19/29 mm with secretory endometrium and normal uterine cavity conformed by 3D ultrasound evaluation. The partner’s spermogram showed the presence of oligoasthenozoospermia and hypospermia. It was decided to perform intracytoplasmic sperm injection (ICSI). Nine donated oocytes were used, and five embryos were obtained that reached the blastocyst stage. A single embryo by day 5 of 4AA quality was transferred. During the embryo transfer preparation, the patient underwent treatment with transdermal spray and oral estrogen, to which injectable and intravaginal progesterone, acetylsalicylic acid and corticosteroid treatment were added.

Pregnancy follow-up was performed in accordance with current guidelines. The patient underwent first-trimester fetal ultrasound, and the noninvasive prenatal testing did not identify the presence of chromosomal or anatomical abnormalities. During pregnancy, careful cardiological and endocrinological surveillance of the patient was necessary, considering the associated pathologies. Throughout the pregnancy, the patient presented normal thyroid and cardiac function.

Given the increased risk of endocrine and autoimmune abnormalities, the patient underwent screening for gestational diabetes, which indicated the presence of this condition. The management of gestational diabetes consisted of a diet to maintain blood glucose levels within normal limits throughout pregnancy.

Due to her short stature, the patient presented with a modified narrow pelvic diameter. In this case, a caesarean section was decided at 38 weeks of pregnancy. The patient gave birth to a live male fetus weighing 2640 g, with an Apgar score of 9. Two hours after delivery, the patient presented profuse vaginal bleeding and uterine atony. Ultrasound scan revealed the presence of a large amount of clots in the uterine cavity. Despite conservative medical and surgical methods for atony, that have failed, we decided and performed peripartum hysterectomy ovarian preservation (Figure 1). Postoperatively, the patient received hematological products. Subsequently, the patient’s evolution was favorable under hydroelectrolytic, anticoagulant, analgesic and antibiotic therapy. The patient was discharged on the fourth postoperative day together with the newborn, who presented good postnatal adaptation and evolution.

Discussion

We present the case of a patient with Turner syndrome who achieved a pregnancy after oocyte donation at the age of 34. Most women with Turner syndrome present ovarian dysgenesis and infertility due to oocyte loss starting from intrauterine life and up to the first years of life. Most patients with karyotype 45,X present streak gonads. A small proportion of patients with Turner syndrome, especially those with mosaic karyotype, may present at puberty a reduced number of follicles, with spontaneous onset of puberty and menstrual cycles. The rate of spontaneous pregnancies and live births is reduced in these patients⁽¹³⁾. Ovarian dysfunction causes premature ovarian failure and early menopause, usually before the age of 40 years old⁽¹⁴⁾.

Given the obstetric risks, patients with Turner syndrome should be carefully counseled and evaluated before birth and throughout pregnancy⁽¹⁵⁾. Pregnancy in patients with Turner syndrome is associated with numerous risks, including miscarriage, chromosomal abnormalities and maternal cardiovascular complications, such as aortic dissection. In the case of oocyte donation, the risk of cardiovascular complications, especially hypertensive disorders of pregnancy, is further increased. These pregnancies have also been associated with a higher risk of low birth weight, preterm birth and caesarean section⁽¹⁶⁾. In our case, the patient was diagnosed with ventricular septal defect, but cardiac function and blood pressure remained normal throughout the pregnancy.

Turner syndrome is frequently associated with hyperglycemia, impaired glucose tolerance and diabetes mellitus. These changes are most likely due to altered insulin secretion^(17,18). Patients with this syndrome have an increased risk of developing gestational diabetes during pregnancy, and their screening and careful monitoring are required⁽¹⁹⁾. Our patient underwent an oral glucose tolerance test at 25 weeks with altered blood sugar values, and thus the diagnosis of gestational diabetes was established. Under careful counseling and monitoring by the diabetologist, the patient maintained her blood sugar within normal limits through an adequate diet, without the need for insulin administration.

Turner syndrome is associated with endocrine abnormalities, the most common of which is thyroid dysfunction, occurring in 24% of these patients. The prevalence of hypothyroidism increases during pregnancy in patients with Turner syndrome, and it is important to test thyroid function during pregnancy to ensure normal fetal development⁽²⁰⁾. The incidence of autoimmune thyroiditis in TS patients has been reported to be approximately 38.6%⁽²¹⁾. In our case, the patient was diagnosed with autoimmune thyroiditis, and she had normal thyroid function throughout pregnancy.

Most patients with Turner syndrome give birth by caesarean section. The main factors that determine the need for caesarean section are cephalopelvic disproportion and hypertensive complications associated with pregnancy, especially preeclampsia⁽²²⁾. Cephalopelvic disproportion was the main indication, being responsible for 35% of caesarean deliveries, and it was due to the patient’s short stature with changes in pelvic diameters that are narrow⁽²³⁾. Our patient gave birth at 38 weeks of pregnancy by caesarean section due to cephalopelvic disproportion as a consequence of pelvic changes.

Turner syndrome may be associated with abnormal development of the uterus in terms of size and shape. There are studies showing that the uterus is smaller in TS patients than in the general population^(24-26). Abnormal or inadequate uterus is a risk factor for uterine atony and postpartum hemorrhage. If uterine atony cannot be corrected and hemorrhage becomes significant, a peripartum hysterectomy is necessary⁽²⁷⁾. Our patient presented with uterine atony and significant bleeding 2 hours after caesarean delivery, and an emergency hysterectomy was performed.

Our case is particular because a 34-year-old woman with TS achieved a pregnancy. During the pregnancy, the only complication was gestational diabetes, that could be managed through diet. Caesarean section was followed by uterine atony and peripartum hysterectomy with ovarian preservation.

Conclusions

Turner syndrome is a rare genetic disorder associated with gonadal dysgenesis and infertility. Patients have a low rate of pregnancies and live births. Pregnancy in patients with Turner syndrome can present multiple complications: increased risk of miscarriage, chromosomal abnormalities, low birth weight, caesarean section and maternal complications, especially cardiovascular diseases. Preconceptional counseling and evaluation of these patients are essential to identify TS-associated abnormalities. Pregnancy management in patients with Turner syndrome should be individualized to reduce the risk of maternal and fetal complications.   

Corresponding author: Mihaela Amza E-mail: mihaela.amza@umfcd.ro

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.