Prenatal diagnosis of sex chromosome aneuploidy—What do we tell the prospective parents?

Abstract

Sex chromosome aneuploidy (SCA) can be detected on prenatal diagnostic testing and cell free DNA screening (cfDNA). High risk cfDNA results should be confirmed with diagnostic testing. This summary article serves as an update for prenatal providers and assimilates data from neurodevelopmental, epidemiologic, and registry studies on the most common SCA. This information can be helpful for counseling after prenatal diagnosis of sex chromosome aneuploidy. Incidence estimates may be influenced by ascertainment bias and this article is not a substitute for interdisciplinary consultation and counseling.

1 |. INTRODUCTION

Sex chromosome aneuploidy (SCA) as a group are the most common chromosomal disorders, affecting up to 1 in 400 newborns.¹ SCAs have a less severe phenotypic range than autosomal aneuploidies and most individuals with a SCA have intelligence in the normal range. However, there are a range of medical, neurodevelopmental, and psychiatric issues that can occur in people with SCA, though phenotypes vary significantly between different SCA and among individuals with the same chromosomal difference. This variability makes it challenging to provide accurate and tailored prenatal counseling for pregnancies with SCA.

Cell free DNA (cfDNA)-based screening for aneuploidy is an established prenatal test available to women from 10 weeks of gestation.² CfDNA is currently the only aneuploidy screening method able to specifically assess the probability of an SCA, and due to its widespread adoption, prenatal detection of it has increased in recent years.² Accurate and balanced patient counseling including discussion of the limitations of cfDNA for SCA and the variability of the phenotypes is essential as it may impact decision-making about the pregnancy.

There is considerable ascertainment bias in the literature on the long-term outcomes of SCA, which hampers accurate prenatal counseling. Individuals with mild or no discernable phenotype may never be diagnosed with SCA, and as a result, our understanding of the phenotypic spectrum of SCA may be skewed toward those with more severe manifestations.^1,3–5

Recent data from Denmark compared the expected prevalence based on historical cytogenetic surveys versus known nationwide prevalence of SCA based on registry data. These newborn data suggest that a clinical diagnosis of an SCA (including mosaic forms) is obtained on: 70% of people with 45,X and mosaics, 23% with 47,XXY, 7% with 47,XXX or higher order X chromosome aneuploidy, and 9% of 47, XYY (including mosaicism and isochromosomes of Y).⁶

In this review, we summarize the essential information to discuss with expectant couples when a diagnosis of SCA has been made in the prenatal setting. Ideally, patients would have their care provided by a multidisciplinary team including obstetricians, maternal–fetal medicine specialists, genetic counselors, geneticists, and pediatric endocrinologists.

2 |. DEFINITION AND EPIDEMIOLOGY

What is sex chromosome aneuploidy?

SCAs are characterized by a numerical gain or loss of the X and Y chromosomes or structural chromosomal rearrangement.¹ The most common SCAs in newborn populations include 47,XXY (Klinefelter syndrome), 47,XYY (XYY syndrome, or Jacobs syndrome), 47, XXX (Triple X syndrome), and 45,X and mosaicism (Turner syndrome [TS]). A cord blood study from 35,000 newborns in Denmark found that SCAs as a group were more common than any individual autosomal aneuploidy with an incidence of 1 per 448 children.⁷ For comparison, trisomy 21 had an incidence of 1 per 592 children (Table 1).

TABLE 1.

The incidence of SCA at livebirth in a cohort of newborns in Denmark (Nielsen 1991) and estimated incidence in Berglund et al. 2020

Type of SCA	Incidence at livebirth in Denmark newborns (Nielsen 1991)	Incidence at livebirth (Berglund et al 2020)
47,XXY and mosaicism	1.73 per 1000	1.52 per 1000 males
47,XYY	1.18 per 1000	0.98 per 1000 males
47,XXX	1.06 per 1000	0.84 per 1000 females
45,X	0.53 per 1000	0.50 per 1000 females
Other SCA	0.09 per 1000

Abbreviation: SCA, sex chromosome aneuploidy.

3 |. CYTOGENETIC ORIGINS OF SCA

What caused this? Am I responsible for this?

