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Genetic Counseling of Prenatally Detected Sex Chromosome Anomalies Haseena Sait, Shubha R Phadke Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, 226014

Correspondence to: Dr Shubha R Phadke Email: [email protected]

Abstract: genetic counselor in terms of counseling and dilemma for the family. The outcome varies greatly Prenatal screening tests are being universally from normal phenotype to those with significant employed in the current era to identify women phenotypic abnormalities. Individuals with SCA at risk of fetal aneuploidies. This unveils usually do not have significant intellectual a high proportion of unanticipated findings disability. Hypogonadism and infertility remain the amongst which sex chromosome abnormalities major issues; both of which have solutions in are frequently encountered. It is imperative that the form of hormone replacement therapy (HRT) geneticists and fetal medicine specialists have and assisted reproductive techniques (ART). The sufficient knowledge about these anomalies in difficulties in decision making are obvious as order to provide appropriate genetic counseling uncertainties about the phenotype are not strong and assist the couples in decision making during enough to consider termination of pregnancy. pregnancy. In the article, we briefly discuss the The decision depends upon parents’ family outcomes and counseling approach for the history and their perspectives to look at the prenatally detected common sex chromosome problem. The parents’ thinking gets influenced abnormalities. by what is conveyed to them by health care professionals involved in prenatal diagnosis and Keywords: Sex chromosome anomalies, prenatal counseling. Hence, it is essential that accurate and screening,Turner syndrome, Klinefelter syndrome, up-to-date information about the likely outcomes genetic counseling. is communicated to the family in a simplified manner. Through this article, we describe the Introduction outcomes of various prenatally detected SCAs and the issues in counseling for the same. Sex chromosome abnormalities (SCAs) are The following case scenarios present some the most frequently encountered chromosomal common problems faced by the clinicians and abnormalities both prenatally and at birth. These families and perspectives in approaching them: are due to the presence of an extra or missing X or Case scenario 1: A 32-year-old G2P1+0L1 mother Y chromosome and most commonly include 45,X; who has a previous child with Down syndrome 47,XXX; 47,XXY; and 47,XYY. The prevalence of (Trisomy 21) visits us at 16 weeks of gestation SCAs is estimated to be around one in 500 for prenatal counseling. After pre-test counseling newborns, twice as common at birth as trisomy regarding the risk of recurrence of 1% for trisomy 21 21. The frequency at prenatal diagnosis is much in the current pregnancy, she opts for prenatal greater and ranges from 1 in 250 to 300 (Linden testing. Amniocentesis followed by quantitative et al., 2002). Though not a primary target for fluorescent polymerase chain reaction (QFPCR) detection in prenatal diagnosis, incidental findings reveals 47,XXY and this finding is confirmed by like SCAs cannot be avoided. With expanding use karyotyping. of population wide screening for chromosomal anomalies by novel genomic technologies like Case scenario 2: A 35-year-old G3P0+2, with non-invasive prenatal screening (NIPS), such previous two abortions, presents with history of two problems will be more commonly seen in the near IVF (in vitro fertilisation) failures and consults us in future. Being an unexpected finding in prenatal view of non-invasive prenatal screening (NIPS) test testing, SCAs pose significant challenge to the showing high risk for monosomy X. This finding is

