chromosome abnormalities

Chromosome AbnormalitiesAbnormalities of chromosome number

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Polyploidy

• Euploid (eu: good, ploid: set)

• Triploidy (15% of the chromosome abnormalities occurring at

Conception: Triploidy is seen in about 1 in 10,000 live births, but it accounts)-

one of the most common causes of fetal loss in the first two trimesters of

pregnancy dispermy

Fusion of an ovum and a polar body- Meiotic failure, diploid sperm/egg cell

• Tetraploidy: much rarer than triploidy, both at conception and among live

births.

• Defect in the heart and nervous system

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Autosomal Aneuploidy

• Aneuploidy (not good set): missing or additional chromosomes; spontaneously

aborted- mental retardation in survival case. The most common cause is

nondisjunction (during meiosis I and II)

• Childeren with the wrong number of chromosomes have trisomy rather than

monosomy (more severe that affected embryo)

• The body can tolerate excess genetic material more readily than it can

tolerate a deficit of genetic material.

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Trisomy 21

• Down syndrome; mongolism (inapproprate term), 95% caused by nondisjunction (90-95%

occur in the mother-75% in meiosis I and remainder in meiosis II) and most of the remainder

caused by chromosome translocations

• Mosaicism: in 2-4% of trisomy 21; 47,XY,+21[10]/46,XY[10] (timing and manner dependent;

tissue specific mosaics; karyotyping difficulties)

The most common cause of mosaicism in trisomy is a trisomic conception followed by loss of the extra chromosome during mitosis in some embryonic cells

• The occiput is flat, and the hands and feet tend to be rather broad and short.

• Approximately 50% of persons with Down syndrome have a single flexion crease

across their palms (single palmar crease, formerly termed a “simian crease,” though

this term is also now considered inappropriate)

• More than 90% of children with Down syndrome will survive to age 5 years, and the

majority survive past 50 years of age. 8

• Moderate to mild intellectual disability (standardized IQ ranging from 40 to 60) occurs

in most persons with Down syndrome, and this condition alone accounts for

approximately 10% of all cases of intellectual disability in the United States.

• Congenital heart defects are the most important single cause of early mortality.

• Over 97% of children without serious structural heart defects will reach their fifth

birthday, as will 92% with heart disease, due to advances in surgery and early

treatment.

• Males with Down syndrome are nearly always sterile, with only a few reported cases

of reproduction. Many females with Down syndrome can reproduce, although

approximately 40% fail to ovulate.

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A female with Down syndrome has a 50% risk of producing a gamete with two copies

of chromosome 21 (which would then produce a trisomic zygote).

However, because about 75% of trisomy 21 conceptions are spontaneously aborted,

the risk of producing affected live-born offspring is considerably lower than 50% in

women with Down syndrome.

Because reproduction is uncommon, nearly all cases of trisomy 21 can be regarded

as new mutations.

10

A, An infant with Down syndrome, illustrating typical features of this disorder: upslanting palpebral fissures, redundant skin of theinner eyelid (epicanthic fold), protruding tongue, and low nasal bridge.B, Same girl as in A, 7 years later. Note that the typical features are present but less obviously expressed. C, A karyogram of a male with trisomy 21.

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Gene associated with Down syndrome

• Using complete DNA sequence for chromosome 21

• DYRK, a kinase gene located on 21q (over expression in mouse: learning and memory defect

• APP: encodes the amyloid β precursor protein, a third copy of this gene causes Alzheimer-like

features in nearly all 40 years down syndrome (mutation of APP ; small percentage occur).

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Trisomy 18 (47, XY,+18)

• Edwards syndrome: second most common autosomal trisomy, less than 5% survive to term,

with a prevalence of about 1 per 6000 live births, it is much more common at conception and

is the most common chromosome abnormality among stillborns with congenital

malformations.

• Prenatal growth deficiency (weight less than gestational age), characteristic facial features,

Minor anomalies of diagnostic importance include small ears with unraveled helices, a small

mouth that is often hard to open, a short sternum, and short halluces (first toes), Congenital

heart defects, particularly VSDs with dysplasia of multiple heart valves, are the most

common and occur in 90% of children

• About 50% of infants with trisomy 18 die within the first few weeks of life, and about

12% survive to 12 months of age.

• Mortality figures from population studies performed in the last three decades showed

only 5% to 8% survival in the first year18

• More than 95% of patients with Edwards syndrome have complete trisomy 18; only a

small percentage have partial 18q trisomy or mosaicism.

• As in trisomy 21, there is a significant maternal age effect, and more than 95% of

trisomy 18 cases are the result of an extra chromosome transmitted by the mother.