An unbalanced complement of the sex chromosomes can arise as the gametes develop (meiotic error), or following fertilization (mitotic errors). The sex chromosomes are more likely to undergo errors than the autosomes due to a distinctive process of replication, pairing, and unique gene content. Two pseudoautosomal region (PAR) sites (PAR1, PAR2) pair to facilitate recombination between the X and Y chromosomes during replication. The X chromosome’s higher guanosine—cytosine nucleotide content and the phenomenon of X-inactivation both contribute to this relative instability.^7–11 In most cases of 45,X, the missing X chromosome is paternal in origin, and the risk of a 45,X conception is therefore not related to maternal age. In contrast, the sex chromosome trisomies are usually associated with an extra maternal copy, and therefore are associated with maternal age.^11–16 Alternatively, an oocyte may be normally fertilized and a sex chromosome lost during early mitotic division errors.^16,17 Mosaicism, where one euploid and one or more aneuploid cell lines develop, is also more common with the sex chromosomes than autosomes, as discussed in subsequent sections.^11,18

Key counseling points

• Most of the people in the world with SCA are probably undiagnosed. Studies comparing newborn screening prevalence to registry studies suggest clinical diagnostic rates of 70% for 45,X, 23% for 47,XXY, 7% for 47,XXX, and 9% for 47, XYY.

• Couples should be reassured that SCAs are not caused by parental behaviors or environmental exposures. Unique molecular features of the sex chromosomes make mosaicism and aneuploidy more common than with autosomes.

4 |. DIAGNOSIS

What further tests are recommended once sex chromosome aneuploidy is suspected in the fetus?

After a positive cfDNA screening test or ultrasound anomaly is detected, patients should be offered a comprehensive ultrasound, genetic counseling, and the option of prenatal or postnatal diagnostic testing. Screening tests alone should not be used to make clinical decisions due to the potential for false positive screening results.^2,12,19–26

When 45,X is suspected by cfDNA, patient counseling should include a discussion of whether to pursue confirmatory diagnosis by a chorionic villus sampling before 14 weeks or await an amniocentesis after 15 weeks.²⁷ This is because confined placental mosaicism is common in 45,X when the fetus does not exhibit any of the usual ultrasound features of monosomy X (increased nuchal translucency, hydrops, and cystic hygroma).^12,28,29 The overall PPV for monosomy X has ranged from 14% to 66% in prior studies.²⁸ With a normal first trimester ultrasound and a high risk cfDNA for monosomy X, a large cytogenetic study estimated that a positive predictive value (PPV) is between 50% and 75%, whereas the PPV may be as high as 99% when an ultrasound finding is present.^12,30 With a normal first trimester ultrasound and positive cfDNA for monosomy X, an amniocentesis would best characterize the fetal composition and avoid confusion with the placental karyotype.²⁹ This high rate of placental mosaicism of 45,X/46,XX is not true for the other SCAs. For positive cfDNA for XXX, XXY, and XYY, the placental karyotype will reflect the fetal karyotype in over 90% of cases.¹²

Key counseling points

• cfDNA screening can detect SCA but with lower accuracy than for trisomy 21.

• Genetic counseling is recommended for couples where a prenatal diagnosis of SCA is suspected.

5 |. 45,X AND MOSAIC 45,X

5.1 |. 45X and mosaic 45,X—Prenatal medical considerations

The gestational age at detection of 45,X and evidence of a mosaic cell line in the fetus are important for pregnancy prognosis and counseling. Non-mosaic 45,X conceptions often present in the first trimester with an enlarged nuchal translucency, cystic hygroma, and/or hydrops and frequently end in miscarriage.^17,31 An additional 7.5% loss rate in the second trimester has been noted.³² The presence of mosaicism increases the chance of a live birth outcome.^32–34

During the second trimester, close ultrasound examination of the fetus is warranted to look for associated abnormalities including renal anomalies, growth restriction, oligohydramnios or polyhydramnios, and congenital heart disease (particularly left-sided anomalies). Coarctation of the aorta is the classic cardiac finding in children with 45,X but can be difficult to discern on prenatal ultrasound.²² In the absence of ultrasound anomalies, a prenatal diagnosis of fetal TS does not require any major changes to obstetric management.

