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1

Clinical Implications of Chromosomal Abnormalities

- Problems of early growth and development
- Dysmorphic features/Multiple Congenital Anomalies
- Neonatal Death/IUFD (Intrauterine fetal demise)
- Family history
- Neoplasia
- Reproductive loss
- Pregnancy with advanced maternal age

2

Impact of Chromosomal Abnormality on Human Morbidity/Mortality (THE BIG ONES)

- Congenital Heart Defects: 13%
- IQ 20-49: 12-35%
- Primary Ovarian Deficiency: 65%

3

Reproductive Loss

- >50% of first trimester spontaneous abortions (SAB)
- 60% are trisomies and error likely occur at maternal meiosis I (Tri 13, 14, 15, 16, 21,22)
- Most commonly seen abnormal karyotypes seen are trisomy 16, monosomy X (20%), and trisomy
- Second trimester losses include tri 13,18, 21, 45, X, & sex chromosome polysomies (20-50% frequency)
- Frequency of chromosomal abnormalities in third trimester losses (stillbirths) is about 5%

4

The most common TRISOMY seen in products of conception from a first trimester spontaneous abortion is?

Trisomy 16 (LOOK THIS SHIT UP THOUGH)

5

Advanced maternal age

- Approximately 20-25% of oocytes are chromosomally abnormal
- Maternal age is the most important factor - the structural integrity of the oocyte's meiotic apparatus declines with increasing age
- 90% trisomies arise during maternal meiosis I including trisomy 15, 16, & 21
- Trisomy 18 is an exception - most are due to maternal meiosis 2 errors

6

Recurrent Aneuploid Abortion

- Assumed that recurrence of aneuploidy is due to randomness and maternal age..in the setting of a high background rate of aneuploidy in humans
- However, there is evidence that a predisposition to aneuploidy recurrence may exist
- The risk is low, however, and only approaches 1% by the mid-thirties
- After age 30, risk is equal to age-related risk

7

Triploidy

3n = 69 chromosome count: 69,XXY or 69,XXX
- 17% of spontaneous abortions
- 1-3% of all clinically recognized pregnancies
- 99.99% are lost during first and second trimester
- No difference in spectrum of anomalies

8

Digynic and Diandric Triploidy

- Digynic (Type 1): additional set of chromosomes are maternal (10%); well grown to moderate, symmetrical IUGR, and large, cystic placenta
- Diandric (Type 2): additional set are paternal (24%-60%); more commonly observed in fetal period, assymetric IUGR; small, non-cystic placenta

9

Common anomalies in Triploidy

- ventriculomegaly
- hologproscencephaly
- NTD
- cleft lip/palate
- hypertelorism
- syndactyly of fingers 3&4
- Congenital heart defects
- omphalocele
- micrognathia
- Dandy-Walker malformation
- club feet
- hydronephrosis

10

Triploid/Diploid Mixoploidy

- Triploid line usually reflects digyny and inclusion of 2nd polar body early after conception of a diploid zygote
- Survival promoted by diploid cell line
- Right side smaller
- ONLY EVIDENT ON CULTURED FIBROBLASTS

11

Tetraploidy

- Rarely progresses beyond 4-5 weeks
- Exceedingly rare at term with only 1 report of a non-mosaic survivor
- Mechanism: normal chromosomal division but FAILURE OF CYTOPLASMIC CLEAVAGE AT THE FIRST DIVISION OF THE ZYGOTE
- Mechanism: dispermic fertilization of an ovum when meiosis I has failed
- Mosaic diploidy/tetraploidy has been described

12

Autosomal Aneuploidies: Trisomies

- Live births: 13, 18, 21; very rarely = 8,7,9,14,22; Mosaic: all

Miscarriages: All

13

Autosomal Monosomies

Monosomy: 2n-1
- May be from meiotic nondisjunction resulting in a monosomic gamete or from anaphase lag
- Livebirths -- RARE: 21,22, mosaic (1,18,20,21,22)
- Miscarriages: 13,14,15,16,18,20,21,22

14

Trisomies vs. Monosomies

- Trisomy usually better tolerated than monosomy
- 150% of a given gene may be less deleterious than 50%
- Regulatory mechanisms may prevent gene overexpression but less likely to prevent gene underexpression
- Monosomy may unmask recessive disease-causing alleles

15

Trisomy 21: Down Syndrome

- Characterized in 1866
- 1959: Jerome LeJeune and colleagues discovered a 3rd copy of chromosome 21
- Human Genome Project: 225 genes on chromosome 21 existing in triplicate

16

Trisomy 21

- Additional dose of an en bloc set of genes
- Is there a DS "critical region" such as 21q22.13-q22.2
- Or is "amplified developmental instability" more appropriate an explanation given the complexity of DS traits
- One-to-one gene-phenotype relationship too simplistic?

