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A conundrum from antenatal testing

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Q1: What is the prognosis and management of mild cerebral ventriculomegaly?

Mild cerebral ventriculomegaly is usually defined as an atrial width of 10–15 mm measured by ultrasound between 15 and 40 weeks’ gestation. Estimates of incidence vary from 1.48 per 1000 to 22 per 1000.1

In a series of 234 cases, 23% had an abnormal outcome as summarised below2:

  • Perinatal death 3.7%.

  • Chromosomal abnormalities (mostly trisomy 21) 3.8%.

  • Malformations undetected at second trimester ultrasound scan 8.6%.

  • Neurological sequelae 11.5%.

Most of the neurological sequelae involved a mild to moderate delay in cognitive and/or motor development. No clinical sequelae occurred in the remaining 77% of cases of isolated mild ventriculomegaly.

The counselling of parents of a fetus with isolated mild ventriculomegaly is complicated by the fact that it is not always possible to predict the fetus that will have abnormal neurological sequelae. The parents should therefore be informed about the possible causes, their prognosis, and the techniques available to help reach an underlying aetiology with their advantages and disadvantages and what the couple would wish to do with this information.3

Amniocentesis is usually performed in preference to chorionic villus sampling (CVS) as pregnancy loss is more common after CVS.4 The procedure estimated increase in miscarriage rate with amniocentesis is generally quoted as 1% above background risk levels5 compared with a generally quoted figure in the literature of 2% for CVS. Chorionic villus sampling is also associated with more sampling and technical failures, and more false positive and false negative results. However, the couple should be made aware that in 0.4% of amniocentesis cases the cell culture will fail and a repeat procedure will be required to obtain a karyotype.4

Furthermore with the availability of FISH providing results from amniocentesis within 24–48 hours, the previous advantage of CVS over amniocentesis in obtaining a faster karyotype (48 hours for direct CVS karyotyping compared with two weeks for standard cytogenetic karyotyping of amniotic fluid) is not as crucial.

The literature generally agrees that maternal blood should be screened for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex (TORCH) as well as parvovirus B19 to exclude congenital infection, although there is no clear evidence that any of these organisms are implicated in the causation of mild lateral cerebral ventriculomegaly.1,3

Fetal echocardiogram should be considered to exclude associated cardiac anomalies. Magnetic resonance imaging (MRI) may be indicated in cases where infection screening is negative and karyotyping is normal because MRI may diagnose agenesis of the corpus callosum,1 a condition that may be asymptomatic in some children through to major neurological manifestations in others.

Ultrasound follow up is necessary if parents decide to continue with the pregnancy to discriminate between progressive and stable ventriculomegaly. In progressive ventriculomegaly consideration for early delivery may be warranted.

If the fetus is reported as being karyotypically normal with no evidence of congenital infection, an ethical dilemma can occur if the parents then request termination of pregnancy because of the risk of mild delay in cognitive and/or motor development.

Q2: What are the causes of two cell lines in a sample of amniotic fluid after amniocentesis?

The causes for the finding of two cell lines in an amniocentesis sample are:

  • Maternal cell contamination.

  • Vanishing twin.

  • Chimaera.

  • Mosaicism.

Q3: What is the “best guess” diagnosis?

Maternal contamination of the amniotic fluid sample is the most common cause for two cell lines in an amniotic fluid specimen but is unlikely in this case as the fluid was not blood stained.

A chimaera, where there is an individual with two cell lines from two separate zygotes, can be caused by:

  • Early fusion fraternal twin zygotes.

  • Double fertilisation of egg and polar body.

  • Exchange of haemopoietic stem cells by dizygotic twins.

A chimaera is an extremely rare condition and so is highly unlikely to be the diagnosis.

Vanishing twin could have been the cause, although the 10 week scan showed no evidence of a twin pregnancy. Before the couple decided on termination of the pregnancy our best guess was that the trisomy of chromosomes 13, 18, and 21 represented a fetus with a triploidy which had demised (vanishing twin) and the 50% diploid cells were from the viable fetus.

However, after delivery the female infant macroscopically had dysmorphic features. Therefore, our working diagnosis changed to a fetus with triploidy and maternal cell contamination giving rise to the diploid cell line. The commonest triploidy is 69,XXY (60%) followed by 69,XXX (37%), and then 69,XYY (<3%). Dispermy accounts for 65% of the cases of trisomy followed by a diploid sperm fusing with a haploid egg (25%) and then a haploid sperm fusing with a diploid egg. If the extra haploid is paternally derived then one would expect to see hydatiform changes in the placenta. The best guess diagnosis before the karyotype being available was therefore 69,XXX with a haploid sperm fusing with a diploid egg.

After the postmortem the best guess changed again because the postmortem findings only added cerebral ventriculomegaly to the macroscopic findings. Triploidies are associated with:

  • Ventricular septal defects.

  • Atrial septal defects.

  • Omphalocele.

  • Gastroschisis.

  • Umbilical hernia.

  • Adrenal and renal abnormalities.

Therefore our new best guess was that the fetus’s genotype was secondary to mosaicism—an individual with two cell lines—and that the presence of the diploid cell line moderated the phenotype.


Triploidy is the presence of three (rather than two) haploid sets of chromosomes so that the fetus has 69 chromosomes instead of the usual complement of 46. It is not an uncommon condition and is estimated to effect 2% of all pregnancies and 20% of miscarriages. The condition causes multiple congenital abnormalities with most fetuses either stillborn or dying soon after birth. The longest survival of a full triploidy infant published in the literature is 10.5 months.6 A mosaic is an individual derived from a single zygote with cells of two or more different genotypes. We suggested our fetus was a mixoploidy—an individual with a diploid cell line and a triploid cell line.

What mechanism can be postulated for this scenario? Examination of the process of fertilisation and early development may explain the process of mixoploidy.

Fertilisation occurs in the fallopian tube when a sperm binds to the zona pellucida of the ovum and undergoes the acromosomal reaction. Enzymes are released that allow the sperm to penetrate the zona pellucida and enter the ovum. Normally, the zona pellucida becomes an impenetrable barrier stopping the entry of further sperm.

Once fertilisation occurs the sperm becomes a pronucleus while the ovum completes the second meiotic division and produces a female pronucleus and a second polar body. During normal fertilisation the two pronuclei fuse to form the zygote and the second polar body is extruded. Multiple mitotic divisions then begin to produce the blastomere.

To explain the occurrence of mixoploidy six hypothetical mechanisms have been proposed.7 However, incorporation of the second polar body into one of the blastomeric cells appears to be the most likely mechanism. If the two pronuclei initially joined and the second polar body was not extruded during fertilisation then at the first mitotic division two different genetic cell lines would be formed—one cell would contain a diploid cell line while the other cell would contain a triploid cell line. Further mitosis of each cell line would result in the fetus becoming a mosaic.

A study of short tandem repeat polymorphisms in lymphocyte and fibroblast DNA of a 46,XX/69,XXX mixoploidy showed that there was a maternal origin of the supernumerary chromosome complement which was best explained by the second polar body being incorporated into the blastomere.7 This in keeping with the extra set of chromosomes being maternally derived and the clinical finding of no hydatiform change in the placenta.

Mixoploidy is an extremely rare condition but there are case reports of babies surviving for up to 5 years of age.8,9 All children suffer from varying degrees of mental and physical disability. Fortunately, the recurrence risk is low and couples can be therefore reassured that their chances of a successful outcome are similar to those parents in the “normal population”.

Final diagnosis



The authors thanks the Cytogenetics Laboratory, Aberdeen Royal Infirmary.


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