Sex chromosome abnormalities

INTRODUCTION — Sex chromosome abnormalities refer to a group of disorders that affects the number or the structure of the chromosomes that are responsible for sex determination. In humans, they are the X and Y chromosomes. Examples of sex chromosome abnormalities include monosomy X or structural abnormalities of the X chromosome such as isochromosome Xq, both anomalies leading to Turner syndrome. Congenital sex chromosome abnormalities occur in at least 1 in 448 births [1]. (See "Genetics: Glossary of terms" and "Genomic disorders: An overview".)

Other congenital cytogenetic abnormalities are discussed in detail separately. (See "Congenital cytogenetic abnormalities" and "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)" and "Microduplication syndromes".)

NUMERIC ABNORMALITIES (ANEUPLOIDIES) — Aneuploidies are abnormalities affecting the number of chromosomes. The most common sex chromosome aneuploidies are 45,X (Turner syndrome); 47,XXY (Klinefelter syndrome); 47,XYY (XYY syndrome); and 47,XXX, which have birth frequencies of approximately 1 in 2500, 1 in 500 to 1 in 1000, 1 in 850 to 1 in 3000, and 1 in 1000, respectively [2-7]. Sex chromosome mosaicism, with a normal cell line and a second cell line with a numeric anomaly involving a sex chromosome, is not unusual. The two most common forms of sex chromosome mosaicism are 45,X/46,XX and 45,X/46,XY [8,9]. The severity of the phenotype in patients with mosaicism is related to the percentage of abnormal cells among critical tissues [10,11].

Monosomy X (45,X or Turner syndrome) — Most patients with Turner syndrome have monosomy for the X chromosome with a 45,X karyotype. Other forms of Turner include mosaicism for X chromosome monosomy (eg, 45,X/46,XX) or 45,X/46,XY mosaic with or without a partial deletion of the Y chromosome. The remaining patients have a structural abnormality of the second X chromosome (eg, an isochromosome of the long arm of X or a deletion involving the short arm of one X). Deletions involving the distal portion of the short arm of the Y chromosome are associated with a Turner phenotype because these persons are missing the so-called "anti-Turner" genes (short-stature homeobox [SHOX], ribosomal protein 4 Y-linked [RPS4Y], and zinc finger protein Y-linked [ZFY]). Deletions of the short arm of the X chromosome are also associated with a Turner phenotype [12]. Most cases represent sporadic events. (See '45,X/46,XX mosaicism' below and '45,X/46,XY mosaicism' below and 'Isochromosome Xq' below and 'Xp22 SHOX deletions' below.)

Turner syndrome is characterized by short stature. Dysmorphic features are common and include low and posteriorly rotated ears, webbing of the neck, shield-like chest (broad chest with wide-spaced nipples), cubitus valgus, short fourth and fifth metacarpals, and hypoplastic nails. Other frequent findings include lymphedema, pigmented nevi, and congenital heart defects. Lymphedema in the dorsum of hands and feet may be the only clinical feature seen in newborns. The heart defects typically involve the left outflow tract, and coarctation of the aorta is a common finding. In addition, Turner patients develop streak gonads with ovarian failure and pubertal delay. Kidney anomalies can also occur (horseshoe kidneys) [13].

Persons with Turner syndrome that carry Y chromosome material (as is seen in some patients with mosaicism) are at increased risk of developing gonadoblastoma. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Management of Turner syndrome in children and adolescents".)

Patients diagnosed with Turner syndrome should have an echocardiogram including views of the aortic arch, cytogenetic studies to determine the presence of Y chromosome material that may increase risk for gonadoblastoma development, kidney ultrasound, and referral to an endocrine specialist for later sex hormone replacement and growth hormone treatment. Turner syndrome is discussed in detail separately. (See "Management of Turner syndrome in children and adolescents".)

47,XXY Klinefelter syndrome — Klinefelter syndrome is associated with a 47,XXY chromosome karyotype. It is the most common sex chromosome abnormality causing primary hypogonadism. The 47,XXY karyotype results from nondisjunction of the sex chromosomes and can be maternal or paternal in origin. Most cases are detected postnatally and are diagnosed during evaluation for infertility or gynecomastia.