Genetic Clinics 2021 | July - September | Vol 14 | Issue 3 14 GeNeViSTA confirmed by chromosomal analysis from amniotic the occurrence of SCAs is a random event; fluid. Ultrasonography evaluation at 18 weeks is incidentally detected sex chromosome normal. • aneuploidies are more often associated with Case scenario 3: A 30-year-old G3P2 mother with • normal to mildly affected phenotypes than previous two healthy children, visits us at 17 weeks postnatally detected SCAs (Pieters et al., for counseling regarding high risk for trisomy 21 2011); (1:151) on quadruple marker testing. Pre-test the possibility of spontaneous abortion of counseling is provided. Options of NIPS and invasive pregnancy especially in fetuses with 45,X testing are given and she opts for invasive testing. • should also be mentioned; Amniocentesis followed by QFPCR and karyotype is variability in the phenotype of the condition suggestive of 47,XXX chromosome complement. can exist and the inability to provide a precise Counseling for the above-mentioned cases • individual prognosis must be discussed; requires in-depth knowledge about the clinical phenotypes of SCAs, variability in presentation uncertainty and complexity in providing and availability of management options for counseling in case of mosaicism for SCAs hypogonadism and infertility. As these situations • should be discussed; are not infrequent, it is important that role of other autosomal genes and clinical geneticists, fetal medicine specialists and environmental factors altering a child’s counselors acquire adequate knowledge to • prognosis should be stressed upon; provide prospective parents with sufficient and unbiased information regarding these SCAs and written material providing comprehensive guide them in decision making. information about the relevant karyotype will • be useful; Pre-test Counseling if possible, showing selected photographs of individuals with SCAs and talking to other Pre-test counseling for prenatal procedures • parents of children with SCAs can be done for varied indications should always reassuring and helpful; include discussion about the various disorders finally, the issue of disclosure ofSCA which can be detected by the test. A brief diagnosis by parents to others and the discussion on the outcome of these disorders • consequences of the same should be in general which would result in mental addressed at the time of diagnosis; or physical abnormalities should be discussed. if the couple decides to continue with The counseling must include the possibility of the pregnancy, they should be adequately detection of unrelated abnormalities including • counseled regarding when and how to SCAs, unbalanced autosomal abnormalities other anticipate the problems and to seek medical than the intended ones, and mosaic forms. Many care; of these may have variable outcomes. Some groups even suggest that obtaining consent from the couple should be informed of couples, as to whether to include or exclude the the available postnatal interventions. The results of these incidental findings, is essential • potential benefit of knowledge of the (Herlihy et al., 2010). condition to facilitate early intervention should be highlighted; and Post-test counseling it is important to be aware that in addition to phenotypic outcome, the obstetric history of Post-test counseling should mainly focus on the • the woman will play an important role in specific disorder which has been diagnosed. The taking decision about the fate of the current following points have to be kept in mind when pregnancy. This can be perceived in the case providing information and counseling to the scenarios discussed above. couples: Apart from the above-mentioned points for couple should be made aware of the general counseling, the major point that has frequency of the condition in the general to be highlighted in the discussion of these • population; SCAs should be its impact on the reproductive

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Table 1 The prenatal and postnatal outcome of few of the commonly detected sex chromosome anomalies.

45,X 47,XXY 47,XXX 47,XYY (Morgan, 2007) (Girardin & Van (Wigby et al., (Bardsley et al., Vliet, 2011) 2016) 2013) Prevalence 1:2500-3000 live born 1:500-1000 live born 1:1000 live born 1:1000 live born girls males females males Risk factor None Advanced maternal None None age Prenatal 99% get aborted High rates of preterm No specific No specific outcome spontaneously; deliveries; no specific antenatal antenatal increased nuchal antenatal malformations malformations translucency (NT), malformations cystic hygroma or hydrops Intelligence Normal but 15-20 Normal but 15-20 Normal but 15-20 Normal points below controls points below controls points below and siblings and siblings controls and siblings Characteristic Short stature (>95%), Tall stature, small Tall stature Tall stature, features webbed neck, low testes, gynecomastia macrocephaly, posterior hairline, in late puberty, macrodontia, narrow palate with sparse body hair scoliosis crowded teeth, broad chest with widely spaced nipples, cubitus valgus, multiple pigmented nevi Associated Cardiac Diabetes, metabolic Rare Hand tremors or abnormalities malformation syndrome, other (coarctation of aorta osteoporosis and involuntary or bicuspid aortic cardiovascular movements valve in 75%) diseases in (motor tics), sensorineural adulthood seizures, and hearing loss, asthma recurrent otitis media, renal malformation (e.g., horseshoe kidney, duplicated or cleft renal pelvis), autoimmune thyroiditis, celiac disease, scoliosis Development At risk of mild delay Reduction in speech, Mild motor delay, At risk for mild in acquiring language abilities, language speech/language nonverbal, social, and verbal processing difficulties and and motor psychomotor skills speed and school decreased school delays, learning performance performance disabilities

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Psychiatric Prone for shyness, Depression, Psychotic illness Attention deficit ailment# anxiety, low paraphilia, autistic like cyclothymic (50%), autism self-esteem and and obsessive- and labile spectrum depression compulsive are personality disorder (29%) common disorder common and anxiety (38%) (26%) Puberty Absent* Normal Normal Normal (hypogonadism occurs later) Reproduction Infertile* Infertile (options like Fertile (4% Normal sperm extraction and develop cryo-conservation premature available) ovarian failure) Management Echocardiogram & Annual physical and Annual physical & Annual physical & follow up renal ultrasound at psychological neuropsychologi- & neuropsycho- birth; annual evaluation; cal evaluation; logical physical, endocrinological ovarian function evaluation psychological, evaluation at assessment cardiac, thyroid, bone adolescence; during early and blood pressure testosterone therapy adulthood evaluation; hormonal during adolescence therapy at adolescence Risk of Rare Rare Rare Rare recurrence

*Normal menstruation and fertility seen in 2-5% mosaic individuals # May be seen more frequently than in the general population and neurocognitive outcomes. These issues are Turner syndrome is difficult to diagnose discussed briefly in Table 1. Though not always prenatally. foolproof, the following issues can be discussed in Risk of infertility is high. With the help brief in selected scenarios. of assisted reproductive techniques, • pregnancy can be achieved in some 1. 45,X (Turner syndrome): women with Turner syndrome.

