Recurrent fetal triploidy: is there a genetic cause?

Abstract

Triploidy is currently understood as a sporadic genetic disorder, with no recognisable risk of recurrence nor identifiable risk factors. In cases of triploidy, chances of thriving through the second trimester of fetal development are very slim, with most of these pregnancies ending as early miscarriage. We report a case of repeated triploid pregnancies in the same woman, from different fathers, achieving the second trimester of pregnancy; elective termination was decided in both cases, after an amniocentesis revealing a triploid karyotype. Both triploid pregnancies are described and compared; prenatal laboratorial markers, sonographic features, clinical course and pathological findings are analysed and matched with fetal autopsy and placental pathological study. Reported findings strongly point to recurrent triploidy of maternal origin, and so the possibility of a genetic predisposition should be considered. Investigation is required to assess the presence of an underlying genetic mechanism in this setting, thus enabling a better genetic/obstetric counselling.

Background

The term triploidy refers to a numeric chromosomal disorder with three complete haploid sets of chromosomes instead of the normal two (69, XXX, 69, XXY or 69, XYY).¹ It constitutes a relatively common condition: 1% of all conceptions are estimated to have triploidy. However, since most of these pregnancies end as early miscarriage, the percentage of triploid pregnancies achieving the second trimester is substantially lower, with triploidy accounting for only 0.002% of pregnancies at 16–20 weeks. In fact, in cases of triploidy, achievement of the second trimester of fetal development is rare.^{2 3} In contrast to aneuploidies due to nondisjunction, increased maternal age is not a risk factor for triploidy and no other susceptibility factor has already been identified. Thus, the mechanism of triploidy remains poorly understood.⁴

Clinically, there is not a single and uniform pattern associated with triploidy, which may hinder an early prenatal diagnosis of this condition.^{1 5 6} In fact, a broad spectrum of phenotypic features have been described in triploid pregnancies, including placental changes, amniotic fluid volume variations, fetal growth restriction, increased nuchal translucency (NT) and a wide spectrum of malformations including the central nervous system, face, heart, limbs and urinary tract^{1 6–8}—the most commonly associated fetal malformation is syndactyly, which represents a characteristic finding, though not pathognomonic.^{5 9} Nevertheless, some of the affected fetuses may not have any apparent anatomic defect on prenatal scans, and only careful assessment of fetal growth and placental morphology may lead to the suspicion of the diagnosis.^{5 6}

Regarding the parental origin of the extra haploid set, there are three different possible scenarios: dispermic triploidy and diantric triploidy, of paternal origin, in which, respectively, two different haploid sperms fertilise one haploid ovum, or one diploid sperm fertilises one haploid ovum, and digynic triploidy, of maternal origin, in which one haploid sperm fertilises one diploid ovum.^{1 7} These definitions are clinically relevant and have major clinical implications, since triploid pregnancies of maternal or paternal origin result in distinct prenatal sonographic features, maternal risks and clinical course.^{6 10 11}

Paternal origin triploidies tend to result in a well-formed fetus with a normal-sized or microcephalic head, increased fetal NT, extremely high levels of free beta human chorionic gonadotropin (β-HCG) and α-fetoprotein, and a large placenta with cystic changes (type I phenotype); the vast majority of these pregnancies fail to thrive through the second trimester, ending as early spontaneous abortions.^{1 10 12} Oppositely, maternal origin triploidies are more likely to result in a severely asymmetric growth-restricted fetus with a relatively large head, normal fetal NT, low levels of pregnancy-associated plasma protein-A (PAPP-A) and free β-HCG along with a small, non-cystic, normal appearing placenta (type II phenotype)^{1 10 12}; these fetuses have a better chance to thrive through the second trimester of gestation or even to be born.^{13 14}

Below, we present a case of recurrent second trimester fetal triploidy in two subsequent pregnancies and describe the clinical features in both, including patient-relevant medical history, fetal sonographic and pathological findings, clinical course and prenatal orientation. Additionally, an analysis of the common features in both pregnancies is made and matched with autopsy and placental pathological study.

