Spontaneous procreation in Turner syndrome: report of two pregnancies in the same patient

Abstract

Spontaneous procreation in Turner syndrome (TS) is a rare condition, and repeated gestation is even rarer. We report two spontaneous and successful pregnancies (at the age of 25 and 28 y) in a patient with TS (karyotype: 45,X/47,XXX, in 30 metaphases). Births were by caesarean section due to fetal-pelvic disproportion. Both children, a boy and a girl, were born at full term, with normal physical exam and karyotype. Despite the elevated pregnancy risks associated with TS co-morbidities, this report presents two successful spontaneous pregnancies with normal children in a patient with TS diagnosis after her deliveries. Gynecologists and obstetricians should be aware of this possibility when evaluating women with unusual short stature or dysmorphic features in order to implement a more cautious prenatal care in those being diagnosed with TS.

Keywords:

• mosaicism
• spontaneous pregnancy
• Turner syndrome

Introduction

Turner syndrome (TS) is caused by the partial or complete loss of one of the sex chromosomes. It affects one in every 2,000 female live-births. The classical karyotype 45,X occurs in 50% of the cases. The remaining half, are karyotypes with an X-isochromosome or mosaicisms [Sybert 2002]. The presence of the Y-chromosome is associated with an increased risk of developing gonadoblastoma [Davenport 2010; Laranjeira et al. 2010]. The main clinical manifestations of TS are: hypergonadotrophic hypogonadism (ovarian dysgenesis), short stature, webbed neck, cardiac and renal anomalies, and hearing loss [Laranjeira et al. 2010; Bondy 2007].

Approximately 20-30% of these patients have spontaneous puberty, but very few have spontaneous menarche [Laranjeira et al. 2010; Bondy 2007; Cabanes et al. 2010]. Spontaneous procreation is extremely rare, occurring in around 2% of the cases [Laranjeira et al. 2010; Bondy 2007; Cabanes et al. 2010; Bouchalarioutou et al. 2011]. Due to the rarity of spontaneous procreation in TS, this clinical case report presents a patient with TS who had two successful spontaneous pregnancies.

The Case

A 29-year-old woman was diagnosed with TS in adulthood at the age of 28 years after being noticed to be short and with cubitus valgus when bringing her children to the Pediatric Outpatient Clinic (Pediatric Outpatient Clinic of Hospital Universitario Prof. Edgard Santos, Faculty of Medicine, Federal University of Bahia). Karyotype analysis of leukocytes from peripheral blood, studying 30 metaphases, revealed 28 cells of 45,X and 2 cells of 47,XXX. Thelarche occurred at the age of 11 years and menarche at the age of 14 years. She used oral contraceptives from 18-21 years of age. Physical examination showed: weight 36.5 kg, stature 131.5 cm (< 5th percentile for patients with non-treated TS); pubertal stage M5/P5, high-arched palate, cubitus valgus, and multiple cutaneous nevi.

Workup to investigate the patient's TS, when she was 29-years-old, demonstrated: LH 10.65 mUI/mL (1.0-11.4); FSH 19.73 mUI/mL (2.0-10.3); and estradiol 50 pg/mL (26-165). Lipid profile, glucose, thyroid function tests and liver enzymes were normal. Transvaginal ultrasonography showed: uterus 90.56 cm³ (reference range: 25-140), with right and left ovarian volumes of 3.18 cm³ and 3.59 cm³ (reference range: 3.0-9.0), respectively. Echocardiogram was normal; audiometry indicated bilateral moderate conductive hearing loss; and bone densitometry showed low bone mineral density in the lumbar spine (Z-score: -2.1SD).

Obstetric history revealed two spontaneous pregnancies, the first at the age of 25 and the second at 28 years, and no reported miscarriages. The two pregnancies were normal with adequate prenatal follow-up. The births were by caesarean section due to fetal-pelvic disproportion. The first child, a boy, was born at full-term weighing 2.25 kg and a length of 44 cm. The second child, a girl, was also born at full-term, with 2.85 kg and a length of 43 cm.

