Genetics Flashcards
Is osteogenesis imperfecta autosomal dominant or recessive?
Dominant
Another name from osteogenesis imperfecta
Brittle bone disease
What causes OI?
Mostly mutations in genes alpha-1 and alpha-2 chains of type 1 collagen (COLA1 or COLA2)
Typing in OI
Type 1: mild (most common)
Type 2: Most severe (prenatal lethal)
Type III-IX: moderate-severe with characteristics of everything in between
Presentation of OI
Excessive/atypical fractures Blue sclerae Progressive hearing loss (short stature, growing deformities, opalescent teeth, ligament laxity) *clinical diagnosis
How can you detect more severe cases of OI?
Maternal u/s
Possible imaging findings of OI
Fractures at various stages of healing (FHx) Wormian bones (accessory bones in suture lines) Codfish vertebrae (compression fractures, bi-concave) Osteopenia
Labs used in OI
Biochemical testing (structure and quality of type 1 collagen)
Vit D, phosphorus, alk phos elevated with recent fracture
Hypercalcemia common and relates to severity
(sometimes molecular testing)
Meds used for OI
Bisphosphonates-pamidronate (IV infusion every 3 mos: 4 hrs daily for 3 days)
Experimental GH or BMT
What does pamidronate do for OI?
Slows down bone reabsorption (reduce fracture rates and increase bone density)
Risk of hypocalcemia, osteonecrosis of the jaw and nephrotoxicity
Other things to consider in the management of OI
Immobilize acute fractures (shorten duration) Low impact exercise recommended Lifting/pulling/holding precautions Car seat and stroller accommodations Avoid alcohol, smoking and steroid use
Is Marfan syndrome autosomal dominant or recessive?
Dominant
What causes Marfans?
Genetic mutation for connective tissue protein (FBN1 fibrillin)
General presentation of Marfans
Cardiac (aortic root dilation/dissection with aortic rupture risk or mitral valve prolapse)
Predisposed to spontaneous pneumothorax
Myopia (nearsight) or lens subluxation/dislocation
MSK presentation of Marfans
Tall thing (increased arm span/ht ratio) Scoliosis Arachnodactyly (positive hand signs) Pectus deformity Hindfoot valgus Hypermobile joints with laxity (steinberg-thumb one and walker-murdoch sign with fingers around wrist)
How can you detect the defective gene in Marfans?
CVS or amniocentesis (both in utero)
Or DNA testing
What should be done with all routine evals in Marfans?
Echo/ECG
Management of Marfans
Beta blockers
Strenuous activity restrictions
Surgery (enlarge aorta, MVP, scoliosis, chest deformity or eye problems)
What causes Prader-Will syndrome?
Long arm of chromosome 15 due to absence of paternal gene expression
(hypothalamic or pituitary dysfunction-primary central GH deficiency)
What is genetic imprinting?
Expression of the gene depends on the gender of the parent donating the gene (Prader Willi is loss of paternal copy)
Maternal disomy of Prader-Willi syndrome
2 copies of chromosome 15 inherited from mother (none from father)
Less distinct features, higher IQ and milder behavioral probs
More likely to be autistic
Presentation of PWS
Almond shaped eyes Triangular mouth Narrow forehead Short stature Small hands and feet Hypogonadism (food seeking, behavior, intellectual disability, development delay)
Difference between infancy and early childhood in PWS
Infants are profoundly hypotonic (decreased muscle tone, FTT)
Early childhood is hyperphagia and weight gain (binge eating)
How do you diagnose PWS?
Molecular genetic test (methylation analysis)
Management of PWS
Limited
Replace HGH and testosterone estrogen
Healthy diet/exercise
Multidisciplinary
Complications with obesity seen in PWS
Type 2 DM Heart disease/stroke Sleep apnea Joint wear and tear Psychological component
What is the most common inherited intellectual disability?
Fragile X
What is Fragile X classified as?
X-linked recessive
Who do you see Fragile X in more?
Males (due to lyon hypothesis in females-variable expression due to X-inactivation)
What is the developmental delay in fragile x?
Language with first words at 18-20 mos
Motor delay with walking around 18-20 mos
Presentation of Fragile X
Soft smooth skin Macrocephaly (prominent forehead and chin) Large ears and long, narrow face Joint laxity, hypotonia and pes planus Mitral valve prolapse Macro-orchidism after puberty
When do you see mitral valve prolapse?
