Genetics

Question 1

What is variable expressivity?

Answer 1

when individuals have the same genetic condition (even the same genotype) but have varying degrees of the phentoype

Question 2

What is mosaicism?

Answer 2

the presence of > 2 genetically different sets of cells in the same person caused by an error in mitosis

Question 3

What does a quad screen check for, when is it done, and what genetic abnormalities does it screen for?

Answer 3

• a-fetoprotein, hcg, estriol, inhibin A
• between 15-18 weeks GA
• measures likelihood of Trisomy 18, Trisomy 21, neural tube defects, abdominal wall defects

Question 4

How do you prenatally screen from chromosomal disorders?

Answer 4

cell-free fetal DNA

Question 5

What are ways to diagnose genetic disorders prenatally?

Answer 5

• ultrasound
• amniocentesis
• chorionic villus sampling (placenta)
• umbilical blood sampling

Question 6

What factor is associated with increased risk of having baby w/ Trisomy 21?

Answer 6

increasing maternal age

Question 7

What prenatal quad screen results are expected for Trisomy 21?

Answer 7

• low maternal serum a-fetoprotein
• low unconjugated estriol
• elevated hcg
• elevated inhibin

can also do early U/S screening fort nuchal translucency (neck thickness) to improve sensitivity/specificity of prenatal screening

Question 8

Describe phenotypic presentation of Trisomy 21

Answer 8

• hypotonia
• poor Moro reflex
• intellectual disability
• brachydactyly (short, broad fingers and toes; big space between 1st/2nd toes)
• upslanted palpebral fissures
• flat midface
• full cheeks
• protruding tongue
• epicanthial folds
• single transverse palmar crease
• Brushfield spots (whitish spots in ringlike configuration of iris)
• high-arched palate
• hypoplasia of middle phalanx of 5th finger

Question 9

What medical issues can kids w/ Trisomy 21 have?

Answer 9

• cardiac: AV canal defect, VSD, ASD
• GI: duodenal atresia (double bubble sign), Hirschprung, celiac disease
• ocular: cataracts
• developmental: intellectual disability, early onset alzheimer/dementia
• hypothyroidism
• onc: leukemia (ALL), transient myeloproliferative disorder (typically self-resolves but increases risk of ALL development)
• atlantoaxial (C1-C2) instability

Question 10

Health Supervision Guidelines for Trisomy 21 patients

Answer 10

• all routine immunizations
• echocardiogram in newborn period
• ophthalmologic eval before 6 mo old
• hearing eval as newborn then again at 6 mo old
• thyroid studies at newborn, 6 mo, 12 mo then annually
• vision screening at 4 yo
• only do cervical spine imaging if symptomatic w/ signs of myelopathy

Question 11

What are features of someone with Trisomy 18 (Edwards Syndrome)?

Answer 11

• IUGR
• intellectual disability
• high forehead
• microcephaly
• small face/mouth
• rocker bottom feet
• overlapping fingers
• short sternum
• hypoplastic nails
• structural cardiac defects

Most die in first week or within first year.

Question 12

What are features of someone with Trisomy 13 (Patau Syndrome)?

Answer 12

Midline deficiency

• orofacial cleft (midline cleft lip)
• microphthalmia
• low-set dysplastic ears
• spinal cord abnormalities
• postaxial (aka ulnar) polydactyly of limbs
• holoprosencephaly
• heart malformations
• hypoplastic or absent ribs
• genital anomalies
• abdominal wall defects
• aplasia cutis congenita (absence of layer of skin)
• rocker bottom feet
• clenched hands

Question 13

What are the Sex Chromosome Syndromes?

Answer 13

• 47XXY Klinefelter
• 47 XYY
• 47 XXX
• 45 X Turner

Question 14

What are the clinical features of Turner Syndrome?

Answer 14

45, X

• short stature w/ ovarian failure/gonadal dysgenesis w/ lack of 2/2 sex characteristics
• cardiac anomalies - bicuspid aortic valves, coarcted aorta
• renal anomalies - horseshoe kidney, duplicate collecting system, abnormal vasculature
• hearing loss (can be progressive sensorineural)
• at birth: broad webbed neck, shield-like chest, posteriorly rotated ears, lymphedema of hands/feet, short 4th metacarpals, cubitus valgus
• childhood/adulthood: chronic AI thyroiditis (hashimoto), alopecia, carb intolerance, vitiligo, GI disorders (ex celiac)
• if have some Y material - ⇡ risk for gonadoblastoma (need to be removed)

Question 15

What are the clinical features of Klinefelter Syndrome?

Answer 15

47, XXY

• male phenotype
• tall
• gynecomastia
• delayed 2/2 sex characteristic development
• azoospermia and small testes → infertile

Question 16

What are the clinical features of someone born 47, XYY?

Answer 16

• not a true syndrome
• taller than average
• severe nodular-cystic acne
• commonly have developmental delay and behavioral problems
• prolonged PR interval

Question 17

How are microdeletion syndromes diagnosed?

Answer 17

• too small to detect via karyotype
• fluorescence in situ hybridization (FISH) - looks at specific pre-defined region
• chromosomal microarray (aka comparative genomic hybridization)
• oligonucleotide microarray and SNP array - can find small areas of deletion

Question 18

What are clinical features of Williams Syndrome (7q11.23 deletion)?

Answer 18

• broad forehead, medial eyebrow flare, short upturned nose w/ flattened nasal bridge, elongated philtrum w/ downturned lower lip (elfin facies)
• friendly personality
• stellate pattern of iris
• strabismus
• supravalvular aortic stenosis
• intellectual disability
• hypersensitivity to loud sounds
• hypercalcemia
• connective tissue anomalies (lax joints, soft skin)
• growth delay and short stature
• perioorbital fullness

Question 19

What are the clinical features of WAGR syndrome (11p13 deletion)?

Answer 19

• Wilms tumor - in 50% of cases
• Aniridia - no iris
• GU abnormalities - male genital hypoplasia (hypospadias, cryptorchidism, small penis, and/or hypoplastic scrotum)
• Reduced intellectual abilities - from low IQ to nml
• gonadoblastoma
• long face
• upward-slanting palpebral fissures
• ptosis
• beaked nose
• poorly formed ears

Question 20

What are the clinical features of Alagille Syndrome (20p12 deletion)?

Answer 20

• AD inheritance
• triangular facies w/ pointed chin
• long nose w/ broad midnose
• bile duct paucity w/ cholestasis
• pulm valve stenosis and peripheral valve stenosis
• ocular defects
• skeletal defects (butterfly vertebrae)

Question 21

What are the clinical characteristics of DiGeorge Syndrome (22q11.2)?

Answer 21

CATCH-22

Developm

• Cardiac defects - ToF > interrupted aortic arch > VSD > truncus arteriosus
• Abnormal facies - tubular nose, hooded eyelids, small chin, small ears
• Thymic hypoplasia
• Cleft defects
• Hypocalcemia - due to parathyroid gland agenesis or hypoplasia
• Chromosome 22
• short stature
• behavioral problems