Mental development and cognition are 2. 47, XXY (Klinefelter syndrome): usually normal. • Major concern for this condition These individuals may have mild is hypogonadism and primary cognitive and psychiatric disturbances. • amenorrhea. Hormone replacement • Major issue is male hypogonadism. therapy (HRT) is indicated to initiate and Treatment with sex hormones for maintain secondary sexual characters. • hypogonadism is indicated. Short stature is common. Early growth Infertility is common but reproductive hormone therapy can help to improve options like testicular sperm extraction • short stature. • (TESE) and cryo-conservation are Associated abnormalities in cardiovas- possible to improve reproductive cular system and renal system should outcomes. • be mentioned. Some of the cardiac 3. 47,XXX and 47,XYY: anomalies can be detected by prenatal echocardiography but coarctation of The reproductive and cognitive outcome aorta, commonly seen in girls with is usually satisfactory. • Genetic Clinics 2021 | July - September | Vol 14 | Issue 3 17 GeNeViSTA

The psychological and behavioural individual. Genetic counseling becomes complex problems reported in studies are usually in such cases due to variability in phenotypic • mild and these individuals have a slightly expression due to variable degree of mosaicism in increased prevalence when compared different tissues. These factors pose uncertainty to normal individuals but ascertainment about the postnatal outcome of such disorders. bias behind these studies should be In prenatally detected 45, X/46, XY mosaicism, a kept in mind. normal male phenotype was present in 90% of cases (Telvi et al., 1999). However, the dilemma Previously, phenotypes of SCAs were known in counseling exists as in 10% of cases, the only for postnatally detected cases as they are phenotypic spectrum can vary from females the only ones who seek medical attention for with Turner syndrome to males with infertility phenotypic abnormalities. This ascertainment bias or individuals with ambiguous genitalia. The reflected in counseling for SCAs where incidentally neurodevelopmental and reproductive outcome detected SCAs during prenatal tests led to will also be highly variable in these individuals termination of most of these pregnancies. This posing significant challenges in counseling. issue was compounded by lack of adequate A favourable prognosis exists for mosaic information about long term follow up of children Turner syndrome (45,X/46,XX) who tend to have with SCAs who were diagnosed prenatally. fewer signs and health problems like near normal However, eliminating such ascertainment bias, stature and may have normal reproductive recent studies have proved that incidentally capabilities and no cardiovascular complications detected prenatal diagnosis of SCAs is associated (Tuke et al., 2019). Similarly, mosaic Klinefelter with normal to mildly affected phenotypes when syndrome are well androgenized and have better compared to postnatal cases (Pieters et al., 2011). reproductive capability than their non-mosaic Studies have evaluated parental attitude counterparts (Samplaski et al., 2013). towards terminating or continuing a SCA-affected pregnancy and have found that factors like specific Genetic counseling for structural type of SCA, parental age, gestational week at diagnosis, counselor’s genetic expertise, number aberration of sex chromosomes of children in the family, previous experience of the family with children having birth defects Structural aberrations involving X chromosome or genetic disorders, socioeconomic status, and commonly include isochromosome Xq and ring ethnicity and religious beliefs, influenced the chromosome. For such structural aberrations decision to continue or abort the pregnancy. involving one X chromosome, the counseling is History of infertility or previous child with similar to that for Turner syndrome. However, ring developmental delay may also complicate the X chromosome may be associated with more decision-making process. This also gets largely severe intellectual disability. influenced by the information one receives froma Cytogenetically visible structural aberrations of health professional (Operto et al., 2019; Shaw et Y chromosome include deletions, translocations, al., 2008; Jeon et al., 2012). In recent times, there rings, inversions and isochromosomes. Structural has been an emerging trend towards continuation aberrations of Y chromosome usually result in of pregnancy of a fetus with SCAs due to mosaicism due to its predisposition to subsequent improved counseling efforts and availability of chromosome instability and loss of the abnormal Y adequate information on prognosis of these SCAs. chromosome, thereby causing mosaic 45,X. The Simultaneous progress in the field of ART has also phenotypes in such case can vary from females totally changed the reproductive outcome of these with Turner syndrome to males with infertility or individuals with SCAs. ambiguous genitalia based on number of cells lines with 45,X and abnormal Y chromosome (Patsalis et al., 2005). Counseling in these cases is Genetic counseling for sex challenging as a definite prediction of phenotype chromosomal mosaicism is impossible and this uncertainty is likely to cause dilemma in decision-making for the family. Mosaicism is defined as the presence of twoor Not all structural aberrations are pathogenic. more cell lines derived from a single zygote but Pericentric inversions involving Y chromosome with different chromosomal complements in an are mostly familial and not associated with any