Male newborns with the 47,XXY karyotype are phenotypically normal, with normal male external genitalia and no dysmorphic features. The major clinical manifestations of Klinefelter syndrome include tall stature, small testes, and infertility (azoospermia) that become noticeable after puberty [14]. Patients with Klinefelter syndrome are at increased risk for psychiatric disorders, autism spectrum disorders, and social problems. Patients diagnosed with Klinefelter syndrome should have a neurodevelopmental evaluation and should be referred to an endocrinologist. Klinefelter syndrome is discussed in greater detail separately. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "The child with tall stature and/or abnormally rapid growth", section on 'Klinefelter syndrome' and "Causes of male infertility", section on 'Klinefelter syndrome'.)

47,XYY syndrome — Persons with 47,XYY have tall stature and may have mild delays in motor and language development. A significant proportion of XYY males require special educational intervention but are generally educated in mainstream school settings. They have normal pubertal development, and most are fertile [15] (see "The child with tall stature and/or abnormally rapid growth"). Due to the subtlety of the phenotype and lack of associated health problems, many persons with 47,XYY remain undiagnosed throughout their lifespan.

In an early report, 47,XYY males were thought to have increased aggressive behavior [16]. However, a subsequent large collaborative study by European and United States geneticists concluded that the increased rate of antisocial behavior in XYY males was related to a lack of judgment and lower socioeconomic status due to a lower mean intelligence quotient (IQ) score (by 10 points), which led them into difficulties with the law and involvement in minor crimes [17-19]. Higher rates of attention deficit hyperactivity disorder and autism spectrum disorders are reported in 47,XYY [20]. A neurodevelopmental evaluation is recommended in patients diagnosed with 47,XYY, given the high prevalence of learning disabilities and behavioral problems.

47,XXX syndrome — 47,XXX, also called triple X, is the most common sex chromosome abnormality in females [5]. Most persons with 47,XXX are diagnosed incidentally on prenatal genetic screening [21]. They do not appear to be at increased risk of having chromosomally abnormal offspring [22].

A review of 155 females with 47,XXX karyotype found that 62 percent were physically normal [23]. Thus, it is estimated that most persons with 47,XXX are never diagnosed [5]. 47,XXX females have a tendency to be tall, with many reaching the 80^th percentile in height by adolescence, but with an average head circumference between the 25^th to 35^th percentile [17]. Puberty and fertility are generally the normal range, but premature ovarian failure can occur [5,17]. Another prospective study of 11 47,XXX females identified in a newborn survey at birth reported that their verbal and performance IQ scores were 15 to 20 points lower than those of their siblings, with verbal IQ often the lowest [24]. Psychotic disorders and cyclothymia are reported more frequently in patients with 47,XXX [25]. Thus, monitoring for developmental delays and neuropsychiatric problems is recommended.

Other rare sex chromosome aneuploidies — Over 100 cases of 49,XXXXY [26], at least 20 cases of 49,XXXXX [27], and a few cases of 49,XYYYY [28] have been reported. There appears to be a direct relationship between the number of additional sex chromosomes and the severity of the phenotype. In addition, a review of tetrasomy and pentasomy of sex chromosomes concluded that polysomy of the X chromosome results in a more deleterious effect than polysomy of the Y chromosome [1]. Studies have shown that the IQ is reduced by 10 points for every extra X chromosome beyond the normal XX or XY complements in females and males, respectively [29].

49,XXXXY — The characteristic clinical features of the XXXXY karyotype are low nasal bridge with a wide or upturned tip, wide-set eyes, epicanthal folds, skeletal anomalies (especially radioulnar synostosis), congenital heart disease, endocrine disorders, and severe hypogonadism and hypogenitalism [26,30,31]. Severe intellectual disability and moderately short stature are common. Although persons with this karyotype are often labeled as Klinefelter variant, the characteristic features of XXXXY all point to a rather distinct phenotype [26,32].

49,XXXXX/pentasomy X — Intellectual disability is always present in females with 49,XXXXX [27]. Other clinical features include craniofacial, cardiovascular, and skeletal abnormalities, which are quite variable. Patients with pentasomy X may have clinical features resembling those seen in Down syndrome. Radioulnar synostosis is also commonly seen in patients with more than three X chromosomes. Some patients have mosaicism of 48,XXXX and 49,XXXXX [33,34]. (See "Down syndrome: Clinical features and diagnosis".)