Fragile X, Marfans
How do you diagnose fragile X?
Genetic screening in males with intellectual disabilities
CGG repeated in FMR1 gene
Management for fragile X
Echo
GERD (med and feeding therapy)
PT, OT, speech etc
What causes DiGeorge syndrome?
22q11.2 deletion syndrome (chromosome 22 deletion)
Is DiGeorge syndrome autosomal dominant or recessive?
Dominant (but most occur randomly)
Classic triad of sxs for DGS
Cardiac abnormalities
Hypoplastic thymus (variable T cell deficits)
Hypocalcemia
Subtypes for DGS
Partial vs complete loss of thymus (based on thymic hypoplasia and immune function)
Presentation of DGS
Cardiac (asymptomatic or more severe with cyanosis, HF, FTT, respiratory distress)
Thymus absent in complete DGS
Immunodeficiency
Underdeveloped parathyroid leading to hypocalcemia
How might a DGS pt present?
Craniofacial abnormalities (low ears, bulbous nose tip, wide eyes)
Palatal defect
GU abnormalities
Recurrent infections and inflammatory disease
How to diagnose DGS
Decreased CD3 T cells and clinical findings (might not have a noticeable deletion)
What to do on the initial eval for DGS
Urgent echo
CBC with diff, Ca and phosphorus
Renal u/s
Thymic shadow (CXR)
DiGeorge pts and live vaccines
Have caution because of immunodeficiency
Management of complete DGS
Life expectancy is less than 1 yr w/o tx
Thymic transplant if possible
Hematopoietic cell transplant
Phenotype for Klinefelter syndrome
47 XXY (maternal or paternal origin) Male
Postpubertal presentation of Klinefelter
Infants and pre-pubertal boys typically asymptomatic
Tall stature, narrow shoulders, long legs, microorchidism, gynecomastia
Mild language delay and learning disabilities
Labs seen in Klinefelters
Testosterone low
FSH/LH elevated in adolescence
Do an infertility eval
Phenotype of Turner syndrome
45 X
Mosaicism when the deletion is a Y and there is a partial deletion and the female has male complications
What can occur due to the loss of an x chromosome in Turner syndrome?
Higher risk for x-linked recessive disorders (hemophilia A/B)
Normal higher risk for males b/c single X
General clinical presentation of Turners
Short stature, webbed neck, shield chest (lymphedema in dorsum of hands and feet for infants)
Average intellect
Cardiac (bicuspid AV, CoA, aortic dissection risk, HTN)
MSK presentation of Turners
Cubitus valgus (wide carrying angle) Short 4th metacarpals Madelung deformity (radius and ulna in V pattern)
GU presentation of Turners
Internal and external female genitalia Streaked gonads (underdeveloped) Premature ovarian failure Primary amenorrhea in adolescent female Horseshoe kidney
Management for Turners
IVF with egg donation but increased risk of aortic dissection in pregnancy
Estrogen and cyclic progesterone therapy to stimulate puberty and assist with bone density
Monitor for gonadoblastoma (remove gonads)
What is trisomy 13 called?
Patau syndrome
Where is the defect in trisomy 13?
Prechordal mesoderm (midline craniofacial, eyes and forebrain)
Presentation of trisomy 13
Midline cleft lip and palate
Holoprosencephaly
Hypotonia (PWS), clinodactyly, polydactyly, vertical talus
CHD
Tx of trisomy 13
Majority die in utero
Affected infants usually die before 1 mo and not many past 6 mos
Surgery can prolong life up to 2 yrs (supportive care)
What is trisomy 18 also known as?
Edwards syndrome
Female
Presentation of trisomy 18
Intrauterine growth restriction with low birth weight, low set ears Hypertonia and spasticity* Overlapping digits/clenched hands Rocker bottom foot defomity Horseshow idney Omphalocele CHD
Tx of trisomy 18
Most die in utero (not many beyond 1 yr)
Severe intellectual disability if survive
Palliative care vs prolong interventions to prolong life
Most common chromosomal abnormality
Trisomy 21
How does a down syndrome pt look?
Flat nasal bridge Folded low set ears Brushfield spots on iris Protruding furrowed tongue Short neck with excessive skin etc
Cardio defects in trisomy 21
AVSD and VSD are common
MSK presentation in trisomy 21
Hypotonia
Transverse palmar crease (Simian)
Joint laxity
When does ACOG recommend all women should be offered aneuploidy screening?
20 wks gestation
