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Chromosomes Exam 2 > 10/10 - Chromosomal Abnormalities and the Implications of > Flashcards

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
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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%
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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%
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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)

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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
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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
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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
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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
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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
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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
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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
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12
Q

Autosomal Aneuploidies: Trisomies

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

Miscarriages: All

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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
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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
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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
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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?
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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
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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

Chromosomes Exam 2 (11 decks)

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