45,X/46,XX mosaicism — This is the most common form of sex chromosome mosaicism diagnosed by amniocentesis and prenatal karyotyping [8,9]. Noninvasive prenatal testing in maternal blood may also ascertain this and other forms of sex chromosome mosaicism [35].

Persons with this type of mosaicism have milder clinical features of Turner syndrome [9,36-38]. Many females with this chromosome constitution may undergo spontaneous puberty and have reproduced [39]. (See 'Monosomy X (45,X or Turner syndrome)' above and "Clinical manifestations and diagnosis of Turner syndrome" and "Management of Turner syndrome in children and adolescents".)

A review of 156 prenatally diagnosed cases of 45,X/46,XX with available outcome information found that 14 percent had an abnormal outcome [40]. There were two stillbirths and 20 cases with an abnormal phenotype (12 had some features of Turner syndrome, and 8 showed anomalies possibly not related to Turner syndrome). Over 85 percent of cases appeared to result in phenotypically normal females either at birth or at termination. However, the major features of Turner syndrome (eg, short stature and lack of secondary sex characteristics) are only manifested later in childhood or adolescence and would not be detected among infants. 45,X/46,XX mosaicism is reported in some females with premature ovarian failure who are otherwise phenotypically normal [41,42].

45,X/46,XY mosaicism — Mosaicism involving 45,X/46,XY has a wide phenotypic spectrum [43,44]. In a retrospective series of 151 postnatally diagnosed cases of 45,X/46,XY mosaicism, for example, 42 percent of patients were phenotypic females with typical or atypical Turner syndrome, 42 percent had ambiguous external genitalia and asymmetrical gonads (ie, mixed gonadal dysgenesis), and 15 percent had a male phenotype with incomplete masculinization [44]. Thus, all postnatally diagnosed cases were phenotypically abnormal. However, this can be explained by the fact that children or adults with mosaicism and a normal phenotype are not likely to seek medical attention (ascertainment bias). In contrast, among 80 prenatally diagnosed cases of 45,X/46,XY mosaicism, 74 (92.5 percent) were grossly normal males [40]. (See 'Monosomy X (45,X or Turner syndrome)' above and "Clinical manifestations and diagnosis of Turner syndrome".)

A high-resolution ultrasound exam of the fetus with special emphasis on the external genitalia is recommended when a diagnosis of 45,X/46,XY is made prenatally. Visualization of male genitalia can be more reassuring to parents than a quantitative estimate of risk of phenotypic abnormality. However, it is not known whether linear growth and fertility may be influenced by the 45,X cell line in phenotypically normal male infants.

SEX CHROMOSOME STRUCTURAL ABNORMALITIES — Structural abnormalities primarily consist of isochromosomes, deletions, duplications, ring chromosomes, and translocations. (See "Genomic disorders: An overview" and "Chromosomal translocations, deletions, and inversions".)

Isochromosome Xq — Isochromosome for the long arm of the X chromosome, isoXq or i(Xq), in which the short arm (p) is deleted and replaced with an exact copy of the long arm (q), is one of the most common structural sex chromosome abnormalities [17,45].

It is not associated with increased parental age [46]. 46,X,i(Xq) can occur as a nonmosaic or as a mosaic along a normal 46,XX cell line; 45,X cell line; or both. Isochromosomes Xq and Yq are associated with Turner syndrome, probably because the major anti-Turner syndrome gene, SHOX (short stature homeobox-containing gene on the X chromosome), is located at the distal portion of the short arms of the X and Y chromosomes (at the pseudoautosomal pairing regions) [44,47]. The Xq isochromosome is also seen in patients with a variant of Klinefelter syndrome, 47,X,i(Xq),Y [48-52]. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome'.)

X-chromosome deletions

Xp11.22 deletions — A number of deletions of the Xp11.22 region, a gene-rich region, have been reported. A deletion including the plant homeo domain finger protein 8 (PHF8) gene has been reported in association with intellectual disability, cleft lip/palate, and autistic spectrum disorders [53]. Truncating pathogenic variants of the PHF8 gene are associated with Siderius-Hamel syndrome (Siderius-type X-linked syndromic intellectual disability; MIM #300263). Other deletions in this region involving the HECT, UBA, and WWE domain-containing 1 (HUWE1) gene that encodes an E3 ubiquitin ligase and the hydroxysteroid 17 beta dehydrogenase 10 (HSD17B10) gene have been reported in patients with intellectual disability [54]. Another deletion syndrome involving shroom family member 4 (SHROOM4) and chloride voltage-gated channel 5 (CLCN5) genes has been reported in association with intellectual disability, short stature, and Dent disease [55,56]. Another deletion has been reported that includes the centromere protein V-like 1 (CENPVL1), centromere protein V-like 2 (CENPVL2), MAGE family member D1 (MAGED1), and G1 to S phase transition 2 (GSPT2) genes and causes syndromic X-linked intellectual disability, relative macrocephaly, and joint laxity [57].