5.2 |. 45,X and mosaic 45,X—Postnatal medical considerations

Infants with 45,X or mosaic 45,X are usually born uneventfully with typical female genitalia if there is no Y chromosome component present. Indeed, many 45,X/mosaic 45,X individuals are not diagnosed until puberty or even adulthood (Table 2).²² There are potential significant health impacts of this diagnosis, however, and clinical assessment and follow-up should be with a multidisciplinary team with cardiology, endocrinology, and otolaryngology expertise. In infancy, a postnatal karyotype, echocardiogram, renal ultrasound, and evaluation for congenital hip dysplasia are recommended.²² Special attention to growth and feeding in the first year of life is needed as 50% of infants may have failure to thrive in this period.²²

TABLE 2.

Selected prevalence of features of individuals with Turner syndrome

Features of Turner syndrome	Approximate prevalence
A. Medical features
Growth failure and reduced adult height	95%–100%
Ovarian insufficiency and infertility	95%
Delayed bone age	85%
Decreased bone mineral content	50%–80%
Hypertension	50%
Bicuspid aortic valve	14%–34%
Coarctation of the aorta	7%–14%
Aortic dilation/aneurysm	3%–42%
Hearing defects	30%
Lymphedema of the hands and feet	25%
Psychological and behavioral problems	25%
Abnormality of renal pelvis, ureters, or vessels	15%
Horseshoe kidney	10%
Glucose intolerance	15%–50%
Thyroid disease	15%–30%
B. Physical differences
Small and recessed jaw	60%
Cubitus valgus	50%
Low posterior hairline, broad chest	40%
Short fourth metacarpals of the hands	35%
Epicanthus	20%
External ear differences	15%
C. Neurocognitive features
Average or above average intelligence	90%
Nonverbal learning disorder	40%
Difficulty with mathematics	50%–75%
Attention-deficit/hyperactivity disorder	25%

^*Adapted from Table 7 of Gravholt et al. (2017).

While some individuals with monosomy X may have characteristic physical features associated with TS, these differences can be subtle and vary considerably (Table 2). Short stature is common and often manifest by 4–6 years of age. All people with a 45, X cell line should be followed at least yearly by a pediatric endocrinologist. Growth hormone therapy may be considered to improve growth and final adult height.²²

People with 45,X are at increased risk of a number of medical conditions including hypertension, hypercholesterolemia, hypothyroidism, celiac disease, autoimmune conditions, liver disease, diabetes, and hyperlipidemia. Epidemiologic studies based on nationwide registry data show an increase in overall mortality for people with 45,X, with 41% of the additional mortality risk due to cardiovascular disease.^1,34 Regular surveillance and standard management for these conditions is important to improve long-term outcomes.²²

5.3 |. 45,X and mosaic 45,X—Gonadal and reproductive issues

Adolescents and adults with non-mosaic monosomy X have hypergonadotropic hypogonadism, which may result in primary or secondary amenorrhea and ovarian insufficiency and infertility. Due to the long-term effects of hypogonadism on health and bone density and to facilitate physical maturation including secondary sex traits, estrogen and progesterone replacement is often started in late childhood or early teen years. Individuals should be followed by pediatric endocrinology even if spontaneous menses occur and oocyte preservation can be discussed.²²

Spontaneous pregnancies occur in only 5% of individuals with 45, X but assisted reproductive technology (with or without oocyte donation) may assist women with 45,X. Discussion of reproductive options and early referral to reproductive endocrinology for discussion of fertility preservation can be considered as early as the teenage years.³⁵ If certain maternal congenital heart lesions are present, such as a dilated aorta (aortic size index greater than 2.0 cm/m²), infertility treatment and/or pregnancy may be deemed unsafe due to the risk of aortic dissection and death. For those people with 45,X who achieve pregnancy, the rate of pregnancy complications and miscarriage is higher than the general population and their pregnancies should be closely monitored.^36,37

5.4 |. 45,X and mosaic 45,X—Neurodevelopmental considerations

With regard to learning and development, there are consistent themes among neurocognitive profiles and personality traits for individuals with monosomy X. The vast majority (90%) of individuals have average or above average intelligence, but learning differences are common (Table 2C). These include variable degrees of nonverbal learning disability, characterized by difficulty with social communication, spatial reasoning, and executive function.²²

