Turner's syndrome and pregnancy

The Journal of Maternal-Fetal and Neonatal Medicine, May 2011; 24(5): 668–672

REVIEW

Turner’s syndrome and pregnancy: has the 45,X/47,XXX mosaicism a different prognosis? Own clinical experience and literature review SOFIA BOUCHLARIOTOU1, PANAGIOTIS TSIKOURAS1, MARINA DIMITRAKI1, APOSTOLOS ATHANASIADIS2, IOANNIS PAPOULIDIS2, GEORGE MAROULIS1, ANASTASIOS LIBERIS1, & VASILEIOS LIBERIS1 1

Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece and 2Department of Obstetrics and Gynecology, Aristoteles University of Thessaloniki, Thessaloniki, Greece (Received 29 April 2010; revised 12 July 2010; accepted 27 July 2010) Abstract Turner’s syndrome is characterized by an ovarian failure which occurs in most cases before puberty and leads to infertility. In less than 10% of women with Turner syndrome, puberty may occur and spontaneous pregnancies is possible but with a high risk of fetal loss, chromosomal and congenital abnormalities. We present the case of a 33-year-old woman with a mosaic Turner’s syndrome karyotype 45,X/47,XXX who conceived spontaneously and had two successful pregnancies. Short stature was the only manifestation of Turner’s syndrome. In the present report, we reviewed the available literature on the fertility of women with Turner’s syndrome and the phenotypic effects of mosaicism for a 47,XXX cell line in Turner’s syndrome. Keywords: Fertility, Turner’s syndrome, 45,X/46,XXX mosaicism

Introduction Turner syndrome, defined as a loss or abnormality of the second X chromosome, occurs in approximately 1/3000 live-born females [1]. The syndrome is characterized by growth retardation, ovarian dysgenesis, phenotypic abnormalities, and inherited defects in internal organs, e.g. the bone, cardiovascular and urinary systems. The cognitive-behavioral phenotype associated with Turner syndrome includes strengths in verbal domains with impairments in visual-spatial, executive function, and emotion processing. There is however considerable variation, with a minority of girls showing minimal dysmorphic features, adequate growth, and spontaneous, progressive puberty or a combination of these [1]. Molecular studies comparing proband and parental X polymorphisms have shown that the maternal X chromosome is retained in about two-thirds of subjects with Turner’s syndrome and the paternal X in the remaining one-third [2]. Of females diagnosed with this condition, half are monosomic for the X chromosome. Among the rest a multiplicity of chromosomal aberrations has been described. The more frequent are the presence of an isochromosome of the long arm of the X (i(Xq)) and ring X and mosaicism for two or more normal or abnormal cell lines (for example, 45,X/46,XX; 45X/46,X(Xq); 45,X/46,XY). A small proportion 3–4% of subjects with Turner syndrome is mosaic for a triple X (47/XXX) cell line [3]. Most women with Turner’s syndrome (95–98%) are infertile due to gonadal dysgenesis [4]. It is caused by oocyte loss from week 18 of pregnancy onwards or over the first few postnatal months and years [4]. However, at

puberty a minority of individuals, mostly those with mosaic karyotypes, have ovaries with a relatively low number of follicles, so that there is spontaneous pubertal development and menarche [5]. Nowadays, it is possible for women with Turner’s syndrome to achieve pregnancy with the help of assisted conception techniques, such as donor oocyte in vitro fertilization, in about 30% of cases [6]. However, spontaneous conception in those women is a rare event. The patients with a detected mosaic genotype usually have milder somatic defects and are more likely to be fertile than those with a typical Turner’s syndrome. In addition, the majority of them end with abortion, still-born, or neonates with congenital defects [7]. The first case with the 47/XXX karyotype was described cytogenetically by Jacobs et al. in 1959 [8]. While the phenotypic characteristics of the 45X have been widely described, reports on the specific the mosaicism are less frequent [2]. The natural history of a few cases of mosaic chromosomal pattern 45X/47XXX has been described and different expressions of somatic stigmata of Turner’s syndrome – mostly milder than that associated with 45X karyotype – have been reported [9]. One-third of girls with this karyotype generally display unremarkable mental and behavioral problems [10]. We present the case of a 33-year-old woman with a mosaic Turner’s syndrome karyotype (45,X/47,XXX) who conceived spontaneously and had two successful pregnancies and one IUGR pregnancy. Short stature was the only manifestation of Turner’s syndrome. This is the first case of successful pregnancy in patient with 45,X/47,XXX mosaic Turner’s syndrome from Greece. In the present report, we reviewed the available literature on the fertility