The first child, examined at the age of 2 y weighed 8.79 kg (<5th percentile), had a stature of 81 cm (<5th percentile), minor dysmorphic features (e.g., anteverted ears, micrognathia, inverted triangular facial shape), with a 46,XY karyotype. The second child, examined at the age of 4.5 months weighed 5.46 kg (10^th percentile), was 61.5 cm tall (10th percentile), had no dysmorphic signs, with a 46,XX karyotype. Genetic evaluation, for both children, did not diagnose any known syndromes.

Discussion

Most women affected by TS have gonadal dysgenesis related to the haploinsufficiency of the X-chromosome genes, evolving with premature ovarian failure and requiring estrogen therapy to induce puberty and maintain feminization [Bouchlarioutou et al. 2011; Bakalov et al. 2007; Campagne and Llazamares, 2009]. However, spontaneous puberty and menarche may occur in 20% of the cases. In these cases the presence of the second X-chromosome is essential for the spontaneous pubertal development, explaining its greater occurrence in mosaicisms. Minimal gonadal dysgenesis occurs in mosaicisms 45,X/46,XX and 45,X/47,XXX and maximum in monosomy 45,X [Campangne and Llazamares 2009]. This is corroborated by the demonstration that mosaicisms, spontaneous puberty and normal sex steroids, and gonadotrophins serum concentration are positive prognostic factors for the occurrence of follicles as demonstrated in ovarian biopsies of women with TS [Borgström et al. 2009]. Another favorable prognostic factor for spontaneous puberty is the 45,X/47,XXX karyotype [Bouchlariotou et al. 2011; Akbas et al. 2009]. The patient of this report had all these favorable features.

Due to the high prevalence of gonadal dysgenesis, the majority of women with TS are infertile [Bouchlariotou et al. 2011]. Therefore, assisted reproductive techniques (e.g., oocyte donation) constitute the only possible way to achieve conception [Bondy 2007], except in patients with katyotypes 46,XX or 47,XXX where there is a possibility of spontaneous pregnancies [Sybert 2002; Bouchlariotou et al. 2011; Eblen and Nakajima, 2003]. Nevertheless, Mortensen et al, [2002] reported recurrent spontaneous pregnancies in 2 women with a 45,X karyotype and Hadnott et al. [2011] found this karyotype in 3 of 5 women who had spontaneous pregnancies among the 246 participants studied. Since few karyotypes performed in peripheral blood lymphocytes are confirmed in the ovarian tissue, it is possible that tissue-specific mosaicism or normal karyotype in germ cells could resolve these cases. Among Danish women, Birkebaek et al. [2002] found 7.6% of fertility in TS. However, only patients with 45,X/46,XX mosaicisms, 46,XX karyotype with structural abnormality of the second X-chromosome spontaneously conceived live children. In Swedish women with TS, pregnancy occurred in 12% with spontaneous pregnancies occurring in 40% of these 12%, mainly in those with 45,X/46,XX mosaicisms [Bryman et al. 2011]. Table 1 summarizes recent studies involving spontaneous pregnancies in Turner syndrome.

Table 1. Spontaneous pregnancies in Turner syndrome.

References	Patients with spontaneous pregnancies	Maternal karyotype	Pregnancies with own oocytes (type)	Healthy children	IUGR/ birth defect/ chromosomal abnormalities
Birkebaek et al. 2002	31	45,X/46,XX46,XX and structural abnormality of the second X	60 (S + IVF)	19	6
Bouchlariotou et al. 2011	1	45,X/47,XXX	3 ( S)	2	1
Bryman et al. 2011	23	45,X/46,XX	82 (S+ IVF)	33	4
Eblen and Nakajima 2003	1	45,X/47,XXX	1 ( S)	1	0
Mortensen et al. 2010	2	45,X	4 ( S)	4	0
Hadnott et al. 2011	5	45,X45,X/46,Xdel(X)	7 (S)	6	1
Present report	1	45,X/47,XXX	2 ( S)	2	0
Legend: (S): spontaneous; (IVF): in vitro fertilization; IUGR: intrauterine growth retardation

