Genetic Diseases

Question 1

Down Syndrome

Answer 1

Trisomy 21
MCC - MR
1. Meiotic nondisjunctions - 95%
2. Robertsonian translocation - 4%
3. Mosaicism - 1%
Risk - advanced maternal age
PE - upslanted eyes, epicanthal folds, simian crease, general hypotonia, atlantoaxial instability
A/W - duodenal atresia, Hirschsprung’s, endocardial cushion (AV canal), ASD/VSD/PDA
Inc Risk - ALL, hypothyroidism, early-onset Alzheimer’s

Question 2

Edward’s Syndrome

Answer 2

Trisomy 18
PE - severe MR, rocker-bottom feet, low-set ears, micrognathia, clenched hands (overlapping 4th/5th digits), prominent occiput
A/W - congenital heart dz, horseshoe kidney
Death - usually w/in 1st yr

Question 3

Patau’s Syndrome

Answer 3

Trisomy 13
PE - Severe MR, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, “punched out” scalp lesions, polydactyly, omphalocele
A/W - congenital heart dz
Death - usually w/in 1st yr

Question 4

Klinefelter’s Syndrome

Answer 4

47, XXY (male)
Barr Body present (inactive X)
Risk - advanced maternal age
MCC - hypogonadism in males
PE - testicular atrophy, tall stature, long extremities, gynecomastia, female hair distribution
Tx - testosterone (prevent gynecomastia, improves 2 sex char)

Question 5

Turner’s Syndrome

Answer 5

45, XO (female)
No Barr Body
NOT a/w advanced maternal age
MCC - Primary amenorrhea (ovarian dysgenesis (dec estrogen)
PE - short stature, shield chest, wide nipples, webbed neck, coarc of aorta (dec femoral pulses), bicuspid aortic valve, horseshoe kidney.
May present w/ lymphedema of the hands/feet in neonate.

Question 6

Double Y Males

Answer 6

47, XYY
Observed with inc freq in penal institutions
Phenotypically normal
PE - tall, severe acne, antisocial behavior

Question 7

Cystic Fibrosis (CF)

Answer 7

AR mutation in CFTR (Cl- channel) on Chromosome 7.
MC severe genetic dz in US
More common in caucasians
Hx- present with FTT, chronic sinopulmonary disease, recurrent pulmonary infections (pseudomonas and S aureus)
PE - cyanosis, digital clubbing, chronic cough, dyspnea, bronchiectasis, hemoptysis, nasal polyposis.
- Meconium ileus (bilious vomiting in the newborn), greasy stools, flatulence, pancreatitis, rectal prolapse
- DM T2, “salty-skin,” male infertility (vas agenesis), unexplained hyponatremia
- AT RISK: fat-soluble vitamin def (A,D,E,K) 2/2 malabsorption
Dx: sweat chloride test >60mEq/L in those 80mEq/L in those >20y), confirm with genetic testing
Labs: hypochloremic acidosis in severe cases
Tx: Pulm: chest PT, bronchodilators, corticosteriods, antibiotics (cover pseudomonas), DNase. GI: pancreatic enzymes and fat-soluble vit (A,D,E,K). High calorie, high protein diet. Lung and/or panc transplants.
LIfe Expectancy: now past 30ys

Question 8

Phenylketonuria (PKU)

Answer 8

AR
Dec in Phenylalanine hydroxylase, or
Dec in tetrahydrobiopterin cofactor
Tyrosine becomes essential and phenylalanine builds up excess phenyl ketones
Presents w/ MR, fair hair and skin, eczema, blonde hair and blue eyes, musty urine odor.
A/W - inc risk of heart dz
Tx: modify diet (eliminate phenylalanine [artificial sweeteners], inc tyrosine.

Question 9

Fragile X Syndrome

Answer 9

XLD, affects the methylation and expression of FMR1 gene. CGG triplet repeat disorder
2MCC - genetic MR
PE - large jaw, large testes, large ears, autistic behaviors.

Question 10

Fabry’s Disease

Answer 10

XLR
Def of alpha-galactosidase A
Accumulation of ceramide trihexoside in heart, brain and kidneys.
1st sign: severe neuropathic limb pain
PE: joint swelling, skin (angiokeratomas and telangiectasias), renal failure, inc risk of stroke/MI

Question 11

Krabbe’s Disease

Answer 11

AR
Absence of galactosylceramide and galactoside (def of galactosylceramidase).
Accumulation of galactocerebroside in the brain
PE: progressive CNS degeneration, optic atrophy, spasticity, death w/in 3 yrs.

Question 12

Gaucher’s Disease

Answer 12

AR
Def of glucocerebrosidase.
Accumulation of glucocerebroside in the brain, liver, spleen, and bone marrow.
Path: “crinkled paper” = Gaucher’s cells, enlarged cytoplasm
PE: anemia, thrombocytopenia
2 forms: Infantile (early, rapid neurologic decline), adult (more common, normal life span, no brain affects)

Question 13

Niemann-Pick Disease

Answer 13

AR
Def of sphingomyelinase
Accumulation of sphingomyelin cholesterol in reticuloendothelial and parenchymal cells
Type A = die by age 3
PE: cherry-red spot and HSM

Question 14

Tay-Sachs Disease

Answer 14

AR
Absence of hexosaminidase
GM2 ganglioside accumulation
Appear nml until 3-6 mo
Then weakness, slowing development, exaggerated startle response
Death by age 3
PE: cherry-red spot, NO HSM
European Jews: carrier rate 1 in 30

Question 15

Metachromatic Leukodystrophy

Answer 15

AR
Def of arylsulfatase
Sulfatide accumulation in brain, kidney, liver, peripheral nerves
Progressive ataxia and dementia 2/2 demyelination

Question 16

Hurler’s Syndrome

Answer 16

AR
Def of alpha-L-iduronidase
PE: corneal clouding, MR, gargoylism

Question 17

Hunter’s Syndrome

Answer 17

XLR
Def of iduronate sulfatase
MIld form of Hurler's syndrome
PE: NO corneal clouding, mild MR
"Hunters need to SEE (no corneal clouding) to aim for the X (XLR)"