In approximately 75% of patients with 45,X, the X chromosome is maternal in origin [37, 45, 46]. There is no parental age effect [46]. Although phenotypic differences have not been found between Turner patients with a maternal or paternal X chromosome, there may be some cognitive differences particularly in memory function [47]. This has been theorized to be on the basis of an imprinted X-linked locus; however, no human imprinted X-linked genes have yet been identified [19, 48].

Clinical features of Turner syndrome in newborns may include decreased mean birth weight (average weight 2,800 g), posteriorly rotated ears, neck webbing (Fig. 10.3a), and edema of hands and feet (Fig. 10.3c, d), although more than half are phenotypically normal [49]. Congenital heart defects, especially coarctation of the aorta, and structural renal anomalies are common and should be checked for. Most older children and adults with Turner syndrome have short stature and ovarian failure, and variable dysmorphic features including down-slanting eyes, posteriorly rotated ears, low posterior hairline, webbed neck (Fig. 10.3a), a broad chest, short fourth metacarpals (Fig. 10.3b), and cubitus valgus [49]. Adults with Turner syndrome have a four- to fivefold increased rate of premature mortality, mainly due to complications of congenital heart disease [50]. There is a risk of aortic dilatation leading to dissection. Regular follow-up throughout life with a cardiologist and cardiac magnetic resonance imaging is recommended [49]. Without hormonal supplementation, there is usually lack of secondary sex characteristics. The gonads are generally streaks of fibrous tissue. Although germ cells normally form in the 45,X embryo, there is accelerated oöcyte loss by 15 weeks of gestation [51]. Standard treatment includes use of growth hormone and estrogen. It is recommended that these patients be followed by endocrinologists familiar with Turner syndrome. There are several published guidelines for health supervision for children and adults with Turner syndrome [49, 52–55].

The SHOX gene, located in the distal part of the pseudoautosomal region on Xp, escapes X inactivation. Haplo­insufficiency for SHOX causes short stature and Turner skeletal features [56–58]. A gene determining lymphedema has been proposed at Xp11.4 [59].

Some degree of spontaneous puberty occurs in 10–30% of girls with Turner syndrome, but fewer reach complete puberty with menarche, and most require estrogen treatment beginning at age 12 for normal secondary sex characteristic development, and throughout adulthood to prevent osteoporosis [49]. Spontaneous pregnancy may occur in 2–5% [49, 54].

Intelligence in individuals with Turner syndrome is average to above average, although there is an increased risk of a nonverbal learning disorder and behavioral problems. Infants can have feeding problems and developmental delay. Problems with visual-spatial skills, working memory, executive functions, and social skills can occur. Verbal IQ scores are typically higher than performance IQ [55]. With appropriate therapeutic and educational intervention, women with Turner syndrome can do well academically and socially.

Approximately half of all individuals with Turner syndrome have a 45,X karyotype. The remainder exhibit mosaicism and/or structural abnormalities of the X chromosome. In a study of cytogenetic and cryptic mosaicism in 211 patients with Turner syndrome, Jacobs et al. reported pure 45,X in 46%, 47% had a structurally abnormal sex chromosome (41% with an abnormal X and 6% with an abnormal Y), and 7% had a 46,XX or 47,XXX cell line [60]. Two patients were found to have cryptic X mosaicism, and none had cryptic Y mosaicism.

Approximately 2% of patients with Turner syndrome have a 45,X/47,XXX mosaic karyotype [60, 91]. A study of seven girls with this type of mosaicism aged 6.1–20.4 years found that three of seven did not require growth hormone, five of six girls older than 10 years had spontaneous puberty, and four of five girls older than 12 years had spontaneous menarche with regular menstrual cycles without medication. No renal or cardiac anomalies and no cognitive or behavioral problems were found in this small group of patients. In general, patients with Turner syndrome caused by 45,X/47,XXX mosaicism are more mildly affected clinically with regard to phenotype and ovarian function [91].

It is important to identify the origin of a marker chromosome in a patient with Turner syndrome, because of the risk of gonadoblastoma if it is made up of Y material (see the section “Mosaicism with a Y chromosome” earlier) or the increased risk of phenotypic and developmental abnormalities if the marker is of autosomal origin. This can be done either with FISH or molecular techniques.

Most 47,XXX conceptions result from maternal nondisjunction at meiosis I, and so there is an association with increased maternal age. Two of the X chromosomes are inactivated, and abnormalities could result from three active X chromosomes early in embryonic development, prior to X inactivation and/or from genes on the X chromosome that escape inactivation.