17

Stats on Trisomy 21

- 1 per 800-1000 live births (most frequent trisomy)
- 95% with extra chromosome 21 - example: 47,XY,+21 karyotype
- 75% Trisomy 21 occurs due to nondisjunction during meiosis I
- 90-95% extra chromosome is maternal in origin

18

Trisomy 21: Translocation

- 3-4% of individuals with DS have a chromosomal translocation
- Robertsonian translocation: extra chromosome 21 is attached to chromosome No. 13,14,15,21, or 22
- 75% arise de novo & 25% are inherited from a parent who is a balanced carrier

19

21q21q Translocation

- 21q21q Translocation: probably originates as ISOCHROMOSOME (not Robertsonian)
- Rare
- All potential progeny will be abnormal
- Either down syndrome or monosomy 21

20

Trisomy 21: Translocation (where at and percentages)

- Unbalanced transmission depends on the chromosome translocation status & parent of origin
- Rob(14q21q) = MOST IMPORTANT: most familial translocation DS is due to this translocation - 10-15% chance if Mom has this; <1% of the time if Dad has this
- Rob(21q-21q): 100% chance of baby with DS if either Mom or Dad have this

21

*How many total chromosomes does a person with DS have when it is due to a Robertsonian translocation between chromosomes 21q and 14q?
*What is the accepted nomenclature for this individual's karyotype?

46 - LOOK UP THESE Q'S

22

Trisomy 21: Mosaic

- 2% of individuals with DS have a mosaic form
- Phenotypic results depend on which tissues are affected and the degree of mosaicism
- However, tissues with 46 chromosomes probably began with 47 and the extra chromosome 21 was lost during development
- Alternatively, a post-zygotic nondisjunction event occurred early in embryonic development
- "unwise" to predict a milder phenotype; usually have same degree of intellectual disability and medical problems

23

Recurrence Risks: Trisomy 21

- Trisomy 21: 1% or age-related risk (whichever is greater), Occult somatic or gonadal mosaicism
- 46,i(21q) recurrence risk is low (if not a carrier)
- t(14; 21): 15% if female carrier, <1% if male carrier

24

Newborn clinical features

- Diagnosis suspected when characteristic hypotonia and facial features are present at birth
- These facial features include flat profile, upslanting palpebral fissures (98%), epicanthal folds, flat nasal bridge, & a short head (brachycephaly)

25

Congenital Abnormalities: Heart

- Cardiovascular: 50% of children with DS have a congenital heart defect
- Atrioventricular septal defects (AVSD) or endocardial cushion defects are the most common (59%)
- Ventricular septal defects (VSD), atrial septal defects (ASD), & Tetralogoy of Fallot are also seen
- All infants with DS require a cardiac evaluation

26

Congenital Abnormalities: GI

- Gastrointestinal malformations occur in 5% of DS children
- Duodenal atresia or stenosis is the most common (50%)
- Imperforate anus, Hirschsprung disease, TE fistula, & pyloric stenosis can also be seen
- Hirschsprung disease is 25 times more likely to occur in DS population than general population

27

Other Congenital Abnormalities

- Congenital cataracts occur in 0.6% of kids with DS & this is an ophthalmologic emergency
- Hearing loss occurs in about 66% of kids with DS
- Congenital hypothyroidism occurs in about 3% of infants with DS
- Polycythemia occurs in 18% of newborns with DS & transient myelodysplasia must be ruled out.

28

Medical Vulnerabilities in kids with DS

- Conductive hearing loss
- Obstructive sleep apnea
- GERD
- Celiac disease
- Atlanto-Axial instability
- Intellectual Disability
- Serous Otits Media
- Refractive Errors
- Constipation
- Obesity
- Neurodevelopment Needs
- Autoimmune Problems

29

Trisomy 18

Edwards Syndrome:
- 1 per 8000 live births
- relationship with maternal age
- 90% of cases are due to meiotic nondisjunction in M2 - rarely caused by chromosomal translocation
- Recurrence risk approx. 1%
- 98% result in miscarriage: by 10 weeks
- 50% Neonates die during first week of life
- only 5-25% survive the 1st year
- Severe MR in survivors
- Causes of death: congenital heart defects, heart failure, pulmonary hypertension, pulmonary failure
- CONGENITAL HEART DEFECTS: >90% of cases (most common VSD)
- GASTROINTESTINAL ANOMALIES: 75% of cases (most common Meckel's Diverticulum or malrotation; 33% have TE-Fistulas)
- GROWTH RETARDATION: prenatal onset with decreased adipose & skeletal muscle
- Overall, increased tone but feeble activity, weak cry, poor suck & apneic episodes

30

Clinical Features: Trisomy 18

- PROMINENT OCCIPUT
- ROCKER-BOTTOM FEET
- CLENCHED HANDS
- Short palpebral fissures
- Micrognathia
- Low-set, malformed ears
- Profound MR
- Short sternum
- Small pelvis
- Renal anomalies
- Cleft lip/palate
- hypoplastic thumbs
- Dorsiflexed halus (hammer toe)