Common Aneuploidies, Microdeletions, and Duplication Syndromes Flashcards
(34 cards)
Which aneuploidies have a 100% rate of spontaneous abortions?
Trisomy 16
Triploid or Tetraploid
Other trisomies that are not T13,18, or 21 have a 99.5% rate
Phenotypic features of trisomy 21
FACE: epicanthal folds, upslanting palpebral fissues, Brushfield spots, flat nasal bridge, small mouth, small ears, protruding tongue
HEAD/NECK: flat facial profile, flat occiput, excessive skin on nap of neck, short neck
EXTREMITIES: single transverse palmar crease, clinodactyly, short broad hands, sandal gap toes
short stature
hypotonia
Trisomy 21:
- Incidence
- Life expectancy
- chromosomes
INCIDENCE: 1/850
- 20-25% of T21 conceptuses survive to birth
- risk increases with maternal age
LIFE EXPECTANCY: 55 yrs old
- most common cause of early mortality is congenital heart disease
CHROMOSOMES
- 95% have T21 (recurrence risk is 1%)
- 4% have Robertsonian translocation (recurrence risk is 10%)
- ~2% are mosaic –> maybe milder phenotype
Trisomy 18:
- Incidence
- Life expectancy
- Chromosomes
INCIDENCE: 1:6,000-8,000 (live births) - risk increases with maternal age - 3:1 female-to-male ratio LIFE EXPECTANCY: - 50% die within the first 2 weeks of life - 5-10% survive the first year of life - Major causes of death: central apnea, cardiac failure (due to malformations), respiratory insufficiency (due to hypoventilation, aspiration, or upper airway obstruction CHROMOSOMES: -T18 - translocation including chr 18 - mosaicism
Phenotypic feature of Trisomy 18
FACE: micrognathia, pointy low set ears HEAD/NECK: prominent occiput EXTREMITIES: clenched fist with overlapping fingers CARDIOVASCULAR: (affects 50%); VSD, PDA GASTRIONTESTINAL: (affects 75%); Meckel diverticulum, malrotation OTHER: - short sternum - hypertonia - IUGR - Feeding difficulties - severe intellectual disability
Trisomy 13:
- incidence
- life expectaqncy
- chromosomes
INCIDENCE: 1:12,000-20,000 LIFE EXPECTANCY: - 50% die within first month - >90% die within first year CHROMOSOMES: - T13 - Unbalanced Robertsonian Translocation - Mosaicism
Phenotypic features of Trisomy 13
FACE: sloping forehead, cleft lip/palate, micro/anophthalmia, colobomata
HEAD/NECK: microcephaly
EXTREMITIES: postaxial polydactyly, rocker-bottom feet
CARDIOVASCULAR: (affects 80%); VSD, ASD, PDA, dextrocardia
CNS: holoprosencephaly
OTHER:
- severe intellectual disability
Sex chromosome aneuploidies
- incidence
- indications for testing
- why is phenotypic expression of sex chromosome abnormalities generally less severe than those of autosomal disorders?
incidence: 1/400 live births
- most common are trisomies, less frequent are monosomies
indications for testing:
- delay in onset of puberty, primary or secondary amenorrhea, infertility, ambiguous genitalia
phenotypic expression of sex chromosome abnormalities is generally less severe than those associated with autosomal disorders because of:
- X-chromosome inactivation
- low gene content on Y chromosome
Klinefelter Syndrome
- incidence
- chromosomes
- causes
INCIDENCE: 1:600 live male births
- underdiagnosed: only 25-50% diagnosed
- mean age of diagnosis: 30 years old
CHROMOSOMES:
- 47,XXY (1:600)
- 48, XXXY (1:25,000)
- 15% are mosaic
CAUSES:
- half of cases result from nondisjunction in paternal meiosis I, other half from nondisjunction in maternal meiosis I
Symptoms of Klinefelter syndrome
- physical
- cognitive
- fertility
PHYSICAL:
- gynecomastia
- narrow shoulder
- long legs
- small testes
- Underdeveloped secondary sexual characteristics
COGNITION:
- low-normal verbal IQ
- learning difficulties
- behavior: poor social adjustments
FERTILITY:
- infertility due to progressive destruction of seminiferous tubules and Leydig cells –> decreased sperm and testosterone production
- hypogonadism
- azoospermia in 10%
- puberty at normal age
- androgen deficiency –> loss of libido, decreased bone deficiency
47, XYY
- incidence
- management
INCIDENCE: 1:1000 live male births