In contrast to the result of a 45,X karyotype, there is not a recognizable syndrome in females with an additional X chromosome. The majority are physically normal, although there is a slight increase in the frequency of minor anomalies. The mean birth weight is at the 40th percentile, the mean birth length is at the 70th percentile, and the mean birth head circumference is at the 30th percentile [95]. In general, as adults, these women have moderately tall stature, with an average height of 172 cm (5 ft and 7.7 in.). Pubertal development is normal, and most have normal fertility, although a small number have ovarian dysfunction and premature ovarian insufficiency sometimes associated with autoimmune thyroid disease [96, 101, 97]. Renal and ovarian abnormalities and congenital heart defects have been reported in small numbers of patients. There appears to be an increased risk of seizures [94]. Most have good health, although one study found that 25% had recurrent nonorganic abdominal pain as teenagers [98].

There is a small but slightly increased risk of chromosomally abnormal offspring of 47,XXX women [99, 100]. Although they do not, remarkably, appear to be at significantly increased risk of having XXX or XXY children, prenatal diagnosis should be offered for all pregnancies.

Usually, 47,XXX females have normal intelligence, but most have lower IQs than their siblings. There is a great deal of variability and many women have normal intelligence and are well adjusted. Precise predictions regarding an individual child’s prognosis are not possible, but there does appear to be a risk for mild to moderate developmental problems in the areas of motor, speech and language, and learning [95, 101 102]. Verbal IQ tends to be lower than performance IQ, with many having problems with expressive language.

Many studies of 47,XXX females have ascertainment bias; however, in a group of 11 females with 47,XXX ascertained at birth by unbiased screening of all newborns who were then followed into adulthood, most had serious patterns of dysfunction [102]. Most showed early delays in motor, language, and cognitive development and were described as shy, withdrawn, and immature, with poor coordination [95]. The full-scale IQ was 26 points lower than in normal sibling controls; average IQ was in the 85–90 range, and subjects were at the 24th percentile in academic achievement scores, but mental retardation was rare. Nine of the eleven needed special education in high school either full time or part time, and less than half completed high school, but two achieved “A”s and “B”s, and one excelled in math. Most did not participate in extracurricular activities. They were described as socially immature. All had heterosexual ­orientation. Compared to individuals with other types of sex chromosome disorders, 47,XXX females seemed to have the most psychological problems, including depression and, occasionally, psychoses. However, one woman attended college, and many were able to overcome psychological problems and become independent, hold jobs, and marry. Stability of the home environment was somewhat related to outcome but not to such an extent as is seen in other sex chromosome disorders [102]. In adulthood most of these women were employed full time (unskilled or semiskilled jobs), had married, and had children [103]. In another long-term study, 47,XXX women were found to have more work, leisure, and relationship problems as compared to a control group [104]. They were found to have poorer psychosocial adaptation and more psychiatric impairment as compared to their female siblings. However, most were self-sufficient and functioned reasonably well as adults. Severe psychopathology and antisocial behavior were rare, and there was a larger variability in behavioral phenotype than originally appreciated [104]. In another longitudinal study of 16 girls with 47,XXX ascertained at birth through a cytogenetic survey of consecutive newborns, 50% had speech delay and IQ scores averaged 85.3 verbal (range 67–109) and 88.3 performance (range 67–110). Higher IQ scores were positively correlated with the level of parental education. All attended regular schools, but most required extra help in math and reading. Behavior problems required psychiatric referral in 25% of the girls [105].

In a study of five girls ranging in age from 7 to 14 years with 47,XXX diagnosed prenatally, only one had motor and language delays and learning problems; the others had normal IQs (range 90–128) and were doing well in school [106]. Another longitudinal study by Linden and Bender of 17 47,XXX females, ages 7–18, initially diagnosed prenatally, found that eleven needed academic assistance and seven required speech therapy. Many were shy in younger years but became more outgoing as teenagers, and three had no developmental problems. Their IQs ranged from 73 to 128, with a mean of 103. The girl with a 73 IQ was from a family with a history of learning problems [107]. Reasons for the difference between the two groups could be the higher socioeconomic status and greater stability of the prenatally diagnosed group.

Experts in this field advocate for anticipatory guidance for these patients, emphasizing the child’s normal development but remaining prepared to identify and provide early intervention when developmental problems occur. Appropriate speech, occupational and physical therapy, educational assistance, and psychiatric treatment should be instituted as soon as a need is identified [104]. There have been several recent reviews of 47,XXX [94, 105, 106].

