Genetics Flashcards
Osteogenesis Imperfecta (OI) aka
“brittle bone disease”
Etiology of OI
Auto dominant
COLA1 and COL1A2 gene mutations (type 1 collagen genes)
Auto recessive subtypes
Types of OI
I: Mild (most common)
II: most severe (prenatal lethal)
III-IX: mod-severe
Clinical presentation of OI
excessive/atypical fractures short stature bowlegs/leg deformities scoliosis/kyphosis (breathing difficulty) Basilar skull deformity (spinal cord concerns) BLUE SCLERAE HEARING LOSS (progressivve) OPALESCENT TEETH ligament and skin laxity
Imaging for OI
maternal U/S detects severe cases
Possible findings:
- fractures @ various stages of healing (may be mistaken for child abuse)
- WORMIAN BONES (suture bones), codfish vertebrae (compression fractures: bi-concave osteopenia)
What is important to consider in OI imaging
minimize radiation if possible
Wormian bones
suture bones in skull in OI
Codfish vertebrae
compression fracture in spine from OI that are bi-concave osteopenia
Dx of OI
clinical
Lab:
- BIOCHEMICAL TESTING (eval structure and quality of type 1 collagen)
- molecular testing may be beneficial
Labs in biochemical testing in OI
Vitamin D, phosphorous, ALP (N or elevated)
HYPERCALCEMIA: common and relates to severity
Meds for OI
Bisphosphonates-Pamidronate (IV infusion every 3 months)
Experimental: GH & BMT
What does bisphosphonates-pamidronate do?
slow bone reabsorption – reducing fracture rates and increase bone density
Risk of Bisphosphonate-pamidronate
hypocalcemia
osteonecrosis of the jaw
Nephrotoxicity
Other management for OI
immobilization (short duration) – surgery for some fracture, deformities, scoliosis
low impact exercise (swimming)
parent education: lifting, pulling, holding precautions
car seat/stroller accomodations, +/- wheelchair
Avoid alc, smoking and steroid use
Marfan Syndrome etiology
Auto dominant
FBNI (fibrillin mutation) – connective tissue protein
Clinical presentation of marfan syndrome
Cardiac: aortic root dilation/dissection
- AORTIC RUPTURE RISK
- mitral valve prolapse
Pulmonary:
- predisposed to spontaneous pneumothorax
Ophthalmologic:
- myopia (nearsitedness)
- lens subluxation/dislocation (ectopia lentis)
Musculoskeletal:
- tall, thin
- increased arm span/Ht ratio
- scoliosis
- arachnodactyly (+ hand signs)
- pectus deformity
- hindfoot valgus
- hypermobile joints w/ laxity
(+) Hand signs for marfan syndrome
Steinberg
walker-murdock
Steinberg sign
fold thumb into closed fist
(+) if thumb extends from palm of hand
Walker-Murdoch sign
grip wrist w/ opposite hand.
(+) if thumb and fifth finger of hand overlap w/ each other
Diagnosis of marfan
CVS (chorionic villi sampling) or amniocentesis - may detect defective gene
Eye Exam - slit lamp
Radiograph: CXR, Skeletal abnormalities
MRI/CT prn
Consults for marfan
cardiology, ortho, ophthalmology
Meds for marfan
beta-block – control rate and pressures (aortic concerns)
Other management of marfan
strenuous activity restrictions
Possible surgery: enlarging aorta, MVP if needed, progressive scoliosis, chest deformity, various eye problems
Prader-Willi Syndrome Etiology
Long arm of Chromosome 15 – absence of PATERNAL genes expression (GENETIC IMPRINTING-UNIPARENTAL DISOMY)
Hypothalamic or pituitary dysfunction – primary central growth hormone deficiency
Genetic imprinting
expression of gene depends on gender of parent donating this gene
In PWS: loss of paternal copy
Angelman syndrome: loss of maternal copy
Types of PWS
- Paternal deletion (most cases) – 15q11-q13
2. Maternal disomy: two copies of chromo 15 from mother (none from father)
Maternal disomy
less distinct features than paternal deletion, higher IQ, milder behavioral problems
more likely to have autistic behaviors
Clinical presentation of PWS