Xp22.11 deletion — A deletion in Xp22.11 involving patched domain-containing protein 1 (PTCHD1) gene was reported in several families with autism spectrum disorder and in three families with intellectual disability [58]. PTCHD1 is a candidate gene for X-linked intellectual disability with or without autism [59]. The function and role of this gene are unknown.

Xp22.3 deletion — Deletion of this region is often associated with microphthalmia and linear skin defects (MLS) syndrome, an X-linked, dominant disorder that is lethal in males and therefore only seen in females [60]. A gene in this region encoding mitochondrial holocytochrome c-type synthetase (HCCS) was found mutated in patients with MLS who did not have the deletion [61-64]. The clinical presentation of MLS consists of microphthalmia and anophthalmia (unilateral or bilateral) and linear skin defects, mostly in the face and neck, that heal with time. Structural brain abnormalities, developmental delay, and seizures are part of the clinical spectrum. Heart defects (such as hypertrophic cardiomyopathy and arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, preauricular pits and hearing loss, and genitourinary malformations are also common clinical findings.

Screening evaluations include ophthalmologic evaluation (consider prosthesis), developmental and dermatology evaluations, echocardiogram, brain magnetic resonance imaging (MRI), and electroencephalogram (EEG). Patient may benefit from physical, occupation, and speech therapy (PT, OT, and ST).

Xp22 SHOX deletions — Deletions of Xp22 encompassing the short-stature homeobox (SHOX) gene are causative for idiopathic short stature [47,65,66]. The SHOX gene is found in the pseudoautosomal region 1 (PAR1) of the X and Y chromosomes. This gene is considered a major player in the short stature of Turner syndrome, and haploinsufficiency of this gene causes Leri-Weill dyschondrosteosis (LWD) [47,67]. LWD is characterized by short stature, more severe in females, and Madelung deformities (focal dysplasia of the distal radial physis). Homozygous deletions of SHOX cause Langer dysplasia, a more severe form of metaphyseal dysplasia [68]. SHOX deletions can also be seen in patients with short stature and no other specific skeletal signs. More than 60 percent of the SHOX rearrangements are gene deletions; therefore, array comparative genomic hybridization (CGH) should be considered in the work-up of idiopathic short stature, followed by sequencing to ascertain point mutations if no deletions are found. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Pathogenesis' and "Overview: Causes of chronic wrist pain in children and adolescents", section on 'Madelung deformity' and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization' and "Genomic disorders: An overview", section on 'Array comparative genomic hybridization' and "Causes of short stature", section on 'Idiopathic short stature'.)

X-chromosome duplications

Xp11.22 microduplication — Microduplications involving the E3 ubiquitin ligase HUWE1 gene have been reported in association with nonsyndromic mild intellectual disability in males [69,70]. Larger duplications involving SHROOM4 and diacylglycerol kinase kappa (DGKK) as well as HUWE1 (Xp11.22-p11.23 duplication) have been reported as a cause of intellectual disability, speech delay with or without dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay [71].

Xp21.22 duplication — Duplications of this region that contain the nuclear receptor subfamily 0 group B member 1 (NR0B1, also called DAX1) gene, an orphan member of the nuclear receptor superfamily, causes dose-dependent sex reversal in XY persons who develop as females with dysgenetic streak gonads [72]. DAX1 is an anti-testis factor and an antagonist of the sex-determining factor (SRY).