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A girl with full trisomy 18 at 3 years (A) and 13 years (B) of age. She shows the typical facial features of an older child with short palpebral fissures and ear variations. A also depicts the overriding of the index finger onto the third finger, a characteristic finding of the hands in the syndrome.

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Trisomy 13 (47,XY,+13)

• Patau syndrome, 1 of every 10,000 births, survival rate is the same as trisomy 18, 95% of

live-born infants dying during the first year of life,

oral-facial clefts, microphthalmia, postaxial polydactyly, frequently: central nervous system

defects, Cutis aplasia (a defect of the skin of the scalp on the posterior occiput) can also occur

and be helpful as a diagnostic clue. Heart defects (80%) and renal abnormalities

• As in trisomy 18, survival are often able to communicate with their family, risk advanced with

maternal age

• About 90% of patients with Patau syndrome have full trisomy 13

• Most of the remaining patients have trisomy of the long arm of chromosome 13 due to a

translocation

• 95% or more of trisomy 13 conceptions are spontaneously lost during pregnancy23

An 8-year-old girl with full trisomy 13 showing her small eyes and prominent, wide nose.

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Sex chromosome aneuploidy

• Monosomy of the X chromosome (Turner syndrome)

• Klienfelter syndrome (47, XXY)

• Trisomy X

• 47, XYY syndrome

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Turner syndrome (45,X)

• Female, proportinate short stature (Mature height is reduced by approximately 20 cm, on

average), sexual infantilism and ovarian dysgenesis (most women with this condition are

infertile: about 5%–10% have sufficient ovarian development to undergo menarche,

and a small number have borne children), a pattern of major and minor malformations

• Triangale-shaped face: posterioly rotated external ears, and a board; webbed neck

• congenital heart defects, most commonly obstructive lesions of the left side of the heart

(bicuspid aortic valve in 50% of patients and coarctation [narrowing] of the aorta in 15%–30%)

• About 50% of persons with Turner syndrome have structural kidney defects

• Lymphedema of the hands and feet at birth, later diagnosed by short stature and/or

amenorrhea

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Cont…

• 50% have a 45,X karyotype in peripheral lymphocytes,

I. 30-40% mosaics (most commonly 45,X/46,XX and less commonly 45,X/46,XY), Patients with

mosaicism who have Y chromosomes in some cells are predisposed to neoplasms

(gonadoblastomas) in the gonadal streak tissue

II.10-20% deletion of some or all of Xp,

• 60-80% caused by absence of a paternally derived sex chromosome, occurring in early mitosis

in the embryo or during meiosis in the father,

• The 45,X karyotype is estimated to occur in 1% to 2% of conceptions, but Turner syndrome is

seen in only about 1/2000 to 1/3000 live-born girls.

• The great majority (more than 99%) of 45,X conceptions are lost prenatally

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Gene associated with Turner syndrome

• Mutation SHOX gene, encodes a transcription factor expressed in embryonic limb (short

stature), located on short arms of X and Y chromosome (in pseudoautosomal region)

• Children who received X chromosome from their father have higher verbal IQ scores and

better social cognition than those who receive it from their mother

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Klinefelter syndrome

• 47,XXY karyotype,

common cause of hypogonadism in the male,

taller than average, long arms and legs,

post pubertal patients reveals small testes,

atrophy of the seminiferous tubules so sterile,

testosterone levels in adolescents and adults are low,

gynecomastia in 1/3 affected males and leads to breast cancer,

hair sparse in postpubertal males,

muscle mass reduced, learning disabilities,

reduction in verbal IQ, usually are not mental retardation41

Cont…

• 50% X chromosome derived maternally

• ½ spontaneously aborted

• <15% mosaicism

• 48,XXXY and 49,XXXXY karyotypes have reported

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Trisomy X

• 47,XXX karyotype,

sometimes sterile,

menstrual irregularity,

90% result from nondisjunction in the mother

47

Jacobs syndrome

• 47,XYY karyotype,

1/1000 in male,

96% apparently normal, 10- to 15-point reduction in average IQ

great height,

acne,

perhaps speech and reading problem, hyperactivity, attention deficit disorder

Speech delay common, 50% learning disabilities

Large teeth

Prominent glabella, asymmetry, long ears

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References

1. Emerys Elements Of Medical Genetics 15th Edition 2017

by Peter D Turnpenny

2. Medical Genetics E-Book 6th Edition 2019

by Lynn B. Jorde, John C. Carey, Michael J. Bamshad

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chromosome abnormalities

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