10/10 - Chromosomal Abnormalities and the Implications of Flashcards
1
Q
Clinical Implications of Chromosomal Abnormalities
A
- 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
Q
Impact of Chromosomal Abnormality on Human Morbidity/Mortality (THE BIG ONES)
A
- Congenital Heart Defects: 13%
- IQ 20-49: 12-35%
- Primary Ovarian Deficiency: 65%
3
Q
Reproductive Loss
A
- > 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
Q
The most common TRISOMY seen in products of conception from a first trimester spontaneous abortion is?
A
Trisomy 16 (LOOK THIS SHIT UP THOUGH)
5
Q
Advanced maternal age
A
- 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
Q
Recurrent Aneuploid Abortion
A
- 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
Q
Triploidy
A
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
Q
Digynic and Diandric Triploidy
A
- 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
Q
Common anomalies in Triploidy
A
- ventriculomegaly
- hologproscencephaly
- NTD
- cleft lip/palate
- hypertelorism
- syndactyly of fingers 3&4
- Congenital heart defects
- omphalocele
- micrognathia
- Dandy-Walker malformation
- club feet
- hydronephrosis
10
Q
Triploid/Diploid Mixoploidy
A
- 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
Q
Tetraploidy
A
- 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
Q
Autosomal Aneuploidies: Trisomies
A
- Live births: 13, 18, 21; very rarely = 8,7,9,14,22; Mosaic: all
Miscarriages: All
13
Q
Autosomal Monosomies
A
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
Q
Trisomies vs. Monosomies
A
- 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
Q
Trisomy 21: Down Syndrome
A
- 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
Q
Trisomy 21
A
- 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
Q
Stats on Trisomy 21
A
- 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
Q
Trisomy 21: Translocation
A
- 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
Q
21q21q Translocation
A
- 21q21q Translocation: probably originates as ISOCHROMOSOME (not Robertsonian)
- Rare
- All potential progeny will be abnormal
- Either down syndrome or monosomy 21
20
Q
Trisomy 21: Translocation (where at and percentages)
A
- 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
Q
- 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?
A
46 - LOOK UP THESE Q’S
22
Q
Trisomy 21: Mosaic
A
- 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
Q
Recurrence Risks: Trisomy 21
A
- 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
Q
Newborn clinical features
A
- 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
Q
Congenital Abnormalities: Heart
A
- 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
Q
Congenital Abnormalities: GI
A
- 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
Q
Other Congenital Abnormalities
A
- 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
Q
Medical Vulnerabilities in kids with DS
A
- 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
Q
Trisomy 18
A
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
Q
Clinical Features: Trisomy 18
A
- 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)
31
Q
*In trisomy 18, during which stage of meiosis does the nondisjunction event almost always occur (I or II)
A
I (LOOK UP)
32
Q
Trisomy 13
A
Patau Syndrome:
- Extra copy of chromosome 13
- 1 per 15,000-20,000 livebirths
- High mortality (90% in first year, but survival into adulthood reported)
- Usually associated with maternal nondisjunction
- If familial 13q14q - recurrence risk is increased 1-2%
- Less than 20% due to rob translocation
- Balanced translocation between chromosomes 13 & 14 is relatively common (1/1000 live birth)
- However, low risk of having live birth w/ unbalanced karyotype because high rate of early embryonic death (99%)
33
Q
Mosaicism for Trisomy 13
A
- Mosaicism for Trisomy 13 occurs (47, +13/46)
- Less severe clinical phenotype
- Wide variation: from full phenotype to near normal
- Degree of MR is variable
- Survival is variable
34
Q
Survival in Trisomy 13
A
- Mean survival for infants in 2.5 days
- > 80% die within first month
- Only 5% survive the first 6 months
- Severe mental retardation in survivors (IQ<20)
35
Q
Clinical Characteristics in Trisomy 13
A
- Honoprosencephaly: two halves of brain fail to separate
- Microcephaly
- Microphthalmia
- Colobomas (fissure) or the iris
- Deafness
- Scalp defects
- Capillary Hemagioma
- Cleft lip and palate (>50%)
- CARDIAC ABNORMALITY ABOUT 80% (VSD, PDA, DEXTROCARDI)
- Genital abnormalities
- POLYDACTYLY
- Omphalocele
- POLYCYSTIC KIDNEYS: or other renal anomalies
- Seizures
- Hematologic abnormalities
36
Q
Holoprosencephaly
A
- Defects of midface, eye, & forebrain
- Consequence of single defect in early development of prechordal mesoderm
- Not only necessary for development of face but also exerts an inductive role on the developing brain
- Varies in severity
37
Q
Trisomy 8 Mosaicism
A
- CHECK FIBROBLAST CULTURE IF NO EVIDENCE ON LYMPHOCYTES
- 1/25,000 - 100 cases reported
- Most common non-13,18,21 trisomy mosaic
- Complete Trisomy 8 is lethal
- M3:F1
- Life expectancy normal if no severe CHD
- Recognizable phenotype
- LONG NARROW FACE WITH POUTING LOWER LIP
- DEEP CREASES IN PALMS AND SOLES
- Mild to severe MR
- Micrognathia
- Ear malformations
- Skeletal & Vertebral anomalies
- Occasional heart, renal, and genital malformations
38
Q
Trisomy 16 Mosaicism
A
- Trisomy 16: uniformly lethal-most frequent chromosomal cause of spontaneous abortion (8-15 weeks)
- One stillborn fetus with non-mosaic T16 described
- T16 mosaicism - excess female karyotypes
- T16 mosaicism on CVS or amnio; risk of IUGR, malformations (hypospadias, cardiac septal defects), maternal preeclampsia, IUFD or neonatal death
- Most continue to term with trisomic line generally absent from most fetal tissues even if 100% trisomy diagnosed on CVS or high levels in AF
39
Q
Uniparental Disomy (UPD) 16
A
- Inheritance of a pair of chromosomes from only 1 parent
- Maternal UPD 16 is one of the most frequently reported instances of UPD
- Almost all cases associated with confined placental mosaicism
- If chromosome loss occurs randomly during trisomy rescue ~1/3 should have UPD (16)
- One study of 83 cases to 33 with UPD 16 (~40%)
40
Q
Maternal UPD 16
A
- May be phenotypically normal; normal growth and development
- Inguinal hernia repair
- Growth retardation
- RARELY, malformations and/or mental retardation
- Oldest patient reported 4 years: long-term outcome not documented
41
Q
Malformations among UPD (16)mat Cases
A
- VSD
- ASD
- Pulmonary hypoplasia, clinodactyly
- Talipes, imperforate anus, hypospadias
- Inguinal hernia hypospadias
- Tracheo-esophageal fistula and lots of others
42
Q
Paternal UPD 16
A
1 case:
- IUGR
- Bilateral pes calcaneus
- Rudimentary mandibular arch
- 13 months: development normal
Another case:
- Hydrops due to homozygosity (2 copies) for paternal alpha-thalassemia 1
43
Q
Autosomal deletions
A
Cytogenetically detectable autosomal deletions are present in about 1 in 7000 live births