Correspondence: Professor Panagiotis Tsikouras, Assistant Professor, Department of Obstetrics and Gynecology, Democritus University of Thrace, Lysimachou /Petrina, Box 106, 6 km Alexandroupolis/Makri, Alexandroupolis 68100, Greece. E-mail: [email protected] ISSN 1476-7058 print/ISSN 1476-4954 online Ó 2011 Informa UK, Ltd. DOI: 10.3109/14767058.2010.520769

The influence of Turner’s syndrome on the women’s fertility of women with Turner’s syndrome and the phenotypic effects of mosaicism for a 47,XXX cell line in Turner syndrome.

Case report A 33-year old woman gravida 2, para 1 presented at 36 weeks’ gestation for ultrasound examination. Her first pregnancy was uncomplicated and resulted in a healthy female infant weighing 2900 g at 37 weeks. The ultrasound examination showed severe symmetrical IUGR-fetal biometry equivalent to 27 weeks’ gestation- with oligohydramnios and absent fetal movement over 30 min. Doppler blood flow studies showed a high resistance pattern in the uteroplacental arteries with absence of enddiastolic flow in the umbilical artery flow velocity waveform. Other organs were unremarkable. A female fetus weighing 1000 g was delivered by emergent cesarean section. The baby showed immediate respiratory distress and was treated with oxygen. She had renal failure, with a BUN level of 41 mg/dl, and the serum potassium level was 8.3 mg/dl. She was thought to have sepsis and disseminated intravascular coagulation and was treated with antibiotics but 24 h later a fetal death occurred. Histology revealed no abnormalities of the fetus. The woman was Rhesus positive and the blood tests for TORCH and parvovirus screen were negative. The couple decided thereafter to have a karyotype examination. After obtaining information regarding her anamnesis and a detailed pedigree analysis a blood sample was obtained for cytogenetic studies. Giemsa-trypsin banding and karyotyping of prepared lymphocyte cultures were performed according to ISCN 1995. When metaphases were examined, it was found out that 88% had 45,X and 12% had 47,XXX chromosomal structure, and it was reported that she had a Turner syndrome and Triple-X mosaicism (45,X/47,XXX). A normal 46,XY karyotype was confirmed on paternal blood. The patient’s previous physical and mental development was reported within normal limits. Menarche had occurred at the age of 12 year, and her menstrual cycles had been almost regular. She weighed 51 kg and was 145 cm tall (BMI: 24.3 kg/m2). At the physical examination she did not have such typical features of Turner’s syndrome as webbing of the neck, low hair line, short fourth metacarpals, and an increased carrying angle at the elbow. She showed normal breast development and normal puberty. The pelvic examination revealed normal external genitalia, vagina uterus and ovaries. Thus, she lacked the clinical manifestation of the characteristic phenotype of Turner’s syndrome except for short stature. 2D and M-mode echocardiogram recordings, pulsed-wave Doppler of the heart, ECG, abdominal ultrasound and urography did not reveal any structural alterations of the cardiovascular and urinary systems. At the neuro-psychological evaluation, which included a semi-structured psychological colloquium, there was not evidence of impaired visual-spatial organization and motorial coordination, difficulties in the construction of more complex phrases, reading difficulties, emotional and social immaturity. She had no history of learning difficulty at school or behavioral problems. Ten months later the patient conceived a third time without any medical intervention. After the patient and her husband had been informed about the recurrence risk for Turner’s syndrome, amniocentesis was carried out at 16 weeks’ gestation for karyotyping, which prenatally

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predicted a normal 46,XY child. The pregnancy progressed uneventfully and fetal growth was normal. At 38 weeks’ gestation, a 3.100 g phenotypically normal male infant was delivered by cesarean section. There were no postpartum complications. Breast feeding lasted 1 month, and the first period occurred 7 weeks after delivery. A normal 46,XY karyotype was confirmed on neonatal blood and no congenital malformations were noted.