Genetic Clinics 2021 | July - September | Vol 14 | Issue 3 18 GeNeViSTA phenotypic manifestations or fertility issues except screening: Klinefelter syndrome as an in rare cases when genes determining sex in the example. J Community Genet. 2010; 1: 41–46. inverted area are disrupted (Motos Guirao, 1989). 4. Jeon KC, et al. Decision to abort after For other rare and complex aberrations, a a prenatal diagnosis of sex chromosome comprehensive use of cytogenetic, microarray abnormalities: A systematic review of the and fluorescent in situ hybridisation techniques literature. Genet Med. 2012; 14: 27–38. are required for accurate identification of such 5. Linden MG, et al. Genetic Counseling for Sex abnormalities. The counseling for these rare SCAs Chromosome Abnormalities. Am J Med Genet. varies on a case-to-case basis and is beyond the 2002; 110: 3–10. scope of this article. 6. Morgan T. Turner syndrome: diagnosis and management. Am Fam Physician. 2007; 76: Other rare SCAs 405–410. 7. Motos Guirao MA. Pericentric inversion of the Chromosomal abnormalities where there is human Y chromosome. An Esp Pediatr. 1989; presence of more than two X chromosomes- 316: 583–587. 8. Operto FF, et al. Cognitive profile, 48,XXY or 49,XXXXY: They are more severely affected in terms of neurocognitive and emotional-behavioral features, and parental behavioural function. The phenotype progressively stress in boys with 47,XYY syndrome. Cogn deviates from normal as the number of X Behav Neurol. 2019; 32: 87–94. chromosome increases. These individuals have 9. Patsalis PC, et al: Identification of high been shown to function at a lower cognitive frequency of Y chromosome deletions in patients with sex chromosome mosaicism and level and with more immature and maladaptive correlation with the clinical phenotype and behaviours as compared to individuals with fewer Y-chromosome instability. Am J Med Genet A. X chromosomes (Visootsak et al., 2007). Infertility 2005; 135: 145–149. and inadequate virilization are anticipated. 10. Pieters JJ, et al. Incidental prenatal diagnosis of sex chromosome aneuploidies: health, Conclusion behavior, and fertility. ISRN Obstet Gynecol. 2011; 2011: 807106. The chances of encountering SCAs are high with 11. Samplaski MK, et al. Phenotypic differences in widespread availability of prenatal tests and mosaic Klinefelter patients as compared with especially after widespread use of NIPS in obstetric non-mosaic Klinefelter patients. Fertil Steril. practice. It is therefore crucial that geneticists and 2014; 101: 950–955. counselors acquire adequate knowledge regarding 12. Shaw SW, et al. Parental decisions regarding the implications of SCAs and develop structured prenatally detected fetal sex chromosomal pre-test and post-test counseling strategies. This abnormality and the impact of genetic in turn would help prospective parents to take a counseling: An analysis of 57 cases in Taiwan. personalized and autonomous decision regarding Aust N Z J Obstet Gynaecol. 2008; 48:155–159. the pregnancy. 13. Telvi L, et al. 45,X/46,XY mosaicism: Report of 27 cases. Pediatrics. 1999; 104: 304–308. References 14. Tuke MA, et al. Mosaic Turner syndrome shows reduced penetrance in an adult 1. Bardsley MZ, et al. 47,XYY syndrome: clinical population study. Genet Med. 2019; 21: phenotype and timing of ascertainment. J 877–886. Pediatr. 2013; 163: 1085–94. 15. Visootsak J, et al. Behavioral phenotype of sex 2. Girardin CM, Van Vliet G. Counseling of a chromosome aneuploidies: 48,XXYY, 48,XXXY, couple faced with a prenatal diagnosis of and 49,XXXXY. Am J Med Genet Part A. 2007; Klinefelter syndrome. Acta Paediatr. 2011; 100: 143A: 1198–1203. 917–922. 16. Wigby K, et al. Expanding the Phenotype of 3. Herlihy AS, et al. Assessing the risks and Triple X Syndrome: A Comparison of Prenatal benefits of diagnosing genetic conditions Versus Postnatal Diagnosis. Am J Med Genet A. with variable phenotype through population 2016;170: 2870–2881.

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