Table of Contents
Overview
Sex chromosome aberrations in humans are changes in the number or structure of the X and/or Y chromosomes. They differ in important ways from autosomal aberrations:
- Many affected individuals survive to birth and adulthood.
- Symptoms often involve sexual development, fertility, growth, and sometimes learning or behavior.
- The pattern of inheritance and appearance of these conditions is strongly influenced by X‐inactivation and the special biology of the Y chromosome.
This chapter concentrates on numerical sex chromosome aberrations (aneuploidies) and their typical clinical features, with brief remarks on structural changes.
Why Sex Chromosome Aberrations Are Often Viable
Most autosomal trisomies or monosomies are lethal early in development. In contrast, many sex chromosome aneuploidies are compatible with life. Reasons include:
- X‐inactivation (Lyon hypothesis): In somatic cells of XX individuals, usually only one X is transcriptionally active; the others become largely inactivated (Barr body). This “doses down” the effect of having extra X chromosomes.
- Pseudoautosomal regions and escape genes: Some genes on the X escape inactivation, especially in “pseudoautosomal” regions shared with the Y. Extra or missing copies of these genes contribute to the phenotype of X aneuploidies.
- Small gene content of the Y chromosome: The Y carries relatively few genes, mostly involved in testis development and spermatogenesis. Gaining or losing a Y has less global impact than most autosomes.
Because of these mechanisms, additional or missing sex chromosomes are less often fatal, but they can still cause characteristic syndromes.
Turner Syndrome (45,X and Variants)
Karyotype and Origin
- Classical karyotype: $45,X$ (only one X chromosome; no second sex chromosome).
- Mosaic forms are common, e.g.:
- $45,X/46,XX$
- $45,X/46,XY$
- Or with structural X abnormalities (e.g. isochromosomes, deletions, ring X).
- Typically arises from nondisjunction or structural errors in meiosis, or early mitotic errors producing mosaicism.
Main Features
Phenotype is usually female, because there is no functional SRY gene (testis‐determining factor) from a Y chromosome.
Common characteristics (severity varies):
- Pre‐ and postnatal growth retardation: Short adult stature.
- Gonadal dysgenesis: Streak ovaries, often leading to:
- Primary amenorrhea (no spontaneous menstruation).
- Infertility or markedly reduced fertility.
- Low estrogen levels, incomplete development of secondary sexual characteristics unless treated with hormones.
- Typical somatic features (variable):
- Broad chest with widely spaced nipples.
- Webbed neck (pterygium colli).
- Low posterior hairline.
- Lymphedema (swelling of hands/feet) in newborns.
- Associated medical issues:
- Congenital heart defects, especially coarctation of the aorta and bicuspid aortic valve.
- Kidney malformations.
- Increased risk of certain endocrine disorders (e.g. hypothyroidism).
Intelligence is often in the normal range, but there may be specific difficulties (e.g. visuospatial, math).
Mosaicism and Phenotypic Variability
- Individuals with mosaic karyotypes (e.g. $45,X/46,XX$) often have milder symptoms and may have some ovarian function and partial fertility.
- When a Y‐containing cell line is present ($45,X/46,XY$), there is an increased risk of gonadal tumors in dysgenetic gonads, so medical management often includes prophylactic removal of such gonadal tissue.
Klinefelter Syndrome (47,XXY and Variants)
Karyotype and Origin
- Classical karyotype: $47,XXY$.
- Variants with more X chromosomes: $48,XXXY$, $49,XXXXY$, etc., usually with more severe manifestations.
- Origin: Nondisjunction in meiosis (maternal or paternal), or early mitotic errors.
Main Features
Phenotype is usually male, because there is a Y chromosome with SRY.
Typical features (again, variable):
- Tall stature, often with disproportionately long legs.
- Testicular atrophy:
- Small, firm testes.
- Reduced testosterone production → decreased facial and body hair, less muscular build.
- Impaired spermatogenesis:
- Usually severe oligozoospermia or azoospermia.
- Frequently leads to infertility; assisted reproduction may be possible in some cases.
- Gynecomastia (breast tissue development) in many patients.
- Metabolic and skeletal issues:
- Increased risk of osteoporosis (due to low testosterone).
- Higher risk of metabolic syndrome and some cardiovascular problems.
Cognitive profile:
- Many have normal global intelligence.
- There may be increased frequency of language‐related learning difficulties, reading problems, and psychosocial challenges.
X‐Inactivation and XXY
Although one of the X chromosomes in $47,XXY$ cells is largely inactivated, some X genes escape inactivation. The extra dosage of these genes is thought to contribute to the phenotype (e.g. tall stature, gonadal dysfunction).
Triple X Syndrome (47,XXX)
Karyotype and Origin
- Karyotype: $47,XXX$ (sometimes called “Triple X” or “superfemale” syndrome).