Discussion Natural pregnancy in women with Turner’s syndrome Only about 10% of women with a 45,X cell line experience pubertal development with menstruation [11]. Spontaneous conception in these women is rare. The molecular basis of 45,X gonadal dysgenesis remains unclear. In most 45,X patient, the oocyte loss takes place in the early stage of meiotic prophase–pachytene and results in a streak ovary composed of white fibrous stromal tissue containing no ova or follicular derivatives [12]. In Turner’s syndrome, the process of substitution of the oocytes by fibrous tissue is accelerated and may already be completed by the time of birth or soon afterwards [13]. It is likely that it is due to haploinsufficiency of multiple genes on the X chromosome, which affect ovarian function and stature [14]. In rare cases, it is possible that a few oocytes survive destruction until a fertile age and the gradual loss of germ cells may last up to 40 years [5]. This may be due to preservation of two copies of the Xq13-q26 region containing genes that allow normal ovarian development [15]. According to Ogata and Matsuo, gonadal dysgenesis might depend on chromosome pairing failure during meiotic prophase, causing failure of synaptic formation at the zygotene and oocyte loss [16]. The degree of gonadal dysgenesis depends on the size of the impaired region of homologue chromosomes. Thus, severe pairing failure causes degeneration of all the oocytes before puberty, primary amenorrhea and poor secondary sexual development, whereas mild pairing failure jades to the survival of a considerable number of oocytes until puberty, leading to secondary amenorrhea and secondary impaired sexual development [16]. Natural pregnancy have been reported both in patients with monosomy X as well as its mosaic forms. According to Pasqualini-Adamo, the frequency of pregnancies in Turner’s syndrome patients is 2%; however, these pregnancies are at high risk of recurrent miscarriage and malformations in the children [17]. By reviewing the literature we came across 216 pregnancies in 106 Turner’s syndrome patients [13,18–20] (Table I). Tarani et al. reviewed the outcome of *160 spontaneous pregnancies in 74 women with Turner syndrome [13]. The median age of these women at pregnancy was 23–24 years and they were usually not 434 years. Most had a mosaic Turner’s karyotype containing a 46XX line [13,21], though some had non-mosaic Turner syndrome [22,23]. Taga et al. reported the first case of successful pregnancy in patient with an X ring chromosome and 45,X/46,Xr(X)/46,XX karyotype [18]. An extraordinary case is described by Ayuso et al., of a Turner syndrome patient with a 45,X/ 46,XXX/47,XXX karyotype who had 14 pregnancies, eight of which ended in abortion and six went to term. One of the children was affected by Turner syndrome [24]. Danish investigators have studied fertility in Danish women diagnosed with Turner syndrome [19]. In total,

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S. Bouchlariotou et al. Table I. Previous reports of spontaneous pregnancy outcome in Turner’s syndrome patients.

Taga et al. [18] Tarani et al. [13]

Schwack and Schindler [20] Birkebaek et al. [19]

Patients

Maternal karyotype

Pregnancies

Healthy

Miscarriages/malformed

1 15 25 12 16 1 3 1 1 1 31

45,X/46,Xr(X)/46,XX 45,X 45,X/46,XX 45,X/47,XXX 45,X/46,XX/47,XXX 45,X/46,XX/47,XXX/48,XXXX 46,X,del(Xq) 46,X,del(X)(p21) 45,X/46,X,r(X) 45,X 45,X/46,XX 45,X/46,XX/47,XXX 45,X/46,XX,46,X,del(X)(p21.1) 45,X/46,XX,46,X,del(X)(p22.1) 45,X/46,XX,46,X.i(X)(q)

2 26 55 20 48 3 3 4 1 3 61

2 13 18 16 14 0 0 1 0 3 19

0 13 37 4 34 3 3 3 1 0 6

Data taken from references 13, 18, 19, 20.

