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Describe the chromosomal abnormalities with their mechanisms and clinical features.

Anatomy · 1st Professional — Pre-Clinical

Definition

Chromosomal abnormalities are alterations in the number (numerical) or structure of chromosomes, and account for a large share of congenital disease and of spontaneous abortion.

Present in about 50% of first-trimester spontaneous abortions and in about 0.6% of live births

Mechanisms

Mechanism	Description	Result
Non-disjunction	Failure of chromosomes to separate at meiosis	Trisomy or monosomy
Anaphase lag	A chromosome fails to reach the pole	Monosomy
Mosaicism	Non-disjunction after fertilisation	Two cell lines; a milder phenotype
Translocation	Exchange of segments between non-homologous chromosomes	Robertsonian translocation causes familial Down syndrome
Deletion	Loss of a segment	Cri-du-chat (5p )
Non-disjunction of sex chromosomes	—	Turner and Klinefelter syndromes

Autosomal Trisomies

Syndrome	Karyotype	Incidence	Features
Down	Trisomy 21 (47,XX or XY, +21)	1 in 700	Mental retardation; flat facies with upslanting palpebral fissures; epicanthic folds; single palmar crease; hypotonia; congenital heart disease (especially atrioventricular septal defect); duodenal atresia; raised risk of leukaemia and of early Alzheimer disease
Edwards	Trisomy 18	1 in 5000	Clenched hand with overlapping fingers; rocker-bottom feet; prominent occiput; micrognathia; most die within a year
PATAU	Trisomy 13	1 in 15,000	Cleft lip and palate; polydactyly; microphthalmia; holoprosencephaly; usually fatal in infancy

95% of Down syndrome is free trisomy 21 from maternal non-disjunction, and the risk rises steeply with maternal age
About 4% is due to a robertsonian translocation, usually 14;21 — this form is familial, independent of maternal age, and carries a high recurrence risk, so parental karyotyping is essential
About 1% is mosaic, with milder features

Sex Chromosome Abnormalities

Syndrome	Karyotype	Features
TURNER	45,X	Female phenotype; short stature; webbed neck; widely spaced nipples; coarctation of the aorta; streak ovaries with primary amenorrhoea and infertility; intelligence usually normal. The only viable monosomy
Klinefelter	47,XXY	Male phenotype; tall with long limbs; small firm testes; gynaecomastia; infertility from tubular hyalinisation; the commonest cause of male hypogonadism
Triple X	47,XXX	Usually normal; mild learning difficulty
XYY	47,XYY	Tall stature; usually normal

Applied Aspects

Antenatal screening — the double marker at 11–13 weeks with nuchal translucency, or the quadruple marker at 15–20 weeks; cell-free fetal DNA is non-invasive with a very high detection rate
In Down syndrome the pattern is low AFP, low oestriol, high hCG and high inhibin A
Screening gives a risk, not a diagnosis; confirmation requires karyotyping of cells from amniocentesis or chorionic villus sampling
Barr body counting was formerly used for sex chromosome disorders; the number is one fewer than the number of X chromosomes
Genetic counselling must be non-directive, and in India must also contend with the legal prohibition on disclosing fetal sex

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