As compared to 47,XXX, there is almost always mild to moderate intellectual disability (mental retardation) in individuals with 48,XXXX or tetrasomy X syndrome, with an average IQ of 60, ranging from less than 30 to 75 [110]. One individual was reported to have a normal IQ [111]. Phenotypic features include mild hypertelorism, epicanthal folds, micrognathia, and midface hypoplasia [112]. Tall stature is common, with an average height of 169 cm (approx. 5 ft and 6 in.) [110]. Skeletal anomalies include radioulnar synostosis and fifth finger clinodactyly. Incomplete development of secondary sex characteristics could occur with scant axillary and pubic hair and small breasts, and some patients have gonadal dysgenesis [113]. Speech and behavioral problems are common. Fertility is reduced, and primary ovarian failure has been reported, although some have had chromosomally normal offspring [114].

Nondisjunction in successive meiotic divisions is the probable mechanism for pentasomy X syndrome, and molecular studies have shown that, at least in some cases, the extra X chromosomes are all maternally derived [115, 116].

Phenotypic features seen in penta-X females include intrauterine growth restriction, short stature, microcephaly, up-slanting palpebral fissures, low hairline, and coarse, Down syndrome-like facial features. Congenital heart defects, renal anomalies, hip dysplasia, and joint subluxation have been reported [117–120]. One individual with penta-X and hyper-IgE syndrome has been reported [121]. An infant with laryngomalacia and extreme neonatal hypotonia has been reported with mosaicism for tetrasomy X and pentasomy X [122]. Most have moderate developmental disability (IQ range 20–75, average IQ 50) and are described as shy and cooperative [110, 120]. There have been no reports of pregnancy in women with this chromosomal aneuploidy [110].

In one study, the extra chromosome arose at paternal meiosis I in 53% of patients, 34% at maternal meiosis I, 9% at maternal meiosis II, and 3% from postzygotic errors. There is an association with increased maternal age in those with maternal meiosis I errors [127]. A recent study found the additional X chromosome to be paternal in approximately 25% of cases, and these were associated with increased paternal age, although other studies have not supported this finding [128, 129].

Maternal nondisjunction during meiosis I leads to uniparental heterodisomy for the X chromosome, while an error during meiosis II results in uniparental isodisomy (see Chap. 20). If the father contributes the X, there are two different X chromosomes with different parental origins. So far, studies have found contradicting results regarding differences in phenotype and development between KS males with a paternal versus a maternal additional X [130]. No phenotypic differences between heterodisomy and isodisomy for the X in KS have yet been found. The repeat length and inactivation status of the androgen receptor at Xq11.2-q12 has also been studied as to its correlation with the KS phenotype, but so far there have been no definitive findings [130].

47,XXY males have taller than average stature, with mean height at the 75th percentile, and might have a eunuchoid build with long limbs and pear-shaped hips, although there is a great deal of phenotypic variability [98]. Head circumference during infancy is usually average but, beginning at age 4 years, tends to be below the mean for age, although generally within normal limits [131]. Testicular and penile size is usually small during childhood, although prepubertal phenotype is often unremarkable. Gynecomastia occurs in up to 50% of 47,XXY males during adolescence. Most enter puberty normally, although there is usually inadequate testosterone production and most require testosterone supplementation. Measurement of serum testosterone level in male infants with Klinefelter syndrome at 6 weeks of age can help predict the amount of natural testosterone production these patients will have.

Testes are small in adulthood, and there is hypergonadotropic hypogonadism. Almost all have infertility with absent spermatogenesis, tubular hyalinization, and Leydig cell hyperplasia. Most are born with spermatogonia, but during early puberty, the spermatogonia are thought to undergo massive apoptosis along with damage to the germinal epithelium [132]. Many men with KS are diagnosed in adulthood, with a chief complaint of infertility, but based on a population study, as many as 74% might never be diagnosed [30]. There have been more than 200 reports of pregnancies resulting from intracytoplasmic sperm injection (ICSI) from nonmosaic 47,XXY patients [130]. In one study of 38 pregnancies, there were 34 karyotypically normal neonates, two karyotypically normal pregnancy losses, one healthy unkaryotyped neonate, and one 47,XXY prenatally diagnosed fetus [133] (see also Chap. 12).

Boys with Klinefelter syndrome have been reported to have decreased muscle tone during infancy, delayed speech and language skills, and an increased incidence of reading disability and dyslexia [134]. IQs are lower than in controls and compared to siblings, with the average between 85 and 90, although there is a wide range [98]. Verbal IQ is usually lower than performance IQ. The majority require special help in school, especially in the areas of reading and spelling. They are often described as awkward with mild neuromotor deficits, shy, immature, restrained, reserved, and lacking confidence [98]. A group of 13 males with Klinefelter syndrome, diagnosed as newborns and followed into adulthood, were said to have struggled through adolescence with limited academic success but were able to function independently in adulthood [102]. Most needed at least some special education help in school; nine completed high school, and four went to college. All were heterosexual. Some had psychological problems, including conduct disorder and depression, and difficulties with psychosocial adjustment. A stable and supportive family environment was found to correlate with better outcome [102]. Another long-term study of this group found that as adults, ten of eleven were employed full time and eight had married [103].