- Can be mosaic, e.g. $46,XX/47,XXX$.
- Arises mostly from maternal meiotic nondisjunction.
Main Features
Phenotype is female.
Typical findings:
- Often mild or no obvious physical abnormalities.
- Tendency to tall stature.
- Many have normal puberty, menstruation, and fertility.
- Some have increased rates of:
- Delays in speech and language.
- Learning difficulties.
- Subtle motor and coordination problems.
- Psychosocial or emotional challenges.
Because signs can be very mild, many individuals are never diagnosed and lead typical lives.
XYY Syndrome (47,XYY)
Karyotype and Origin
- Karyotype: $47,XYY$.
- Usually arises from paternal nondisjunction (error during meiosis II in spermatogenesis, resulting in YY sperm).
Main Features
Phenotype is male.
Common characteristics:
- Tall stature.
- Typically normal sexual development and fertility.
- Many have normal intelligence; however, there is:
- Increased risk of learning difficulties (especially language).
- Higher frequency of attention and behavior problems in some studies.
- Earlier suggestions of a predisposition to aggression or criminality are now considered oversimplified and largely unsupported when socioeconomic and environmental factors are controlled.
Most affected individuals live independent, typical lives and may never know their karyotype.
Structural Abnormalities of Sex Chromosomes
While numerical aberrations (extra or missing whole chromosomes) are most common, structural changes also occur and can lead to sex chromosome syndromes:
- Deletions: Loss of part of the X or Y (e.g. deletion of the short arm of the X can resemble Turner syndrome).
- Isochromosomes: Chromosome with two identical arms instead of one short and one long arm (e.g. isochromosome Xq in Turner variants).
- Ring chromosomes: Ends of a chromosome break and fuse, forming a ring (e.g. ring X), sometimes associated with growth and developmental problems.
- Y microdeletions: Small deletions (especially in AZF regions on the long arm of the Y) that affect genes required for spermatogenesis; often cause male infertility with otherwise normal phenotype.
The clinical outcome depends on which genes are lost or rearranged and whether cells are mosaic.
Patterns of Inheritance and Recurrence Risk
Sex chromosome aneuploidies usually arise as sporadic events due to meiotic nondisjunction. As a result:
- Recurrence risk for parents with normal karyotypes is generally low, but slightly increased compared with the general population.
- Advanced maternal age increases risk for some aneuploidies (including certain sex chromosome aneuploidies), broadly similar to autosomal trisomies.
- Structural rearrangements (e.g. translocations or inversions involving sex chromosomes) can be inherited; in such cases, recurrence risk is higher and depends on the specific rearrangement.
Genetic counseling uses karyotype analysis and family history to estimate individual risks.
Diagnosis and Management
Detection
Sex chromosome aberrations can be detected by:
- Karyotyping (classical chromosome analysis).
- Molecular cytogenetic techniques, such as:
- FISH (fluorescence in situ hybridization).
- Chromosomal microarrays (array‐CGH, SNP arrays).
- Prenatal diagnosis:
- Chorionic villus sampling or amniocentesis when indicated (e.g. maternal age, screening results).
- Non‐invasive prenatal testing (NIPT) from maternal blood can suggest sex chromosome aneuploidies but may need confirmatory testing.
Some individuals are diagnosed postnatally due to growth, developmental, or fertility issues; others through incidental findings.
Treatment and Support
There is no way to “correct” a chromosomal aberration itself; management aims to:
- Support normal development:
- Growth hormone therapy in Turner syndrome to improve adult height.
- Estrogen and progesterone replacement in Turner syndrome to induce and maintain secondary sexual characteristics and bone health.
- Testosterone replacement in Klinefelter syndrome to support secondary sexual characteristics, bone density, and well‐being.
- Address fertility issues:
- Assisted reproductive technologies (e.g. sperm retrieval with ICSI in some Klinefelter patients).
- Counseling regarding options (donor gametes, adoption).
- Target learning and behavioral needs:
- Early interventions for speech, motor, or learning difficulties.
- Psychological and educational support, tailored to the individual.
- Monitor and treat associated medical problems:
- Cardiac, renal, and endocrine evaluations in Turner syndrome.
- Bone density and metabolic monitoring in Klinefelter syndrome.
Ethical and Social Considerations
With increasing use of prenatal and preconception testing, more sex chromosome aberrations are detected in individuals who may have mild or no symptoms. This raises issues such as:
- How to communicate highly variable prognoses without causing unnecessary anxiety.
- Respect for the autonomy and privacy of affected individuals.
- Avoiding stigmatization or discrimination based on karyotype.
Genetic counseling plays a central role in providing balanced information and supporting informed decision‐making by individuals and families.