GeNeViSTA

1 Abstract:

Prenatal screening tests are being universally employed in the current era to identify women at risk of fetal aneuploidies. This unveils a high proportion of unanticipated findings amongst which sex chromosome abnormalities are frequently encountered. It is imperative that geneticists and fetal medicine specialists have sufficient knowledge about these anomalies in order to provide appropriate genetic counseling and assist the couples in decision making during pregnancy. In the article, we briefly discuss the outcomes and counseling approach for the prenatally detected common sex chromosome abnormalities.

Keywords: Sex chromosome anomalies, prenatal screening,Turner syndrome, Klinefelter syndrome, genetic counseling.

2 Introduction

Sex chromosome abnormalities (SCAs) are the most frequently encountered chromosomal abnormalities both prenatally and at birth. These are due to the presence of an extra or missing X or Y chromosome and most commonly include 45,X; 47,XXX; 47,XXY; and 47,XYY. The prevalence of SCAs is estimated to be around one in 500 newborns, twice as common at birth as trisomy 21. The frequency at prenatal diagnosis is much greater and ranges from 1 in 250 to 300 (Linden et al., 2002). Though not a primary target for detection in prenatal diagnosis, incidental findings like SCAs cannot be avoided. With expanding use of population wide screening for chromosomal anomalies by novel genomic technologies like non-invasive prenatal screening (NIPS), such problems will be more commonly seen in the near future. Being an unexpected finding in prenatal testing, SCAs pose significant challenge to the genetic counselor in terms of counseling and dilemma for the family. The outcome varies greatly from normal phenotype to those with significant phenotypic abnormalities. Individuals with SCA usually do not have significant intellectual disability. Hypogonadism and infertility remain the major issues; both of which have solutions in the form of hormone replacement therapy (HRT) and assisted reproductive techniques (ART). The difficulties in decision making are obvious as uncertainties about the phenotype are not strong enough to consider termination of pregnancy. The decision depends upon parents’ family history and their perspectives to look at the problem. The parents’ thinking gets influenced by what is conveyed to them by health care professionals involved in prenatal diagnosis and counseling. Hence, it is essential that accurate and up-to-date information about the likely outcomes is communicated to the family in a simplified manner. Through this article, we describe the outcomes of various prenatally detected SCAs and the issues in counseling for the same.

The following case scenarios present some common problems faced by the clinicians and families and perspectives in approaching them:

Case scenario 1: A 32-year-old G2P1+0L1 mother who has a previous child with Down syndrome (Trisomy 21) visits us at 16 weeks of gestation for prenatal counseling. After pre-test counseling regarding the risk of recurrence of 1% for trisomy 21 in the current pregnancy, she opts for prenatal testing. Amniocentesis followed by quantitative fluorescent polymerase chain reaction (QFPCR) reveals 47,XXY and this finding is confirmed by karyotyping.

Case scenario 2: A 35-year-old G3P0+2, with previous two abortions, presents with history of two IVF (in vitro fertilisation) failures and consults us in view of non-invasive prenatal screening (NIPS) test showing high risk for monosomy X. This finding is confirmed by chromosomal analysis from amniotic fluid. Ultrasonography evaluation at 18 weeks is normal.

Case scenario 3: A 30-year-old G3P2 mother with previous two healthy children, visits us at 17 weeks for counseling regarding high risk for trisomy 21 (1:151) on quadruple marker testing. Pre-test counseling is provided. Options of NIPS and invasive testing are given and she opts for invasive testing. Amniocentesis followed by QFPCR and karyotype is suggestive of 47,XXX chromosome complement.

Counseling for the above-mentioned cases requires in-depth knowledge about the clinical phenotypes of SCAs, variability in presentation and availability of management options for hypogonadism and infertility. As these situations are not infrequent, it is important that clinical geneticists, fetal medicine specialists and counselors acquire adequate knowledge to provide prospective parents with sufficient and unbiased information regarding these SCAs and guide them in decision making.

3 Pre-test Counseling

Pre-test counseling for prenatal procedures done for varied indications should always include discussion about the various disorders which can be detected by the test. A brief discussion on the outcome of these disorders in general which would result in mental or physical abnormalities should be discussed. The counseling must include the possibility of detection of unrelated abnormalities including SCAs, unbalanced autosomal abnormalities other than the intended ones, and mosaic forms. Many of these may have variable outcomes. Some groups even suggest that obtaining consent from couples, as to whether to include or exclude the results of these incidental findings, is essential (Herlihy et al., 2010).

4 Post-test counseling

Post-test counseling should mainly focus on the specific disorder which has been diagnosed. The following points have to be kept in mind when providing information and counseling to the couples:

• couple should be made aware of the frequency of the condition in the general population;
• the occurrence of SCAs is a random event;
• incidentally detected sex chromosome aneuploidies are more often associated with normal to mildly affected phenotypes than postnatally detected SCAs (Pieters et al., 2011);
• the possibility of spontaneous abortion of pregnancy especially in fetuses with 45,X should also be mentioned;
• variability in the phenotype of the condition can exist and the inability to provide a precise individual prognosis must be discussed;
• uncertainty and complexity in providing counseling in case of mosaicism for SCAs should be discussed;
• role of other autosomal genes and environmental factors altering a child’s prognosis should be stressed upon;
• written material providing comprehensive information about the relevant karyotype will be useful;
• if possible, showing selected photographs of individuals with SCAs and talking to other parents of children with SCAs can be reassuring and helpful;
• finally, the issue of disclosure of SCA diagnosis by parents to others and the consequences of the same should be addressed at the time of diagnosis;
• if the couple decides to continue with the pregnancy, they should be adequately counseled regarding when and how to anticipate the problems and to seek medical care;
• the couple should be informed of the available postnatal interventions. The potential benefit of knowledge of the condition to facilitate early intervention should be highlighted; and
• it is important to be aware that in addition to phenotypic outcome, the obstetric history of the woman will play an important role in taking decision about the fate of the current pregnancy. This can be perceived in the case scenarios discussed above.

Apart from the above-mentioned points for general counseling, the major point that has to be highlighted in the discussion of these SCAs should be its impact on the reproductive and neurocognitive outcomes. These issues are discussed briefly in Table 1. Though not always foolproof, the following issues can be discussed in brief in selected scenarios.