In a group of five boys ranging in age from 7 to14 years who had been prenatally diagnosed with 47,XXY karyotypes, there were fewer language and motor deficits in childhood as compared to the postnatally diagnosed group, and all were doing well in school. IQs ranged from 90 to 131. The reason for the better outcome might be the result of environmental and other genetic factors [108]. In a long-term study of 14 prenatally diagnosed boys with Klinefelter syndrome followed to 7–18 years, ten had average school performance, eight required educational assistance, three had attention deficit disorder, and four had speech problems. In general, they were healthy and had pleasant personalities [109]. A study of 50 boys with KS diagnosed prenatally and through clinical ascertainment found problems with complex language processing, impaired attention, and motor function [134]. An excellent review of the developmental phenotype in KS is by Boada et al. [135].

In summary, individuals with Klinefelter syndrome can have productive and fulfilling lives but often require special assistance in school and could have social and behavioral problems. Early evaluation and intervention are strongly recommended because the prognosis can be improved signi­ficantly with appropriate therapeutic intervention [136].

This is the most common variant of Klinefelter syndrome [110]. There is overlap between this condition and both Klinefelter and XYY syndrome (see the section 47,XYY). The incidence is estimated at 1 in 50,000 male births [137]. Men are tall statured, with adult height above 6 ft, a eunuchoid body habitus, and long thin legs. There is hypergonadotropic hypogonadism, small testes, and sparse body hair. Gynecomastia occurs frequently [110].

Most 48,XXYY patients have mild intellectual disability, although IQs ranging from 60 to 111 have been reported. Speech and motor delays and hypotonia are seen in 75%, with average age at ambulation of 18 months [138]. Developmental outcomes described range from milder language-based learning disability (reading disability, dyslexia) to mild mental retardation in 30% of patients. Overall adaptive functioning is often more impaired than would be expected based on IQ scores [139]. Psychosocial and behavior problems are generally more severe than in 47,XXY individuals, although patients without significant behavior problems have been reported [110, 140]. Four patients with 48,XXYY observed over a 10-year period had psychiatric disorders, including aggressiveness, self-injury, and mental retardation [141].

48,XXYY is not associated with advanced parental age. Nondisjunction in both the first and second male meiotic divisions leading to an XYY sperm has been hypothesized [142].

This is a rare condition, with more abnormal features and developmental disability as compared to 47,XXY. It was first described by Barr in 1959 [143]. Stature is normal to tall, and dysmorphic features include epicanthal folds, hypertelorism, protruding lips, prominent mandible, radioulnar synostosis, and fifth finger clinodactyly. There is hypergonadotropic hypogonadism and hypoplastic penis in 25% of patients, and gynecomastia is common. Testosterone therapy has been shown to be beneficial. Affected individuals are infertile.

Males with this condition have mild to moderate intellectual disability, with most in the 40–60 IQ range, although an individual with an IQ of 79 has been reported [110]. Most have speech delay, slow motor development, and poor coordination. Behavior is immature, with personality traits described as passive, pleasant, placid, and cooperative [110]. A 10–15 point decrease in IQ for each additional X chromosome has been reported, although there is still wide variability in outcomes [144].

49,XXXXY has an approximate incidence of 1 in 85,000 male births, and more than 100 cases have been described in the literature since this karyotype was first reported by Fraccaro et al. in 1960 [145]. It results from nondisjunction of the X in maternal meiosis I and II [146].

Common features include low birth weight, short stature in some patients, craniofacial features consisting of round face in infancy, and coarsening of features in older age, with hypertelorism, epicanthal folds and prognathism, and a short, broad neck [110, 142]. Congenital heart defects are found in 15–20%, with patent ductus arteriosus the most common defect described, but atrial ventricular septal defects and tetralogy of Fallot are also reported [110, 147, 148]. Skeletal anomalies include radioulnar synostosis, genu valgus, pes cavus, and fifth finger clinodactyly. Muscular hypotonia and hyperextensible joints are often present. There is hypergonadotropic hypogonadism [110]. Genitalia are hypoplastic with short penile length, small testicular volume, and cryptorchidism [110, 139]. Because of the distinctive phenotype, some authors have suggested classifying this condition separately from Klinefelter syndrome [139, 148].