Case presentation

A Caucasian woman, with previous history of anxiety, medicated with ethyl loflazepate. There were no other relevant medical conditions and family history was unremarkable, with no evidence of consanguinity, multiple miscarriages, genetic disorders or congenital malformations. Regarding her reproductive history, she had three spontaneous pregnancies. Her first pregnancy occurred at the age of 29 and had a normal evolution, resulting in a healthy female newborn delivered at term. Her second pregnancy, at the age of 32, was found to be a triploid pregnancy, resulting in a second trimester elective termination—both of these pregnancies were from the same male progenitor. She had her third pregnancy at the age of 34, which was also found to be a triploid pregnancy, ending likewise as a second trimester elective termination—in this case, from a different male progenitor. Features and evolution of both triploid pregnancies are presented separately below.

First triploid pregnancy

A single spontaneous pregnancy case referred to our institution at 12 weeks for first trimester screening. PAPP-A was 0.03 multiples of the median (MoM) and free β-HCG was 0.25 MoM. First trimester ultrasound showed no major anatomic defects and NT measurement was normal. Combined first trimester screening was positive for trisomy 18 and negative for trisomy 21. An ultrasound was performed at 18 weeks, showing oligohydramnios, severe asymmetric fetal growth restriction (estimated fetal weight less than the fifth percentile) with a disproportional large head circumference, and the presence of hypertelorism. An amniocentesis was performed, revealing a triploid karyotype (69, XXY) and pregnancy was electively terminated at 19 weeks. Fetal autopsy revealed a small-for-gestational-age macrocephalic fetus, with hydrocephaly, cerebellar vermis hypoplasia, hypertelorism, proptosis, low implantation of the ears, bulbous nose, severe micrognathia, left unilateral clubfoot and clenched hands with syndactyly between the second and the third fingers on the left hand; additionally, external female genitalia was identified (figure 1). Umbilical cord had a single umbilical artery (SUA); placenta had a low weight for gestational age and no gross morphologic alterations were seen. Microscopy showed severe chronic intervillositis (figure 1B). This placental phenotype is associated with high risk of recurrence in subsequent pregnancies, fetal growth restriction and intrauterine demise.

Figure 1.

First triploid fetus: (A) large head and micrognathia, single umbilical artery (inset); (B) placental severe chronic intervillositis; (C) proptosis, bulbous nose, syndactyly, unilateral clubfoot and bizarre appearance of toes; (D) syndactyly of the second and third fingers; and (E) female external genitalia.

Second triploid pregnancy

A single spontaneous pregnancy case referred to our institution for first trimester screening at 11 weeks. PAPP-A was 0.028 MoM and free β-HCG was 0.219 MoM. First trimester ultrasound was unremarkable, including a normal NT, and combined first trimester screening was negative. At second trimester scan at 22 weeks, severe oligohydramnios was detected and the fetus was found to be severely restricted (estimated fetal weight < first percentile), with a relatively large head circumference, and a posterior fossa malformation compatible with cerebellar vermis agenesis; placenta was small with a normal appearance. An amniocentesis was performed which revealed a triploid karyotype (69, XXX) and pregnancy was electively terminated at 23 weeks. Fetal autopsy showed a small female fetus with a large head, hypertelorism, proptosis, low implantation of the ears, small nose, micrognathia, bilateral clubfoot and syndactyly between the third and the fourth fingers on the left hand and between the second and the third fingers on the right hand (figure 2); brain evaluation was not possible due to visceral autolysis. Umbilical cord had an SUA with an eccentric insertion; placenta was found to have a very low weight for gestational age and no morpho-histological alterations were seen.

Figure 2.

Second triploid fetus: (A) large head, proptosis and small nose; (B) low implantation of the ears and micrognathia; (C) syndactyly of the second and third fingers; and (D) bilateral clubfoot and bizarre appearence of toes.