410 women in the fertile age registered in the Danish Cytogenetic Central Register with Turner syndrome between January 1973 and December 1993. Thirty-one women, 27 with mosaicism and 4 with 46,XX and a structural abnormality of the second X, gave birth to 61 children. Twenty-five of the 61 children had a chromosome analyzed. Six of the 26 examined children had chromosomal aberrations. According to these investigators, fertility in women with Turner syndrome is higher than earlier reported (7.6%) but only women with 45,X/ 46,XX mosaicism or 46,XX and structural abnormality of the second X, gave birth to live children after spontaneous pregnancies [24]. However, Schwack and Schindler described a woman with 45,X karyotype who had three spontaneous pregnancies and delivered three healthy children [20]. As reported before, in the majority of women with Turner’s syndrome who conceive these is an increased risk of miscarriage, stillbirths and malformed babies [1,4,7,13]. Possible explanations for the miscarriages can be the chromosomal abnormalities in the fetuses, mostly trisomy 21 and Turner syndrome, which have been noted in both the aborted fetuses and the live-born children of these patients at a higher rate than in the general population (4 versus 0.4% for trisomy 21 and 15 versus 0.5% for Turner syndrome) [25]. One reasons for these chromosomal abnormalities may be the imbalance of genic regulation present in the mother and transmitted to offspring [13]. Furthermore, since autoimmune disorders are common in Turner’s syndrome patients, some of the miscarriages might have an autoimmune origin, as the presence of autoimmune antibodies is connected to recurrent abortions [2,25]. Current evidence from oocyte donation programs has additionally shown that diminished endometrial receptivity might be another cause of the miscarriages [26]. The question of whether or not there is a high risk of chromosomal abnormalities in biological children of Turner’s syndrome women cannot be neglected. Published cases are few, and calculation if the risk is unreliable [27]. Possible all women with Turner’s syndrome should be offered preimplantation diagnosis, chorion villous sampling, or amniocentesis if fertilization with their own oocytes is successful. The congenital deformities in patients with Turner’s syndrome also place their pregnancies at high risk [4].

Cardiovascular complications occur in 10–44% of these women [28], mainly because of congenital coarctation of the aorta and bicuspid aortic valves [2]. Aortic dissection can be a fatal complication during pregnancy [29]. In addition, the high rate of glucose intolerance and disturbances in carbohydrate metabolism associated with Turner syndrome can complicate pregnancy [2]. Finally, because of their short stature, all women with Turner syndrome have a small pelvis, which may indicate a Caesarean section as a mode of delivery [28]. To avoid these complications, women with Turner syndrome require careful pregnancy screening which must include, in addition to routine check-up, comprehensive cardiovascular examination, glucose challenge test and liver and thyroid tests [29].

Phenotypic characteristics in 45,X/47,XXX mosaicism In the subset to subjects with Turner’s syndrome approximately 3–4% are mosaic for a 47,XXX cell line [30]. The etiology of 45,X/45,XXX may be explained by post-zygotic nondisjuction in a normal disomic cell line, resulting in monosomy/trisomy-derivative cell lines [31]. In Turner syndrome cases with 45,X/45,XXX karyopype, the disease has a mild severity [32]. The woman described above lacked the clinical manifestation of characteristic phenotype of Turner’s syndrome. On review of medical publications, there are some major differences between those females with a 47,XXX cell line and those with 45,X only or 45,X/46,XX. In general, females with Turner syndrome with sex chromosome aneuploidy, have oedema at birth, are short and have streak gonads. Many of the infants without postnatal oedema show stigmata of prenatal oedema such as webbing of the neck and anteverted ears [3]. Subjects with 47,XXX are unlikely to present with perinatal oedema and more likely to be diagnosed in childhood for short stature, or later for primary or secondary amenorrhoea or during evaluation for pregnancy loss [3]. Individuals with this karyotype, phenotypically do not show the characteristics of Turner syndrome. Thirty-seven percent of adult have a normal stature and secondary amenorrhea, while 0–5% have skeletal anomalies [33]. Congenital malformations are frequently observed in Turner syndrome women (17–56% vs. *2% in the general