5.5 |. 45,X/46,XY mosaicism

45,X mosaicism with a 46,XY or other Y chromosome-containing cell line has very different implications from 45,X/45,XX mosaicism. The presence of Y chromosome material can lead to differences in sexual development (DSD). External genitalia may develop into typically female, typically male, or neither typically male nor female (intersex). The presence of Y chromosome material with a dysgenic gonad increases the risk of gonadoblastoma, which is further increased if the gonad is undescended.^38,39 The percentage of Y chromosome-containing cells on the peripheral blood karyotype may correlate with degree of virilization of the external genital structures, but this association is imperfect. Some features of TS are common in those with Y chromosome mosaicism, such as reduced growth, and gonadal dysfunction. Liver dysfunction, autoimmune disease, and learning concerns are also common, and warrant routine screening and follow-up.²² Notable ascertainment bias has been noted in postnatal cohorts, which makes precise prenatal counseling challenging. In one retrospective series, 92% of prenatal diagnoses were noted to have a normal male postnatal phenotype whereas among the postnatally ascertained patients, 43% were phenotypic females with TS features, 42% had mixed gonadal dysgenesis (asymmetric gonadal development with a unilateral dysgenic testis), and 15% had a male phenotype with incomplete masculinization.⁴⁰

Up to 12% of phenotypically female patients with a diagnosis of TS have some Y chromosome sequence.^22,41 PCR of Y chromosome centromeric sequences should be considered in 45,X individuals with unexplained virilization (where the previous karyotype or FISH has not detected the Y chromosome), or when a marker chromosome is present.²² Due to the 10% risk of gonadoblastoma, gonadectomy is recommended for phenotypically female patients when Y chromosome mosaicism is present, though the ideal timing of gonadectomy is unclear.^22,39

5.6 |. 45,X and mosaic 45,X key counseling points

• People with 45,X and 45,X mosaicism have an increased risk of a range of health issues, including short stature, congenital heart disease, kidney and urinary tract anomalies, cardiometabolic disease, autoimmune disorders, hypogonadotropic hypogonadism, ovarian insufficiency, and infertility.

• The characteristic physical features include short stature, a low hairline, and distinctive facial features. There is also a higher chance of learning differences in the setting of normal intelligence. These features can be subtle and variable.

• Fetuses with 45,X are at increased risk of miscarriage or stillbirth and congenital anomalies, structural differences to the heart, and other health complications.

• The presence of 45,X with mosaicism including Y chromosome material can lead to DSD or gonadoblastoma risk and influences patient counseling.

• The postnatal care of infants and children with 45,X +/− mosaicism should be managed by a multidisciplinary team, including pediatric endocrinology.

6 |. 47,XXY (KLINEFELTER SYNDROME)

Infants with 47,XXY are usually born healthy and without major physical differences. Prior to the use of cfDNA screening, it was estimated that only 25%–35% of people with 47,XXY were diagnosed in their lifetime and of those diagnosed, 20% were diagnosed in adulthood in the setting of hypogonadism or infertility.^1,3 A prenatal diagnosis of 47,XXY, or Klinefelter syndrome (KS), should not result in any major changes to prenatal care or the plan for delivery in the absence of congenital malformations. There is an increased risk of cryptorchidism and, rarely, microphallus, and this should be considered in the fetal and newborn assessment.^42–44

6.1 |. 47,XXY medical and psychiatric considerations

Medical and psychiatric conditions are reported to be more common in 47,XXY, but estimates should be interpreted with caution in light of the known ascertainment bias that exists in the literature. A Danish registry study of 832 individuals with Klinefelter syndrome showed increased overall mortality (hazard ratio 1.4, 95% CI 1.1–1.7) with a median survival 5.6 years lower than controls.^1,42 The median age of diagnosis of KS was 27.5 years (range: 0.0–82.8) (Table 3).¹ The range of diagnoses associated with hospital episodes for individuals with KS is broad but include seizures, venous thromboembolism, cancers, respiratory disorders, metabolic and endocrine disorders, infections, and trauma.^45,46 There are inherent limitations of hospital diagnosis code-based research, which is evident from the lower-than-expected rate of gynecomastia and hypogonadism in this study. The most accurate data for counseling comes from epidemiologic studies of newborn screening with the karyotype, as registry and clinical data may overestimate risks for prenatally diagnosed cases.^5,45,46

TABLE 3.