Mild to moderate intellectual disability (mental retardation) is seen in most patients, although reported IQs range from 20 to 78. Language development is most severely impaired with some patients having speech aphasia [148]. Behavior has been described as timid, shy, pleasant, anxious, and irritable [110]. Testosterone replacement therapy has been found to be beneficial in some patients, with improvement in attention and behavior [149]. Recent studies have suggested that there may be less significant cognitive impairment in these individuals than previously thought [150]. In 13 children aged 2–7 years, the mean nonverbal IQ was 87.1 [139].

Only five cases of live-born males with this sex chromosome disorder have been described. Physical features include tall stature, dysmorphic facial features, gynecomastia, and hypogonadism. All have had moderate to severe mental retardation, with passive but occasionally aggressive behavior and temper tantrums. One patient had autistic-like behavior [110].

There have been reports in the literature of 19 individuals with Klinefelter syndrome with an isochromosome Xq or i(Xq) [151]. The phenotype is very similar to typical Klinefelter syndrome with azoospermia, hypogonadism, and gynecomastia, but height is in the normal range, presumably due to a normal copy number of the pseudoautosomal region on Xp/Yp, including the SHOX gene. Using microdissection, Hockner et al. demonstrated the i(Xq) chromosome observed in their patient was an isodicentric, maternally derived, true isochromosome and not the result of an Xq;Xq translocation [151]. These findings are consistent with the proposed mechanism of origin for most of the i(Xq) chromosomes observed in Turner syndrome females (see section “Isochromosome X” above).

One in 800–1,000 males has an extra Y chromosome [92]. This arises through nondisjunction at paternal meiosis II.

Males with 47,XYY tend to have normal birth length and weight, but when older, most are above the 75th percentile in height. Minor anomalies are found in 20% of patients, but the rate of major malformations is not increased. Most infants are normal in appearance [152]. Pubertal development is usually normal, although onset of puberty in one group of patients studied was approximately 6 months later than average for males with no sex chromosome disorder. Patients often have severe facial acne, are described as tall and thin, and have good general health. Sexual orientation is typically heterosexual. Individuals are described as somewhat awkward and have minor neuromotor deficits [98]. Most have normal fertility and are able to father children. It has been estimated that only 12% of men with XYY are ever diagnosed. Half of those identified were karyotyped because of developmental delay and/or behavior problems [30].

Intelligence is normal, although there is an increased incidence of learning disabilities. There have been two groups of patients with 47,XYY studied long term: one diagnosed in a newborn screening program and the second diagnosed prenatally. The latter group of patients comes from families with an above-average socioeconomic status. The first group had an IQ range of 93–109, and all required part-time special education. The second group had an IQ range of 109–147, and all were reported to be getting “A”s and “B”s in school. IQ is usually somewhat lower than in siblings [98, 108]. Most older boys attend college or have jobs after high school. Longer follow-up of the boys in the second group found that five of 14 required extra assistance in school for academic difficulties and two were in special education programs for the learning disabled [109]. Overall, school performance in this group was above average. IQ scores were available for six of the boys and ranged from 100 to 147. Most were involved with sports, although five were described as poorly coordinated. Two had serious emotional problems. Five had no academic or behavior problems. In general, there was wide variability of development and adaptation [109].

Delays in speech and language development occur in some boys. An increased rate of autism spectrum disorder in boys with XYY has been reported [153]. In a systematic literature review, Leggett et al. found that although males with XYY had lower IQ scores than expected for their social background, they were not impaired in relation to general population norms. Although some have problems with reading, others report reading as a relative strength, and some are noted to have proficiency in science and mathematics [105].

Hyperactive behavior, distractibility, temper tantrums, and a low frustration tolerance are reported in some boys in late childhood and early adolescence. Aggressiveness is not common in older boys. Although early studies raised the possibility of an increase in criminal behavior in these individuals, recent studies have shown that although there is a higher percentage of males with 47,XYY in prisons than in the general population, there was not an increase in violent behavior in these individuals [154]. Differences in rates of incarceration may be due to the lower intelligence of some XYY males. A study of a newborn cohort of XYY males followed into adulthood reported a higher proportion with antisocial behavior than their peers, but there was no statistical difference when diagnostic criteria for antisocial behavior disorder was used and compared with a group of unaffected males [105, 155].

The condition is clearly variable. Most blend into the population as normal individuals. Better outcomes seem to be associated with a supportive, stable environment.

There is no consistent phenotype for males with two additional Y chromosomes. Mild mental retardation to low normal intelligence and sterility has been described [156, 157].