Investigations

The establishment of an early triploidy diagnosis may require a high index of suspicion, bearing in mind the wide phenotypic variation. An active effort to establish the parental origin of the triploidy should be made, since it entails different implications, and so particular attention should be taken to the aspects of the placenta and fetal growth.

In this particular clinical case, the presence, in both pregnancies, of low levels of PAPP-A and free β-HCG in the first trimester screening as well as the identification of an abnormally small placenta during ultrasound scans is highly suggestive of a maternal origin for the extra haploid set of chromosomes.¹ Additionally, in both cases, a severe asymmetric intrauterine growth restriction with a relatively large fetal head was detected on second trimester screening, which is also a finding suggestive of a digynic triploidy.^{10 12} Achievement of second trimester of gestation itself also supports this hypothesis, since the majority of diandric triploid pregnancies end as spontaneous abortion during the first trimester.¹⁰ With regard to fetal anatomic characteristics, in both affected pregnancies, there was identification of cerebellar anomalies (cerebellar vermis hypoplasia/agenesis), facial anomalies (hypertelorism, proptosis, low implantation of the ears, small nose and micrognathia) and limb anomalies (such as syndactyly and clubfoot); both pregnancies had an SUA.

As described, several features were similar in the two consecutive triploid pregnancies, which reinforces the concept that there are typical findings in triploid pregnancies in general, and in digynic triploid pregnancies in particular. One limitation of our report is the absence of an appropriate molecular investigation of fetal DNA in both pregnancies, which could unequivocally prove the parental origin of the repeated triploidies. However, the association of the laboratorial markers, sonographic features, clinical course and pathological findings makes the hypothesis of a digynic origin extremely likely in this context.

Outcome and follow-up

This case report elucidates the importance of a multidisciplinary interaction between obstetrics, pathology and medical genetics for a better understanding of this condition. A multidisciplinary discussion concluded that the risk of a recurrent triploid pregnancy should not be neglected and the patient was referred to a preconception appointment: in an attempt to clarify a possible chromosomal underlying disorder, progenitors karyotype was performed, which was found to be normal (46, XX for the female progenitor and 46, XY in both male progenitors). Since the possibility of an underlying genetic aetiology could not be excluded, further genetic counselling was offered in an attempt to identify any personal or familiar factor possibly involved.

Discussion

In triploid pregnancies, chances of fetal development and survival beyond the first trimester are very slim. The finding of two consecutive pregnancies, from different fathers, with triploid fetuses in the second trimester makes this case particularly rare and interesting. Despite the theory that there are no identifiable risk factors for triploidy and that couples who have one triploid pregnancy do not have an increased risk for recurrence in future pregnancies,¹⁰ there are already some reports of recurrent diandric triploid pregnancies in a few families, which turned to be proven as inherited in an autosomal recessive way.^{15 16} Similarly, three previous publications reported cases of recurrent proved maternally inherited triploidies.^{4 17 18} Here, we report a case of triploidy recurrence with features of maternal origin in two consecutive pregnancies, which supports the possibility of an underlying genetic aetiology. Moreover, and despite the reported substantial phenotypic disparity in triploidy,^{5 6} in this report, we describe two consecutive triploid pregnancies with a very similar phenotypic presentation, which also favours a genetic mechanism for this condition.

Reported findings strongly point to recurrent triploidy of maternal origin, and so the possibility of a genetic predisposition should be considered. This elucidates the need to have a meticulous prenatal evaluation and a cautious approach when assessing this disorder. Additional investigation is required in order to evaluate the presence of underlying genetic factors in this setting, which could improve the scientific knowledge on recurrent triploidy, thus enabling a better genetic and obstetric counselling.

Learning points.

• Triploid pregnancies thriving through the second trimester of fetal development are rare.

• The finding of two consecutive second trimester pregnancies with triploid fetuses with features of a maternal origin for the extra haploid set of chromosomes supports the possibility of a genetic underlying aetiology.

• Additional investigation is required in order to evaluate the presence of an underlying genetic mechanism for recurrent digynic triploid pregnancies, thus enabling a better genetic and prenatal counselling.