Hazard ratio of mortality, cohabitation, having children, and attaining a bachelor’s degree for sex chromosome aneuploidies

	Turner syndrome HR (95% CI)	Klinefelter syndrome HR (95% CI)	47,XXX syndrome HR (95% CI)	47,XYY syndrome HR (95% CI)
Mortality	2.9 (2.4–3.5)	1.4 (1.1–1.7)	2.5 (1.6–3.9)	3.6 (2.6–5.1)
Cohabitation	0.45 (0.40–0.50)	0.66 (0.59–0.72)	0.68 (0.49–0.95)	0.50 (0.37–0.66)
Children	0.18 (0.16–0.21)	0.24 (0.21–0.27)	0.64 (0.48–0.85)	0.35 (0.26–0.46)
Bachelor’s Degree	1.00 (0.87–1.15)	0.27 (0.20–0.37)	0.36 (0.18–0.73)	0.35 (0.18–0.71)

Abbreviation: HR, Hazard ratio.

^*Adapted from Berglund et al. (2020).

In one clinically ascertained series of 57 prenatal and postnatal diagnoses, 36% of participants met criteria for ADHD, mostly of the inattentive subtype.⁴⁶ Rates of Autism spectrum disorder (ASD) in clinical series range from 5% to 27% (relative to general prevalence of 1%–1.4% in male children) and psychiatric diagnoses of anxiety in 14%–32% and depression 12%–24%, respectively.^47,48

6.2 |. 47,XXY gonadal and reproductive issues:

Adolescents and adults with 47,XXY have hypergonadotropic hypogonadism with decreased production of testosterone, though testosterone production may be preserved well into the third decade.³ While most adolescents enter puberty normally, they should be monitored by a pediatric endocrinologist and in some cases, testosterone replacement therapy may be indicated.⁴⁹ Adults with 47,XXY have infertility, small testicles, and reduced sperm numbers. Indeed, many adults first receive their diagnosis during investigations for infertility. Reproductive therapies utilizing testicular sperm extraction and intracytoplasmic sperm injection have current success rates of up to 50%.^42,50 The risk of SCA in their offspring is estimated at less than 1% and is similar to the aneuploidy rate of other individuals with nonobstructive azoospermia.^3,50

6.3 |. 47,XXY neurodevelopmental profile

Although individuals with 47,XXY are at increased risk for developmental delays, learning disabilities, and psychiatric concerns compared with the general population, these are variable and not always present. Precise quantification of the incidence of neuropsychiatric findings is challenging due to ascertainment bias in most studies. The studies with the least risk of ascertainment bias are based on newborn screening data and are excellently summarized in a paper by Tartaglia and colleagues (see Table 4).⁴⁶

TABLE 4.

Summary of neurodevelopmental, medical, and gonadal function in sex chromosome trisomy described in the 1970s birth cohorts, adapted from Tartaglia et al. 2020