almond eyes triagnular mouth narrow forehead short stature small hands/feet DEPIGMENTATION: skin and eyes HYPOGONADISM: typically sterile, inc. risk for osteoporosis Other concerns: developmental delay, intellectual disability, behavior problems, FOOD SEEKING BEHAVIOR
Presentation of PWS infants
HYPOTONIA: feeding difficulties, FTT
Presentation of PWS in early childhood
HYPERPHAGIA & weight gain – binge eating
Dx of PWS
molecular genetic test – METHYLATION ANALYSIS
Management of PWS
replace HGH and testosterone/estrogen healthy diet/exercise multi therapies group home? monitor for complications
Complications w/ PWS
type 2 DM heart disease/stroke sleep apnea joint "wear and tear" psych component
Most common inherited intellectual disability
Fragile X (FX)
FX etiology
X-linked recessive; 90% of x-linked mutations are new mutations
Epidemiology of FX
M>F
Lyon hypothesis
Father transmits to 100% of his daughters (50% of daughters transmit it further)
Lyon hypothesis
FX is more common in males because females have variable expression due to x-inactivation
Clinical presentation of FX
intellectual impairment developmental delay (first words 18-20 months) (motor delay: walk 18-20 months) autistic behaviors poor ability to cope w/ transitions hyperactive anxiety behavior/tantrums seizures Soft smooth skin macrocephaly w/ prominent forehead and chin large ears and long, narrow face MSK: joint laxity, hypotonia, pes planus Eye: strabismus, blue iris Cardiac: MVP (murmur) Macro-orchidism after puberty
MVP
FX and Marfans
Blue sclera
OI
Blue iris
FX
Lens subluxation
Marfans
Dx of FX
Consider genetic screening in males w/ intellectual disabilities
CGG repeat in FMR1 gene**
Pre-mutations (enhance sx you may have): primary ovarian insufficiency (FXPOI) & tremor/ataxia syndrome (FXTAS)
Pre-mutations w/ FX
FXPOI
FXTAS
Management of FX
ECHO
MRI and eval if seizure activity
GERD: medication, feeding therapy
PT, OT, Speech
DiGeorge Syndrome (DGS) etiology
22q11.2 deletion syndrome (Chromo 22 defect)
Auto dominant but most often occurs randomly
Symptoms of DGS
Triad:
- cardiac abnormalities
- hypoplastic thymus: variable T-cell deficits
- hypocalcemia (underdeveloped thyroid)
Subtypes of DGS
partial vs. complete
based on thymic hypoplasia and immune function
Cardiac abnormalities in DGS
asymptomatic w/ mild defects
more severe present w/ cyanosis, HF, FTT, respiratory distress
Thymus hypoplasia
thymus is absent in complete DGS
immunodeficiency
Other concerns/presentations for DGS
craniofacial: low ears, wide set eyes, underdeveloped chin/small mouth, BULBOUS NOSE TIP
PALATAL DEFECTS (speech delay and difficult)
GU abnormalities
Skeletal (scoliosis)
dev. and intellectual delay
behavioral/psych issues
recurrent infections and inflammatory diseases
Dx of DGS
Decreased CD3 + T cells + clinical findings
Initial eval in those w/ DGS
urgent echo
Labs: CBC w/ diff, calcium and phosphorous (T and B cell subsets)
Renal U/S
CXR: absent thymic shadow
Urgent echo
marfan syndrome
DGS
Management of DGS
Cardiac consult: observe vs. surgery
Genetic consult for screening
Endocrine consult
speech/feeding (clef palate requires surgery)
behavioral/psych counseling
CAUTION W/ LIVE VACCINES (immunodeficiency)
Isolation
Complete DGS
life expectancy < 1 YO w/o treatment; thymic transplant if possible, HCT
Aneuploidies
Klinefelter - sex Turner - sex Trisomy 13 trisomy 18 trisomy 21
Klinefelter
47, XXY (maternal or paternal origin)
When is klinefelter normally diagnosed
usually not caught until they try to start a family and are sterile
Presentation of Klinefelter
infants/pre-pubertal boys typically have no obvious signs
Tall stature, narrow shoulder, long legs, microorchidism, gynecomastia
Mild language delay (expressive) and learning disabilities
macroorchidism
FX
microorchidism
Klinefelter
Labs for klinefelter
testosterone low
FSH/LH elevated in adolescents
Get endocrine consult to consider testosterone replacement
Evals for klinefelter
Endocrine