Five nonmosaic cases of 49,XYYYY have been reported. Facial features include hypertelorism, low-set ears, and micrognathia. Skeletal abnormalities include clinodactyly, radioulnar synostosis, scoliosis, and spina bifida occulta. Mental retardation and speech delay, along with impulsive and aggressive behavior, were reported [110, 158–162]. In a patient followed from age 4 months to 26 years, adult height was at the 80th percentile, walking began at 2 years, and IQ at age 7 years was 75, but he was described as having mild to moderate mental retardation as an adult with impulsivity, behavioral disturbance, and difficulties with social interaction [162].

In females, balanced X;autosome translocations can be divided into four phenottypic categories: normal phenotype with or without history of recurrent miscarriage, gonadal dysfunction with primary amenorrhea or premature ovarian failure (POF), a known X-linked disorder, or congenital abnormalities and/or developmental delay [185]. The reasons for the variable phenotypes are complex and not fully understood, making genetic counseling in cases of prenatal detection of these translocations very difficult.

Translocations involving the X chromosome and an autosome often lead to primary or secondary ovarian failure and sometimes Turner syndrome-like features if the translocation occurs within the critical region of Xq13-q26 [186–188]. There are several different hypotheses concerning the cause of gonadal dysfunction in these cases, including disruption of POF-related genes, a position effect resulting from local alteration of chromatin caused by the translocation, and incomplete pairing of X chromosomes at pachytene [186–190]. In cases in which the derivative X chromosome is inactive, inactivation will spread from the translocated X segment to the attached autosomal material, where it will inactivate genes. The other X-chromosome segment will remain active. There is incorrect dosage of both autosomal and X-linked genes in these cells, with functional autosomal monosomy for the derived (X)t(X;autosome) chromosome that contained the X-inactivation center and functional X-chromosome disomy for the portion of the X chromosome translocated onto the active (autosomal) reciprocal translocation product [191]. There is strong selection against such cells. In general, the normal X is preferentially inactivated in approximately 75% of such patients [191, 192]. When the translocation disrupts a gene located on the X chromosome, a female with such a translocation could manifest a disease condition [193, 194]. Any mutated genes on the derivative X chromosome will be fully expressed, as they would be in a male [5]. Several X-linked genes have been mapped in this way.

A “critical region” determining normal ovarian function has been hypothesized at Xq13-Xq26 [188, 195]. The majority of females with balanced translocations with breakpoints in this region usually have premature ovarian failure (secondary amenorrhea associated with elevated gonadotropin levels before the age of 40 years). Although there have been several candidate genes for POF identified in this region, molecular characterization of the translocation breakpoints of women with balanced translocations involving the critical region has often shown no gene disruption [196, 197]. This supports the hypothesis that a position effect secondary to chromatin alteration or pairing abnormalities at meiosis causes ovarian dysfunction.

It has been thought that the majority of females with balanced X;autosome translocations with breakpoints above the X-inactivation center at Xq13 are phenotypically normal [198, 199]. Schmidt and DuSart found that most X;autosome translocation patients with phenotypic abnormalities or developmental delay had breakpoints clustered in the subtelomeric bands Xp22 and Xq28 [191]. This was thought to be the result of persistence of cells with inactivation of the translocated X in these patients. However, in a study by Waters et al. that reported 104 cases ascertained from cytogenetics laboratories in the United Kingdom, female X;autosome translocation carriers had a significantly higher number of abnormalities, including developmental delay and learning problems, than would be expected from literature review [185]. Those with congenital anomalies and/or developmental delay showed random X-chromosome breakpoint distribution. De novo translocations were significantly more likely to be associated with an abnormal outcome (18 of 19 cases), suggesting that de novo status versus breakpoint location is the most important risk factor in predicting phenotypic outcome [185].

Some studies have indicated that in those patients with phenotypic and/or developmental abnormalities, the translocated X was late replicating (inactive) [200]. However, Waters et al. did not find an association with aberrant late replication and abnormal phenotype. Eight of their patients showed a deviation from the expected pattern of consistent early replication of the derived X chromosome and late replication of the normal X chromosome. Five of these patients were phenotypically normal [185].

Because of variability in X inactivation from one person to another with the same X;autosome translocation, it is possible for a phenotypically normal mother to have a daughter with phenotypic abnormalities and intellectual disability (mental retardation) even though both carry the same such rearrangement. This can be because of skewed (nonrandom) X inactivation in the former and random X inactivation in the latter, leading to functional X disomy and functional autosomal monosomy in some cells. This is estimated to occur in approximately 25% of females with X;autosome translocations [193].

A fertile woman with a balanced X;autosome translocation is at risk for having offspring with an unbalanced rearrangement (Fig. 10.5). There is also the risk that even balanced offspring could be abnormal as a result of random or skewed inactivation of the abnormal X in a female child or by disruption of a functional gene on the X in a male. The risk for a female with a balanced X;autosome translocation to have a live-born child with a structural and/or functional aneuploidy has been estimated at 20–40% [192]. Phenotypic abnormalities can range from mild effects to severe intellectual disability (mental retardation) and birth defects.