		XXY (Klinefelter syndrome) N = 95	XYY (Jacobs syndrome) N = 59	XXX (triple X) N = 46
Neurodevelopmental	Early developmental delay	70%, usually mild, speech delay more than motor	80%, usually mild, speech delay more than motor	55%, usually mild, speech delay more than motor
	Learning disabilities	64%–85% (esp. reading)	~55%	75%–100% (esp. reading)
	Mean cognitive (IQ)	10–15 points lower than normal; nonverbal more than verbal	5–10 points lower than normal; usually verbal = nonverbal	10–15 points lower than normal; nonverbal more than verbal
	Behavior/Social-emotional	Shy, social difficulties; immature, attentional problems	Hyperactivity; negative mood; impulsivity	Shy, anxiety, social difficulties; sensory integration problems
	Motor skills	Motor delays, coordination and motor planning problems	Increased rate of balance and coordination problems	Motor delays, coordination problems, low strength
Physical/medical	Average birth size	Slightly smaller	Normal	Smaller
	Congenital anomalies	Modest increase	Rare	Rare
	Dysmorphisms	Minimal: Hypertelorism, epicanthal folds, clinodactyly, small head circumference	No dysmorphisms reported, normal head circumference	Minimal: Hypertelorism, epicanthal folds, clinodactyly, small head circumference
	Growth and body habitus	Tall stature; long legs, increased growth velocity starting at 5 years; excess weight gain	Tall stature, long legs, thinner than XXY, delayed growth spurt	Tall stature; increased growth velocity starting at 7 years; abdominal pain (25%)
	Muscle tone	Hypotonia	Hypotonia	Hypotonia
Gonadal function	Prepubertal gonadal function	Cryptorchidism in 10%–20%; small testes in 65% at 6 months; slow penile growth; testosterone under assay detection limit; bone age delayed (−2 SD)	Testes and penile size in the normal range; normal testosterone	Nothing reported in infancy, high FSH in mid-childhood; bone age delayed (−1 SD)
	Puberty timing and course	Testes enlarge to max of 10 ml, high LH & FSH after Tanner 3, testosterone plateaus in late puberty	Early onset testicular enlargement, normal testosterone levels	Thelarche and menarche late-normal, precocious puberty also reported
	Adult function/fertility	Infertility, 90% with low testosterone	Assumed normal fertility	~10% secondary amenorrhea; pregnancies in 9 of 37

Learning differences can range from mild to more severe.^3,47 A study based on newborn screens found that intelligence scores were shifted 5–10 points lower than controls and siblings but still in the average range.^3,47 Individuals can have particular difficulties in expressive language, auditory processing, and auditory memory.^47,51,52 An increased frequency of dyslexia has been noted as well.^44,50,51 These learning differences may be responsive to intervention, and thus regular evaluation and developmental supports are important. Hypotonia may affect some infants, which may contribute to delayed milestones such as crawling and walker in 50% of children with 47,XXY.³

There is evidence that children with a prenatal diagnosis have better functional and cognitive outcomes, better social-emotional functioning, and fewer behavioral difficulties.^5,52,53 In many states, children with SCA automatically qualify for early intervention (from birth to 36 months) or early childhood special education (from 3 to 5 years) for additional developmental support.^54,55 Use of testosterone in the neonatal period for infants with 47,XXY remains controversial and is not the standard of care. Previous work has suggested a benefit for neurodevelopmental outcomes, but to date, this has not been borne out in head-to-head trials.^3,56,57

6.4 |. 47,XXY key counseling points

• Many people with 47,XXY are not diagnosed in their lifetime (65%–75%) or not identified until an infertility workup in adulthood.

• People with 47,XXY generally have normal intelligence but may have developmental delays, mental health disorders, and learning differences. These respond well to developmental supports.

• Early diagnosis of 47,XXY allows monitoring of testosterone levels and learning supports that may modify disease risks and lifestyle differences.

• Infertility treatments (ICSI/IVF) are available with success rates of up to 50%.

7 |. 47,XYY

Individuals with 47,XYY typically have few physical differences compared with the general population and have normal pubertal development. Studies have suggested an increased risk for different medical conditions, developmental delays, learning disabilities, and mental health disorders compared with the general population.⁷ However, given the historically low rate of diagnosis of 47,XYY (~10%), most available data is complicated by ascertainment bias and/or small sample sizes, making quantification of the incidence of medical and neurodevelopmental findings very challenging.⁶

7.1 |. 47,XYY medical considerations

In Danish registry data of hospital discharge diagnoses from 251 individuals with 47, XYY, there were significant differences in several health conditions. Specifically, the incidence rate ratio (95% CI) for chronic obstructive lung disease was 5.79 (2.42–15.15), lower respiratory tract infection 12.52 (6.23–25.16), asthma 5.88 (3.38–10.22), cryptorchidism 4.88 (2.25–10.56), and malformations of the feet 29.76 (5.55–159.58).⁴⁵ This data has the inherent limitations of coding and prescription-based research, and it was estimated that 20% of individuals with 47,XYY in Denmark were diagnosed; so these figures are likely biased by clinical ascertainment. However, the more nuanced information on medical comorbidities in 47,XYY may be helpful for patient counseling. This data also showed that overall mortality for people with 47,XYY was increased with an HR of 3.6, which lowered to 2.7 when marital and education status were taken into account. The median survival was 10.4 years shorter than controls and diagnosis was made at a median of 15.1 years (range: 0.0–70.7).^45,58

