Shereshevsky-Turner syndrome and pregnancy

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Shereshevsky-Turner syndrome (ST) is one of the causes of sexual infantilism in women. It is generally assumed that a patient with ST will never be able to get pregnant and carry a child, but according to the clinical cases described in the literature, it turns out that the probability of physiological pregnancy is 3.6-7.6 % [1]. In 1960, F. Bahner and co-authors [2] for the first time declared the preserved reproductive function in a patient with ST and with karyotype 45, X0.
Most women who gave birth to a child with ST have structural rearrangements of the X hromosome or mosaic karyotype 45, X/46, XX [1]. The mosaic shape of the SHT is about 50%. Geneticists suggest that 60 % of patients with X chromosome monosomy are most likely mosaics on the X chromosome, and 40 % of them on the Y chromosome. This means that there is a "hidden" mosaicism on the X chromosome, which is not detected by traditional methods of cytogenetics, the estimated statistics of which are from 2.4 to 48 % [3, 4, 5, 6]. The frequency of "hidden" mosaicism on the Y chromosome ranged from 0 to 61 % [7, 8]. In one study, 90% of patients with monosomy X had additional cell lines with X and Y chromosomes [9]. Genetic analysis will also determine the karyotype 45,X0/46,XY in some patients. This is very necessary to perform a timely gonadectomy operation for the prevention of gonadoblastoma and dysgerminoma [10].The probability of getting pregnant and giving birth to a genetically native child in women with a mosaic variant of ST is explained by the fact that they sometimes have a spontaneous puberty and menarche, a regular menstrual cycle [11].
An important problem is the timely diagnosis of SHT and its reproductive capabilities, since, despite the spontaneous puberty and regular menstrual cycle, many of these girls still need help in order to become pregnant after a certain amount of time with the help of assisted reproductive technologies (ART). Tests allow you to study the hormonal level, which will help in determining the functional state of the reproductive system. It is proposed to evaluate the level of anti-Muller hormone (AMH), which is stable from the period of middle childhood to early adulthood, and its level is normally high [12]. It is also necessary to examine the level of FSH, normally it should be less than 10 mIu / ml [13].
Patients and their parents should be informed about the possibilities of reproductive medicine. IVF programs can be carried out both with the use of donor eggs, and with the use of eggs of the woman herself. But regardless of whose material is used — the donor or the patient herself, it is necessary to take care of preserving the reproductive function in advance, in adolescence. Pregnancy and childbirth are also carried out against the background of hormone replacement therapy( HRT), which creates conditions for the successful maturation of eggs.
Ovulation should be stimulated using FSH, human menopausal gonadotropin, or recombinant LH, and GnRH antagonists are used during the follicular phase to prevent peak LH. SHT is characterized by rapid ovarian depletion, so patients aged 13-15 years should be referred to the reproduction clinic for oocyte vitrification and/or cryopreservation of ovarian tissue. Cryopreservation of ovarian tissue is well established as an ART method for preserving fertility in girls in the periods before and after puberty due to the absence of the need for stimulation. Vitrification of oocytes without laparoscopic assistance is a less invasive method and is well suited for a young patient after puberty [11; 14].
According to foreign statistics, the results of ovarian stimulation in 7 patients with SHT are known. One patient was found to have an X-chromosome monosomy, while the others had different variants of the mosaic shape. The age of the patients is from 18 to 26 years. The level of AMH ranged from 0.4 to 3 ng / ml. From 4 to 13 oocytes were obtained, and mature eggs were frozen in all patients [15]. In another study, it was found that ovarian biopsy is technically possible in 47 out of 57 girls with SHT aged 8 to 19 years. In 15 of the 57 patients, follicles were found during histological examination. Follicles were found in ovarian tissue in 6 out of 7 girls with a mosaic shape, in 6 out of 22 — with structural chromosomal rearrangements, in 3 out of 28-with karyotype 45, X. 8 of 13 girls with follicles had the first menstrual period, and 11 of 19 with spontaneous puberty had follicles. Most often, the follicles were found in girls aged 12-16 years. Low FSH, high AMH, and pronounced puberty are associated with the detection of follicles [16].
The use of these ART methods is impossible without HRT, which should be started from the age of 12-13. Estrogens are designed to ensure the development of the breast and internal genitalia, puberty growth spurt and prevention of osteoporosis. In the absence of signs of sexual development, it is recommended to start HRT with small doses (1/10-1/8 of the adult dose). It is proved that with the simultaneous use of recombinant growth hormone with low doses of estrogens in patients, another painful problem with SHT is better solved — low growth [17]. Within 2-3 years, the dose of estrogens is gradually increased. After 2 years from the beginning of monotherapy with estrogens or with the appearance of a menstrual-like reaction, therapy is supplemented with progestin.
When performing IVF, you should not forget that due to the small size of the uterus, it is possible to transfer only one embryo. Also, in IVF, if autologous oocytes are used, preimplantation genetic diagnosis should be prescribed [11; 14].
The probability of giving birth to a healthy child is approximately 40% [18]. A French study of the oocyte donation program provides the following statistics: 151 embryo transfers were performed in 73 women with SHT. 38% of the patients had X-chromosome monosomy, and the remaining 62% had different mosaic karyotypes. There were 39 pregnancies, 23 of which ended in childbirth with the birth of live children; 11-spontaneous miscarriage, in 1 case ectopic pregnancy was registered. There was 1 case of maternal mortality in a patient with epileptic status, and 3 pregnancies were terminated by abortion for medical reasons [19].
A study of 410 women of childbearing age was conducted in Denmark between January 1973 and December 1993. 49% of patients had X-chromosome monosomy, 23% had mosaic karyotypes and structural abnormality of the second X chromosome, 19% had 45,X/46, XX mosaicism, and 9% had karyotype 46, XX and structural abnormality of the second X chromosome. 33 women, 1 with 45, X,27 with mosaicism and 5 with 46, XX and structural abnormality of the second X chromosome, gave birth to 64 children. 2 patients became pregnant after IVF, including a woman with 45, X after egg donation. Thus, 31 women (7.6%) had at least one spontaneous pregnancy, but 48% of fertile women with karyotype 45,X/46,XX, had 45, X in less than 10% of the cells. 6 of the 25 children examined, including three siblings, had chromosomal aberrations. There were no cases of Down syndrome, and only two children had malformations. But only women with 45,X/46, XX mosaicism or structural abnormality of the second X chromosome gave birth to live children after natural pregnancy [1].
The patient, 25 years old, born in 1991, 26-27 weeks pregnant, complained of moderate general weakness, fatigue, drowsiness,bruising. At the age of 5, she was diagnosed with SHT, mosaic variant 46, XX/45, X. She was observed by gynecologists, menarche at the age of 12, there were no menstrual disorders, and did not receive HRT.
In May 2004, jaundice first appeared, and an increase in transaminases was detected. She was hospitalized, and antinuclear antibodies were detected. A liver biopsy confirmed the diagnosis of autoimmune hepatitis. Treatment with glucocorticosteroids (corticosteroids) was prescribed, against which the indicators of functional tests improved. In 2006, splenomegaly, combined with portal hypertension syndrome, developed during therapy. Another liver biopsy was performed, which confirmed the formation of cirrhosis of the liver. The woman continued to take GCS therapy.
In 2016, the patient became pregnant. At the term of 10 weeks-the threat of spontaneous abortion, treatment in the hospital, therapy-dicinon, utrozhestan, no-shpa. At the term of 12 weeks — ultrasound screening of the fetus is normal. At the age of 24 weeks, a low location of the auricle was revealed. She was hospitalized for diagnostic measures.
In the anamnesis, there were: epilepsy in remission, GI, open aortic duct. During an objective examination, the "stigmas"characteristic of the SHT were identified. The condition is satisfactory, the weight is 46 kg, the physique is normosthenic. The abdomen is enlarged due to the pregnant uterus, participates in the act of breathing, soft, painless. The size of the liver according to Kurlov is 9-8-7 cm, palpation is difficult. Splenomegaly was detected. In the general blood test—hypochromic anemia of moderate severity. In the biochemical analysis of blood, serum iron is reduced, ALT and AST are normal. Ultrasound of the abdominal cavity revealed a small increase in the liver, signs of moderate hepatosis, increased echogenicity. Portal veins are dilated. Numerous small concretions were found in the gallbladder. Splenomegaly was detected. Cirrhosis of the liver in the compensation stage, class A according to Child-Pugh.
Ultrasound of the fetus at the gestation period of 26-27 weeks revealed edema of the soft tissues of the fetus and polyhydramnios. ST and symptomatic epilepsy did not affect the course of pregnancy. It was decided to maintain the condition of the mother and fetus with the help of medications. At 37-38 weeks, the patient was delivered by caesarean section and a healthy boy weighing 2400 g and 46 cm tall was born [20].