Pregnancies, either spontaneous or not, pose a high risk to TS mothers and their offspring. Since 5-50% of these women have cardiac anomalies, the most serious maternal complications are cardiovascular, such as worsening of pre-existing arterial hypertension or aortic dissection [Cabanes et al. 2010]. It is estimated that 2% of women with TS are at risk of death by aortic dissection or rupture [Bouchlatiotou et al. 2011; Mortensen et al. 2010]. The chance of dissection in pregnancy reaches 10% in some reports, particularly in the third trimester of the pregnancy and in the puerperium, and its main risk factors are hypertension, aortic coarctation, and bicuspid aortic valve [Bouchlariotou et al. 2011]. Bryman et al. [2011] reported aortic dissection during pregnancy in women with a postnatal diagnosis of TS, demonstrating that a delayed diagnosis may pose additional risk to pregnancies.

Non-insulin dependent or gestational diabetes mellitus and dysregulation of thyroid disease are other causes of pregnancy complication in TS [Mortensen et al. 2010]. Bryman et al. [2011] identified gestational diabetes and hypertension in 10% of pregnant women with TS. The patient of the present report did not develop cardiac or endocrine gestational complications.

Chromosomal abnormalities in the offspring of TS (e.g., Turner and Down syndromes) are reported [Bouchlariotou et al. 2011]. Birkebaek et al. [2002] reported chromosomal abnormalities in 6 of 25 children and major malformations (e.g., hydrocephalus and ambiguous genitalia) in 2 children born from women with TS. Bryman et al. [2011] reported birth defects in 5 (7%) of 68 children born alive, 4 of them being spontaneously conceived. Despite a cerebral palsy case, Hadnott et al. [2011] found 7 live-born, normal-appearing children without chromosomal anomalies that were spontaneously conceived by 5 women with TS. Although the karyotype 45,X/47,XXX does not reduce the risk for congenital malformations in the offspring [Bouchlariotou et al. 2011], in the present study the patient gave birth to 2 children with normal karyotypes and absence of birth defect.

In TS, 85% of the deliveries are by caesarean section, because of the small maternal pelvis. Other gestational complications are miscarriage, stillbirth, prematurity, and intrauterine growth retardation [Cabanes et al. 2010]. Because of all these maternal-fetal risks, pregnancies of women with TS should be carefully followed (e.g., blood pressure monitoring, electrocardiogram, echocardiogram, thyroid function tests, antithyroid antibodies, fasting blood glucose, glycated hemoglobin, liver enzymes, renal function, urine culture, and renal ultrasonography) [Cabanes et al. 2010]. Although there is no international consensus about these recommendations yet, the French College of Obstetricians and Gynecologists considers that pregnancy in TS is contraindicated when there is history of aortic surgery, aorta coarctation or dissection, aortic diameter greater than 25-35 mm/m², intractable hypertension, and portal hypertension with oesophageal varicose veins [Cabanes et al. 2010]. Follow-up is needed in the puerperium, with echocardiogram performed 5 to 8 d after delivery due to the persistent cardiovascular risk. The newborn should be assessed for the presence of features of Turner or Down syndrome, except those conceived by egg donation [Bondy 2007; Cabanes et al. 2010].

In summary, spontaneous pregnancy in TS is rare, and recurrent pregnancies are even rarer, being more common in karyotypes with mosaicisms. As reported above, TS diagnosis in this case was delayed until after the second pregnancy but could be suspected by her significant short stature. It is known that such a delay in diagnosis may have serious consequences, especially on pregnancy. Despite gestational risks posed by possible maternal co-morbidities associated with the syndrome and the lack of previous investigation, this report presents two successful pregnancies in a woman with mosaicism 45,X/47,XXX. Gynecologists and obstetricians should be aware of this possibility when evaluating women with unusual short stature or dysmorphic features in order to implement a more cautious prenatal care in those being diagnosed as having TS.

Declaration of Interest: The authors state that there is no financial or other relationship which might lead to conflict of interest.