Males with balanced X;autosome translocations are usually phenotypically normal but almost all are infertile [201] (see also Chap. 11). There have been reports of severe genital abnormalities in males with such translocations and of multiple congenital anomalies in a man with an apparently balanced (X;6) translocation inherited from his mother [202, 203]. As noted earlier, there is also a risk of an X-linked recessive disorder because of disruption of a gene by the translocation.

Further characterization of breakpoint regions in X-chromosome rearrangements has revealed that although some interrupt specific genes, others are in gene-poor regions. X-linked gene interruption is not a common finding in patients with POF and X;autosome translocations. Two critical regions on Xq associated with POF have been proposed. Critical region I at Xq21 has a low meiotic recombination frequency, is gene poor, is high in repetitive sequences, and is close to the X-inactivation center [204]. Translocations in this region could cause POF as a result of a position effect of autosomal genes important in ovarian function or as a result of meiotic pairing abnormalities [205, 206]. Deletions in this region rarely cause POF. Critical region II, at Xq23-q28, has different properties. Translocations involving this region could cause POF because of a position effect of X-linked genes. Since deletions in this region are frequently associated with POF, haploinsufficiency for missing or interrupted genes in this region could be the cause.

In females with unbalanced X;autosome translocations, the abnormal X is generally inactive if the X-inactivation center is present, probably secondary to selection against cells with an autosomal imbalance and functional X disomy. If the X-inactivation center is not present in the translocated segment, phenotypic abnormalities usually result from such imbalances and can include intellectual disability (mental retardation) and multiple congenital anomalies [207]. There have also been patients described who have unbalanced X;autosome translocations but no phenotypic abnormalities and only mild behavioral problems [208].

Earlier studies relied on replication timing to investigate inactivation in X;autosome translocations. The translocated autosomal material can become delayed in its replication timing, and this has been used to examine the extent of the spread of X inactivation in such cases. It has recently been demonstrated that late replication is a poor correlate of the spread of gene silencing [209]. The spreading of late replication is often incomplete and might skip some autosomal bands and affect others [210]. This suggests that autosomal chromatin does not transmit or maintain the inactivation signal as efficiently as the X chromosome [209].

Sharp et al. reported a family with both a balanced and unbalanced (X;10) translocation segregation [209]. A female with the unbalanced form was phenotypically normal except for secondary amenorrhea. Although the derivative X chromosome was late replicating, the late-replicating region extended only to the X;autosome boundary and did not appear to spread into the translocated segment of 10q. However, transcriptional analysis showed that the translocated segment of 10q was mostly inactive, consistent with the phenotype of the patient. There have been several other reports of patients with X;autosome translocations with mild phenotypes in which no spreading of late replication into the attached autosome was observed [211, 212]. This suggests that silencing of autosomal genes by X inactivation can occur without apparent delay in the replication timing of the surrounding chromatin. The use of replication-timing studies to evaluate the extent of spread of inactivation in X;autosome translocations can be misleading and should not be used to make predictions of phenotype [209]. In a study of five cases with X;autosome translocations, there appears to be some correlation between the pattern of gene silencing and clinical phenotype [15]. However, use of such techniques for prognostic purposes on a clinical basis awaits further studies. Cytogenetic features such as depletion of histone acetylation and H3 lysine 4 dimethylation provide more reliable indicators of the extent of spread of X inactivation than replication-timing studies [15].

Prenatal detection of an unbalanced X;autosome translocation presents a difficult genetic counseling problem (see Chap. 21). Although there have been reports of affected females having only secondary amenorrhea or mild developmental delay, many have had a more severe phenotype with mental retardation and birth defects [15, 200, 209, 213].

In males with unbalanced X;autosome translocations, there is in utero lethality or, if they survive, multiple congenital anomalies and intellectual disability (mental retardation) [214].

Functional disomy for the distal long arm of the X caused by unbalanced X;autosome translocations involving Xq28 appears to cause a distinctive phenotype [215] (see also the section on “Xq Duplications” later).

Paracentric inversions of the X chromosome (Fig. 10.6) are relatively rare. There has been a wide range of phenotypes described. In general, when long-arm paracentric inversions involve the critical region at Xq13-26, females have some degree of ovarian dysfunction [253]. When the inversion is outside the critical region, normal phenotype and fertility have been reported, although there are exceptions to this [254, 255]. There has also been variability in mental function in females, with some having mental retardation and others with normal intelligence, even in the same family [256]. Males can be phenotypically normal or have mental retardation [255, 257]. Fertility in males is also variable [258, 259].