The influence of Turner’s syndrome on the women’s fertility population) [34]. Cardiovascular abnormalities in Turner syndrome patients involve structural defects of the urinary systems, of the heart and large vessels along with the consequences of the presence of several cardiovascular risk factors included arterial hypertension, hyperlipidemia, obesity and impaired glucose tolerance. Some authors have reported associations between phenotype and karyotype patterns in these individuals [34]. Cardiovascular and renal anomalies have been reported in less than 4% of cases with 45,X/45,XXX karyopype and coagulation disorders have been found in about 3% [34]. The educational difficulties of girls with 45,X have been well documented [35]. Adolescent girls with Turner syndrome are at greater risk for having problems related to lower social activity, poor social coping skills and increased immaturity, hyperactivity and impulsivity compared to their peers. In addition, females with Turner syndrome tend to demonstrate significant deficits on tests of mental rotation, object assembly, and face recognition [35]. Although there are relatively few studies, in general, it is believed that the triple X syndrome in the non-mosaic state (47,XXX) is associated with verbal processing deficits, a decrement in IQ predicted by sib achievement, social immaturity, and global delays [36]. It is surprising, therefore, that girls who are mosaic for these two chromosomal abnormalities appear to have no cognitive or behavioral abnormality [37]. It would seem that the clinical effects of haploinsufficiency of the genes in the 45,X cells are ameliorated by the 47,XXX cell line [37]. Our patient presented no mental retardation or social immaturity. Gonadal dysgenesis and infertility are the primary features of Turner syndrome. It is clear that the presence of an XXX cell carries with a greater likelihood of residual ovarian function. These women are more likely to have spontaneous menarche than those with 45,X (70% compared to 11%) [3]. Borgstro¨m et al. demonstrated currently that five prognostic factors were positive and statistically significant for finding remaining follicles in the ovaries of girls with Turner syndrome: mosaicism, sings of spontaneous puberty, and normal hormone concentrations [27]. However, a significant number of these women did not maintain normal menstrual cycles and secondary amenorrhoea or premature menopause were common occurrences. The ovarian function in 45,X/47,XXX women has been described as ranging from normal to completely absent with mono or bilateral streaked gonad findings [38]. Moreover, the premature ovarian failure can be explained in part by a further loss of the X chromosome with age [38]. Pregnancy is more probable for women with the present of either a 46,XX or a 47,XXX cell line or both, compared with those with monosomy alone [3]. In fact, mosaicism may be found in all fertile women with Turner syndrome if extended examinations were offered [19]. Most reports on fertility in women with Turner syndrome are from women with mosaicism [13,18,19]. Tarani et al. reviewed the outcome of spontaneous pregnancy in 74 women with Turner syndrome, including 12 patients with the 45,X/ 47,XXX karyotype. Although only the 62 (38%) of 160 pregnancies in the whole group resulted in healthy liveborn children, the outcome was normal in 16 of 20 pregnancies in the 45,X/47,XXX group [13]. However, the presence of maternal mosiacism does not seem to reduce the risk of malformations in the offspring and should be counseled appropriately [13]. In summary, Turner syndrome seem to be characterized by a more variable phenotype expression than the 47,XXX phenotype. This can reflect the simultaneous presence of

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different genetic material under the form of cryptical mosaicism or sex chromosome fragments in Turner subjects [34]. However, no linear correlation has been found between karyotype and phenotype in subjects with chromosomal aberrations [2]. The lack of direct karyotype–phenotype correlation indicates that several factors are involved in the development of the phenotypes of the phenotypes and these relationships have not yet been completely clarified [38]. Moreover, the mechanism by which the mosaicism occurs in different tissues is still unknown, as are the factors influencing survival of an aneuploid cell line [34]. Despite these limitations, the demand for prognostic counseling in Turner syndrome has increased, especially for the more uncommon karyotypes and in mosaicism, and even more so when the sex chromosome aneuploidy is detected prenatally.

Conclusions Natural pregnancies are rare in women with Turner’s syndrome and mostly occur in those with mosaic karyotype. Women with Turner’s syndrome who conceive are known to be at increased risk of miscarriage, still birth and having an offspring with congenital malformation or aneuploidy. Therefore, in all pregnancies genetic counseling and prenatal diagnosis should be considered. A small proportion (3–4%) of women with Turner’s syndrome are mosaic for a 47,XXX cell line. These women are more likely to have spontaneous menarche than those with 45,X and more likely to be fertile. However, the presence of 45,X/47,XXX mosaicism does not seem to reduce the risk of malformations in the offspring. The woman described above is a unusual case of a 45,X/ 47,XXX mosaicism who had three natural pregnancies and has given birth to two healthy children. In Turner syndrome cases with 45,X/45,XXX karyopype, the disease has usually a mild severity. However, establishing phenotype–karyopype correlations in Turner syndrome has been problematic. Many have been proposed and few confirmed. Overt chromosomal mosaicism for monosomy X and a second or third cell line occurs in almost 50% of patients with Turner syndrome and it is difficult to assess the relative contribution of each cell line to each organ system. In our patient, the 45,X/45,XXX mosaicism was diagnosed quite late due to the normal sexual development and the long period of regular menstrual cycles. However, sex-chromosomal alteration should be always suspected when at least two clinical features of the disorder exist [2]. It is very important to perform an accurate diagnosis of the karyotype and to search for all the possible impairments described in Turner’s syndrome and related mosaicisms, because the consequences of a late diagnosis of this illness are severe and life-long. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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