7.2 |. 47,XYY neurodevelopmental profile

Learning differences have been noted including mild developmental delays and a 5–10 point downward IQ shift from siblings and controls, see Table 4.⁴⁶ As with 47,XXY, there have been noted differences between behavioral and developmental profiles in prenatal versus postnatal diagnosis.^4,59 In one series, 11% of 35 individuals from a prenatal cohort had a diagnosis of ASD or pervasive developmental delay, which is increased relative to the general childhood prevalence of 1%–1.4%.⁴ In this same series, 40% of the 55 postnatally diagnosed individuals had ASD or pervasive developmental delay. Bipolar disorder was present in the postnatally diagnosed group and not present in the prenatal diagnosis group (bipolar childhood prevalence of 0.4%–6.3%).⁴

7.3 |. 47,XYY key counseling points

• Data on medical and neurodevelopmental differences in 47,XYY should be interpreted with caution because based on expected incidence from newborn studies, only 10%–20% of individuals with 47,XYY receive a diagnosis in their lifetime, leading to ascertainment bias.

• An example of the ascertainment bias includes the markedly different rates of neuropsychiatric disorders in cohorts diagnosed before birth or during childhood.

• Those with 47,XYY may have an increased risk of lung disease, foot malformations, and cryptorchidism.

8 |. 47,XXX

Most children born with 47,XXX will not have notable physical differences. This is reflected in the estimate that only 10% of cases of 47,XXX are ever clinically detected.^5,7 However, 47,XXX is associated with an increased risk of congenital abnormalities compared to the general population including orofacial clefts, clubfoot, and cardiac anomalies, which may be identified on anatomic ultrasound. The most common abnormalities are of the genitourinary system.^5,55,60 47,XXX fetuses are not known to be at increased risk for other prenatal or neonatal complications compared to the general population. In the absence of an ultrasound anomaly, a prenatal diagnosis of 47,XXX should not result in any major changes to prenatal care or the plan for delivery. Postnatally, a neonatal echocardiogram and renal ultrasound can be considered to rule out structural anomalies that may not have been seen prenatally.

8.1 |. 47,XXX medical and psychiatric considerations

Other health concerns include dental disorders, pes planus, scoliosis, tremor, seizure disorders, constipation, and environmental or food allergies. Individuals with 47,XXX had menarche at a mean age of 12 but have an increased risk of primary ovarian insufficiency with 67% of people in one study having an anti-Mullerian hormone less than the 2.5%.^5,61,62

Epidemiologic studies based on registry data from individuals diagnosed postnatally have shown that overall mortality for people with 47,XXX was increased with an HR of 2.5 and median survival 7 years shorter than controls. Diagnosis was made at a median age of 17.9 years (range: 0.0–73.2). Hospital discharge data utilized to assess health issues in adult life showed an increased risk of cardiovascular disease (HR 2.4), urologic disease (HR 10), unspecified diseases (HR 7.4), and chromosomal disorders and congenital defects (HR 64).⁶³ The same risks of ascertainment bias should be considered when interpreting this data, as discussed in the 47,XXY and 47,XYY sections.

8.2 |. 47,XXX neurodevelopmental profile

Individuals with 47,XXX are at increased risk of developmental delays, learning disabilities, and mental health disorders compared with the general population, though these findings are variable and not present in every case.⁴⁶ Among a prenatally detected cohort, about 30% of people with 47,XXX did not have learning differences while 70% had learning differences.⁵ In a series of 74 individuals, when prenatal and postnatal diagnoses were considered together, 72% had a speech delay, 31% had a current language disorder, 50% had a motor delay, 49% had ADHD, 19% had an anxiety disorder, 13% had intellectual disability, 13% had bipolar disorder or psychosis, and 11% had ASD. Among the prenatally diagnosed, mean standardized testing for intelligence scores were in the average range, though 10–15 points lower than siblings and controls (Table 4).⁵

8.3 |. 47,XXX key counseling points

• Individuals with 47,XXX may have increased rates of congenital abnormalities relative to the general population; specifically, findings in the genitourinary system, orofacial clefts, clubfoot, and cardiac defects can be seen.

