Cytogenic Disorders

Question 1

Mosaicism

Answer 1

A term used to describe the presence of two or more populations of cells with different complements of chromosomes in the same individuals

Usually affects sex chromosomes and NOT autosomal chromosomes

Question 2

What is the most common isochromsome in live births?

Answer 2

Involving the long arm of the X-chromosome i(Xq)

- this results in monosomy in genes for Xp chromosome and trisomy for genes on Xq chromosome

Question 3

Trisomy 21 (downs)

Answer 3

Trisomy of chromosome 21
- IS THE MOST COMMON CHROMOSOMAL DISORDER**

most common cause = mitotic nondisjunction

Maternal age has the strongest influence on Down syndrome

• younger than 20 = 1:1550 births
• older than 45 = 1:25 births
• *this also suggests that the nondisjunction takes place in the ovum rather than the sperm**

Features

• flat facial profile w/ oblique palpebrae tissues and epicanthic folds
• • leading cause of severe intellectual disability
• palmar crease
• brushfield spots on iris (gray-white spots)
• strabismus
• short neck with excess skin at nape of neck
• clinodactyly of 5th digit (Varus deformity)
• atlantoaxial instability
• congenital heart defects (most common = endocardial cushion defects)

patients have 10-20x increased risk for acute leukemia (ALL or AML)

all Down syndrome patients develop Alzheimer’s disease in some magnitude by age 40

Question 4

22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome)

Answer 4

Small deletion of band 11 on the long arm of chromosome 22
- this primarily results in a defective development of the 3rd and 4th pharyngeal pouches due to deficient TBX1 transcription factor

DiGeorge = severe hypocalcemia and immune deficient

Velocardiofacial = mild immune deficient with prominent facial and cardiac abnormalities

Symptoms

• thymus hypoplasia/aplasia (results in severe immunodeficiency especially to virus and fungal pathogens)
• parathyroid hypoplasia (risk of hypocalcemia chronically w/ tetany)
• commonly shows tetralogy of Fallot or VSDs and ASDs
• always shows cleft palate
• *both syndromes are at increased risk for schizophrenia and bipolar disorder**
• as high as 25% in adulthood

MUST use FISH to diagnosis

Question 5

The Lyon hypothesis

Answer 5

States that only ONE X chromosome is genetically active in females (the other is inactivated in fetal life and this occurs in all somatic cells in females)

This results in mosaicism for X-linked genes in females (since the X chromsome is randomly inactivated in each cell, so not all are the same)
- **this also explains why X-linked disorders in women present a more variable phenotype compared to males with an X-linked disease

• *the X-inactivation occurs via the XIST gene function**
• if XIST is activated in a a chromsome = coats/masks an X chromosome and silenced it

Question 6

Klinefelter syndrome (47-XXY)

Answer 6

Male hypogonadism caused by an extra X chromosome
- caused by nondisjunction during meiosis

Is the most common cause of hypogonadism is males

• *Increased risk for advanced maternal age and a history of irradiation in either parent**
• breast cancer risk is increased 20x
• *almost always shows Marfan habitus on top of hypogonadism and infertility**
• often shows gynecomastia also with reduced or no pubic hair

While intellectual impairment isnt always seen, the more X chromosomes present directly correlations with intellectual disability

Question 7

Turner syndrome (45, XO)

Answer 7

Results in a partial monosomy of the X chromosome in phenotypic females

• caused by meiotic nondisjunction in paternal gametes (NO BARR BODY)
• results 1:2500 live-born females
• the absence of one X-chromosome results in an accelerated loss of oocytes (with complete by age 2 years) “menopause before menarche”

If showing a deletion = deletion of short arm of X chromosome (46,X,i(X)(q10) is the most common

Short stature is caused by loss of one SHOX gene at Xp22.33

• this gene is responsible for normal height so loss of 1 copy results in short stature
• this is found on the X chromsome short arm and the Y chromsome short arm in males (so males have 2 copies despite having only 1 X chromsome)

Symptoms:

• growth retardation
• leading abnormally short stature
• shield like chest
• high arched palate
• lymphedema of the hands/feet
• horseshoe kidney
• bicuspid aortic valve
• short stature
• high-arched palate
• 50% = hypothyroidism
• coarctation of the aorta

Adolescence affected girls dont develop normal secondary sex characteristics
- pubic hair is little

Shows primary amenorrhea with streak fibrous white stroma devoid of follicles in the ovaries