Another clinical case reflects the inheritance of Turner syndrome. A mother with ST became pregnant and gave birth naturally to two girls with SHT. The eldest daughter became pregnant on her own in preparation for IVF. At the time of the last observation, the gestation period was 17 weeks. According to ultrasound: male fetus without gross malformations. The woman refused prenatal diagnosis of the fetus. All the women showed simple mosaicism with two cell clones: the first clone 45, X; and the second with the ring chromosome X as the second sex chromosome. Inheritance of ST in this case is associated with the transmission of the ring X chromosome through the mother [21].

Conclusions

1.ST is a serious diagnosis, in which the majority of patients suffer from infertility. But according to the literature, it is found that exceptions are possible. As a rule, these are women with a mosaic shape of the SST. It is assumed that the possibilities of genetic diagnosis have not yet been fully disclosed, and the number of women with a mosaic form of ST is actually greater than we think.

2. Women with a mosaic form of SHT can have a pregnancy and give birth to children due to the relatively good state (compared to women with X-chromosome monosomy) of the reproductive system. But many of them still need to use ART-IVF with a donor or own egg, cryopreservation of ovarian tissue and vitrification of oocytes. Carrying out these activities is unthinkable without training, which must begin in adolescence. It is necessary to identify such girls in a timely manner and perform an ovarian puncture at the age of 13-15 years in order to collect follicles, since SHT is characterized by increased ovarian depletion.

3. A prerequisite for success in the use of ART is HRT with estrogen preparations, which will create conditions for the maturation of eggs. To date, statistics reflect an increased risk of somatic and obstetric pathology in the mother, miscarriages, and cases of birth of a sick child both when using their own oocytes and when using donor ones.

About the authors

Vladimir P. Cheremiskin

E.A. Vagner Perm State Medical University

Author for correspondence.
Email: 79024797428@yandex.ru

MD, PhD, Professor, Department of Obstetrics and Gynecology No. 1

Russian Federation, Perm

Anna V. Filyanina

E.A. Vagner Perm State Medical University

Email: filianina.anya@yandex.ru

student

Russian Federation, Perm

References

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