Most females with pericentric inversions of the X have normal phenotypes and fertility [260–264]. However, pericentric inversions of the X have been reported in females with gonadal dysgenesis and with mental retardation [261]. Keitges et al. reported dizygotic twins with the same pericentric X inversion [inv(X)(p11;q22)] [261]. One twin was phenotypically normal with normal intelligence and menses and had random X inactivation. The other was mildly mentally retarded and had psychiatric problems, irregular menses, minor anomalies, and selective inactivation of the inverted X. Proposed explanations for these findings include different normal Xs, a nondetectable deletion or duplication in the abnormal twin, or chance. This also raises the likelihood that the replication pattern of the inverted X is a better predictor of fertility than the breakpoints. Interestingly, females with random X inactivation are more likely to have normal fertility than those with skewed inactivation of the inverted X [261]. Offspring of females with pericentric inversions are at risk for inheriting a recombinant chromosome with associated phenotypic abnormalities [260, 263–265].

Most males with inherited pericentric inversions of the X have a normal phenotype and fertility [260, 265, 266]. However, X-linked disorders have been found to segregate with pericentric inversions of the X, presumably by disruption or deletion of a gene by the inversion [267–270].

Analysis of X-chromosome inactivation in women with apparently balanced pericentric inversions might determine whether an imbalance is present at the molecular level. Random inactivation is usually associated with a balanced inversion, whereas skewed inactivation is more likely associated with an unbalanced inversion [266, 268]. Inactivation status of the mother might provide helpful information in cases of prenatal detection of a male fetus with a maternally inherited inversion [271]. Chromosome microarray is also helpful (see Chap. 18).

Isodicentric X chromosomes are formed by the fusion of two X chromosomes [272]. The phenotypic effects are variable and dependent on whether the chromosomes are fused at long or short arms, as well as on the location and extent of the deletion. The isochromosomes that are composed of two copies of the entire short arm [i(Xp)] are rare and have only been reported in females; they are believed to be nonviable in male conceptions [273]. These i(Xp) chromosomes are typically pseudodicentric with one active and one inactive centromere, and the XIST locus is retained in at least one of the deleted long arms [273, 274]. Most of these females have gonadal dysgenesis that could be explained by the mosaicism for a 45,X cell line that is often present, loss of critical regions on Xq, and/or meiotic pairing abnormalities. Emotional and behavioral problems and intellectual disability have been reported in these patients [273]. Stature ranges from tall to short. Tall stature could be related to the presence of three copies of SHOX in those patients with long arms joined.

Isodicentric X chromosomes consisting of two copies of the long arm joined at the proximal short arms with two centromeres are the most common structural abnormality of the X chromosome seen in Turner syndrome. Although most look monocentric in a G-banded karyotype, they are actually dicentric with one active centromere. The correct nomenclature (in the absence of direct evidence of a dicentric chromosome) is 46,X,i(X)(q10), with the understanding that in many instances it would be more accurate to use 46,X,idic(X)(p11.2).

Females with isodicentric X chromosomes joined at their short arms exhibit short or normal stature, gonadal dysgenesis, and, occasionally, Turner syndrome features [275]. Expla­nations for the phenotype of short stature when the short arms are joined include deletion of the distal short arm at the region of SHOX and/or as a result of a 45,X cell line. There are some males with Klinefelter syndrome who have one normal X and one isochromosome X [276] (see also the previous section on “47,XXY (Klinefelter Syndrome)”).

Mechanisms to explain formation of terminal rearrangements between homologous chromosomes include the following:

The isodicentric X is almost always late replicating, suggesting nonrandom inactivation of the derivative X. The second centromere is usually nonfunctional, making it a pseudodicentric chromosome [278] (see also the subsections “Turner Syndrome,” “Isochromosome X” earlier). Studies have shown that those that are functionally dicentric tend to have anaphase lag and, therefore, are more likely to be found in association with a 45,X cell line. Those that are functionally monocentric tend to segregate normally in mitosis [278, 279]. The occurrence of a 45,X cell line also correlates with the distance between the centromeres, presumably due to less mitotic stability of the isodicentric chromosome [75]. Most are thought to be derived from exchanges between sister chromatids. Analysis of breakpoints in cell lines with idic(X)(p11.2) has found that they lie within large inverted repeat sequences associated with low copy repeats or highly repetitive elements on Xp11.2, suggesting that the principal mechanism in their formation involves nonallelic homologous recombination. The Xp11.2 region appears to be susceptible to rearrangements leading to isochromosome formation and other rearrangements [280].