- underdiagnosed
MANAGEMENT: neurodevelopmental evaluation and special education
Trisomy X
- incidence
- phenotype
- cognition and behavior
- fertility
- management
INCIDENCE: 1:1000 live female births
- most common sex chromosome abnormality in females
- usually diagnosed incidentally on prenatal screening, but most never diagnosed
PHENOTYPE: taller than average, hypotonia
COGNITION:
- delayed milestones
- language and learning difficulties
- verbal and performance IQ decreased
BEHAVIOR: may have reduced social skills
FERTILITY: may have premature ovarian failure
- not at increased risk of having chromosomally abnormal offspring
MANAGEMENT: monitor for developmental delays
Turner Syndrome
- Incidence
- Chromosomes
- Management
INCIDENCE: 1:2500-4000 live female births
CHROMOSOMES:
- 45, X –> 45% of cases; usually derived from mother
- mosaic (45,X/46,XX) –> 50% of cases
- X-chrom abnormalities –> ring chrom or isochromosome or p/q deletion
MANAGEMENT: monitor for developmental delays
Symptoms of Turner Syndrome
- phenotype
PHENOTYPE:
- short stature
- webbed neck
- low set, posteriorly rotated ears
- low posterior hairline
- Broad chest and wide spaced nipples
- lymphedema in newborns
- Cubitus valgus
Features of Turner syndrome
- cardiac
- renal
Recurrent otis media in 50-70% of patients Increased risk of autoimmune disorders CARDIAC - up to 50% of patients - coarctation of aorta - bicuspid aortic valve RENAL - 20-30% of patients - horseshoe kidney
Turner syndrome management
Cardiovascular evaluation
- MRI to monitor for aortic dilation at least every 5 years
- aggressive BP control
Growth hormome therapy
estrogen replacement therapy, starting at puberty
What is the mechanism for deletion or duplication products in Microdeletion and Duplication syndromes?
unequal crossing over between misaligned sistids or homologous chromosomes containing highly homologous copies of segmentally duplicated sequences
- -> results either in haploinsufficiency or overexpression of 1+ genes
- occurs mostly in pericentromeric and subtelomeric regions
22q11. 2 deletion syndrome
- what is it?
- cause
- incidence
WHAT IS DIGEORGE SYNDROME? defective development of the pharyngeal pouch syndrome - thymus, thyroid, parathyroids - maxilla, mandible - Aortic arch, cardiac outflow tract - external/middle ear
CAUSED BY: heterozygous del of 3 Mb (includes TBX1)
INCIDENCE: 1:4000 births
- most prevalant microdeletion syndrome
- underdiagnosed (phenotype can be mild)
- 90% of cases are de Novo
22q11. 2 syndrome features
- phenotype
- cardiovascular
- “other”
PHENOTYPE:
- low set, posteriorly rotated ears
- hypertelorism
- bulbous nasal lip
- palate abnormalities
CARDIO:
-80% of patients have congenital heart disease, including interrupted aortic arch, truncus arteriosus, ToF, ASD, VSD
OTHER:
- developmental delay
- T-cell deficits
Williams syndrome
- incidence
- cause
incidence: 1:7500
cause: heterozygous del of 1.5 to 1.8 Mb at 7q11.23 (includes elastin gene)
Williams syndrome features
PHENOTYPE: - broad forehead, periorbital fullness, hypertelorism, stellate pattern of iris, long philtrum, thick vermillon border of lips, wide mouth, small jaw Mild to moderate intellectual disability Renal artery stenosis constipation failure to thrive SN or conductive hearing loss
Prader Willi syndrome
- causes
- incidence
most common cause of obesity CAUSES - 15q11.2-q13 del: 70% (pat) - uniparental disomy: 20-30% (mat) -Imprinting center mutation - 2.5% - gene mutations - rare - unknown: <1%
INCIDENCE: 1:10,000
PWS phenotype
FACE: narrow, bifrontal diameter, almond-shaped eyes, narrow nasal bridge, thin upper lip, small hands and feet neonatal hypotonia, poor suck Hyperphagia Obesity and concern of diabetes small hands and feet Short stature hypogonadism ID
Angelman syndrome
- causes
- incidence
CAUSES:
- 15q11.2-q13 del: 70% (mat)
- uniparental disomy: 7% (pat)
- Imprinting center mutation - 3%
- gene mutations - 10% (UBE3A mut)
- unknown: 10%
INCIDENCE: 1:12,000