• Data on medical and neurodevelopmental differences should be interpreted with caution because only 10%–20% of people with 47,XXX are thought to be diagnosed, leading to ascertainment bias.

• 47,XXX have increased risk of developmental delays, learning disabilities, and mental health disorders compared with the general population, though these are variable.

9 |. FETAL THERAPY

Can we do anything before birth?

The chromosomal differences that are detected through prenatal testing and screening cannot be changed with prenatal interventions. Specifically, there are no current gene therapies or intrauterine procedures that can be utilized to change the DNA content of fetal cells affected by SCA.

10 |. COUNSELING IMPLICATIONS

How will counseling about an SCA diagnosis influence my patient?

A prenatal diagnosis of SCA can be very anxiety-producing for patients.^64,65 The majority of those who receive an SCA diagnosis have no prior knowledge before their conversations with disclosing providers.^64,65 Thus, the initial conversations with a care team may influence the patient’s next steps, sometimes despite subsequent counseling by subspecialists more familiar with SCA.^65–68 Results disclosure in person with both parents present is preferred by patients.⁶⁶ Prior studies have noted significant increased rates of termination when counseled by providers without genetic specialization.^69,70 The use of person-first, inclusive, and non-stigmatizing language when discussing genetic diagnoses and possible disability is imperative for counseling. There is uncertainty in every diagnosis, but the range of possible outcomes and bias in existing data in SCA requires updated information, nondirective counseling, and patientcentered communication. Patients should be supported with updated reference materials and connected to additional resources (such as those below) for additional information.^65,66 Given the challenges with these diagnoses, routine testing is controversial, and several countries such as the Netherlands do not permit prenatal screening for SCA.

11 |. FUTURE RECURRENCE RISK/PREVENTION

Can I do anything to prevent this from happening again in future pregnancies?

Most parents will have chromosomally typical children in subsequent pregnancies.⁷⁰ Rarely, some families may have an increased risk of recurrence due to testicular or ovarian mosaicism or a structural rearrangement of the chromosomes. A careful family history and parental karyotypes can give patients more refined recurrence risk estimates if there are recurrent pregnancies with SCA or recurrent pregnancy loss. In three quarters of cases of 45,X, the paternal X chromosome is absent. Fathers of non-mosaic 45,X fetuses may be at slightly increased risk to produce sperm that are missing a chromosome.¹⁶

Polysomies (XXX, XXYY, XYYY, XXXY, XXXXX, and XXXXY) are individually quite rare as they are the product of multiple nondisjunctions in one parent and they seem to arise sporadically.⁷¹ There is no evidence that the recurrence risk is elevated above the age-specific risk in future pregnancies.

12 |. CONCLUSIONS

Differences in the sex chromosomes can be detected in pregnancy through screening and confirmed with diagnostic testing in pregnancy or after birth. With increasing use of cfDNA technologies, providers are more likely to be returning high risk SCA screening results to patients and providing further counseling. As detailed above, the health and learning differences of people with SCA can be subtle and variable, and there is significant bias in the literature due to ascertainment bias. Patients should be offered counseling by a multidisciplinary team of obstetricians, maternal-fetal medicine specialists, genetic counselors or geneticists, and pediatric endocrinologists to discuss the implications of an identified SCA for future health.

13 |. RESOURCES FOR PATIENTS

The Association for X and Y Chromosome Variations (AXYS): www.genetic.org.

Living with XXY: livingwithxxy.org.

Early intervention programs: https://livingwithxxy.org/early-intervention-programs-for-xxy/.

https://www.turnersyndrome.org/

rarechromo.org.

Key points.

What is already known about this topic?

• Sex chromosome aneuploidy (SCA) can be detected on prenatal diagnostic testing and cell free DNA screening (cfDNA).

• High risk cfDNA results should be confirmed with diagnostic testing.

What does this study add?

• This summary article serves as an update for prenatal providers and assimilates data from neurodevelopmental, epidemiologic, and registry studies on the most common SCA.

• This information can be helpful for counseling after prenatal diagnosis of sex chromosome aneuploidy.

• Incidence estimates may be influenced by ascertainment bias and this article is not a substitute for interdisciplinary consultation and counseling.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.