Xp22.31 duplication — Duplications in Xp22.31 have been extensively reported in the literature. There has been much debate about whether this duplication is pathogenic or a benign finding, underscoring the difficulties in determining the consequences of copy number variations (CNVs) [73,74]. This duplication involves the steroid sulfatase (STS) gene. Deletions of this gene are associated with X-linked ichthyosis in males. This duplication has been reported in patients with intellectual disabilities. However, it has also been seen in the patients' normal relatives as well as in the general population. While duplications of this gene may have no phenotypic consequences, triplications are consistently associated with intellectual disabilities [75]. Fluorescent in situ hybridization (FISH) studies can ultimately aid in distinguishing duplications from triplications or multiple copy number gains. (See "Genomic disorders: An overview", section on 'Copy number variations' and "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)

Xq26.3 microduplication — Microduplications in the Xq26.3 region that include the G protein-coupled receptor 101 (GPR101) gene are associated with gigantism due to an excess of growth hormone, termed X-linked acrogigantism (X-LAG) [76,77].

All patients identified with this microduplication had disease onset before five years of age. The G protein-coupled receptor was overexpressed in the patients' pituitary lesions. A recurrent pathogenic variant in GPR101 is found in some adults with acromegaly. (See "Pituitary gigantism" and "Causes and clinical manifestations of acromegaly", section on 'Causes'.)

Xq26.2 microduplication — Microduplications in Xq26 may lead to under- or overgrowth due to involvement of glypican genes GPC3/GPC4. Duplications in these genes have been reported in association with microcephaly and undergrowth [78]. Defects in GPC3 are involved with Simpson-Golabi-Behmel syndrome (SGBS) type 1, an X-linked recessive disorder characterized by overgrowth, coarse facies, congenital heart defects, and phenotypic similarities often compared with Beckwith-Wiedemann syndrome. Most duplications causing SGBS are intragenic and disrupt the gene, leading to haploinsufficiency [79]. (See "Beckwith-Wiedemann syndrome", section on 'Clinical manifestations'.)

MECP2 duplication syndrome — Pathogenic variants in the gene encoding methyl-CpG binding protein 2 (MECP2) located in Xq28 are responsible for Rett syndrome. Duplications of this region have little or no phenotypic significance in females, who are most likely normal due to X inactivation of the abnormal X chromosome. Males with this duplication are severely impaired (MIM #300260). The clinical presentation includes early hypotonia, severe-to-profound intellectual disability, speech delay, feeding difficulties, gastroesophageal reflux, severe constipation, frequent respiratory infections in up to 75 percent of males, and progressive spasticity and seizures (ranging from tonic-clonic type to absence seizures) that are sometimes refractory to treatment [80-84]. Many patients with this duplication have been diagnosed with autism or autism spectrum disorder [85]. Similar to what is seen in Rett syndrome, patients with MECP2 duplication experience developmental regression. In addition, they develop ataxia, progressive lower limbs spasticity, and often lose their ability to ambulate. The prognosis is guarded, and most males with this duplication die in their mid-20s secondary to respiratory infections. The gene for interleukin 1 receptor-associated kinase 1 (IRAK1) is often involved in the duplication and may play a role in the immune abnormalities seen in this group of patients [85]. Triplication of this region produces an even more severe phenotype in males.

Screening studies for these patients include an EEG, swallowing studies, and assessment of humoral and cellular immunity. Treatment may include management of hypotonia (PT and OT) and spasticity, ST, gastrostomy tube (g-tube or g-button) for feeding difficulties, and management of respiratory infections.

SUMMARY

●Types of sex chromosome abnormalities – Sex chromosome abnormalities can be caused by numeric abnormalities (aneuploidies) or structural defects of the chromosomes. (See 'Introduction' above.)

●Aneuploidies – The most common sex chromosome aneuploidies are 45,X (Turner syndrome); 47,XXY (Klinefelter syndrome); 47,XYY; and 47,XXX. Sex chromosome mosaicism involving a normal cell line is not unusual. The two most common sex chromosome mosaicisms are 45,X/46,XX and 45,X/46,XY. The severity of the phenotype in patients with mosaicism is related to the percentage of abnormal cells. (See 'Numeric abnormalities (aneuploidies)' above.)

●Structural defects – Structural abnormalities of the X and Y chromosomes primarily consist of isochromosomes, deletions, duplications, ring chromosomes, and translocations. One example of a genomic disorder is duplication of methyl-CpG binding protein 2 gene (MECP2) in males, which is associated with hypotonia, severe-to-profound intellectual disability, speech delay, feeding difficulties, frequent respiratory infections, and seizures. (See 'Sex chromosome structural abnormalities' above.)