Infertility: 50% may father w/ assistance
Speech therapy and school-based interventions
counseling
Turner Syndrome
45, X
Mosaicism:
- 45 X/46, XX
- 45, X/46, XY with partial or complete deletion of Y
Risk of turner patients
higher risk for x-linked recessive disorders such as Hemophilia A/B
Clinical features of turners
SHORT
low hairline
WEBBED NECK
broad chest w/ wide spaced nipples (SHIELD CHEST)
pigmented nevi
infants: lymphedema in dorsum of hands and feet, CHD
AVERAGE INTELLECT
Cardiac: bicuspid AV (aortic stenosis), coarctation of aorta (aortic dissection risk), HTN
MSK: cubitus valgus (wide carrying angle), short 4th metacarpals, MADELUNG DEFORMITY
GU: internal and external female genitalia
streaked gonads: underdeveloped
premature ovarian failure
primary amenorrhea (small % can get prego)
horeschoe kidney
others: hypothyroidism, hearing loss, liver function abnormalities, strabismus, ADHD, emoitional/social difficulties
Aortic dissection risk
marfan
turner
MVP
Marfan
FX
Bicuspid AV (aortic stenosis)
Turner
Madelung Deformity
in turners;
V-patttern bone alignment
Hearing issues
OI (progressive)
Turner
Trisomy 21
Management of Turners
infertility eval: IVF w/ egg donation but increased risk of aortic dissection during pregnancy
endocrine: estrogen and cyclic progesterone therapy to stimulate puberty and assist bone density
Monitor for gonadal malignancy: gonadoblastoma – prophylactic removal of gonads
Trisomies
13 (Patau)
18 (edwards syndrome)
21 (down syndrome)
Patau syndrome
trisomy 13
defect in PRECHORDALMESODERM: midline craniofacial, eyes, forebrain
Presentation of Patau
midline cleft lip and palate sloping forehead scalp defect (cutis aplasia) micro- opthalmia holoprosencephaly
MSK: hypotonia, clinodactylyl of fingers/toes, polydactylyl, vertical talus (“rocker bottom”)
Severe intellectual disability
kidney defects
CHD***
Omphalocele
Clef lip risk
Patau
DGS
Vertical talus (“rocker bottom”)
Trisomy 13
Trisomy 18
Horseshoe kidney
Turner
Trisomy 18
CHD
Turner infants
all trisomies
Tx for trisomy 13
most die in utero
die before 1 mo
<5% survive beyond 6 months
supportive care – “noninterventional paradigm”
Edwards syndrome
Trisomy 18 (F>M)
Features of Edwards syndrome
intrauterine growth restriction (IUGR)
LBW, low set ears, microcephaly, small jaw/mouth, prominent occipital
MSK: hypertonia/spasticity, overlapping digits/clenched hands, rocker bottom, short sternum
Horseshoe kidney
airway obstruction
omphalocele, diaphragmatic hernia
CHD: VSD and PDA
Microcephaly
Trisomy 18
diaphragmatic hernias
edwards
VSD
edwards
Tx for edwards
majority die in utero; only 5% survive beyond 1 year
school age and adulthood is possible (severe intellectual disability)
palliative care vs. aggressive intervention
support group
Most common chromosomal abnormality
Trisomy 21 (down syndrome)
Development of trisomy 21
mild to mod delay
typical developmental delay is 2x average age;
risk increases w/ advanced maternal age
Clinical features of trisomy 21
epicanthic folds flat nasal bridge folded low set ears brachycephaly Brushfield spots (speckled iris) protruding furrowed tongue short neck w/ excessive skin narrow palate upslanting palebral fissures
HEENT: visual (cataracts, refractive errors), hearing loss, abnormal teeth
CHD: AVSD, VSD, ASD, PDA, TOF
Pulm: Pulm HTN, hypoxia intermittent, OSA, recurrent pneumo
GI: duodenal atresia, chronic constipation, hirschsprung disease, celliac
MSK: hypotonia, joint laxity, SiMON PALMAR CREASE
autism ADHD, aggressive behaviors
Hypertonia
trisomy 18
Eval for down syndrome
cardiac, hearing, opthalmology, neck/spine, endocrine GI
Developmental specialist
therapy (PT, OT, speech and feeding)
genetic screen
pt risk for having fetus w/ disorder: pre and pos-test risks and determine need for more invasive tests
Genetic diagnostic testing
diagnose w/ varying certainty the existence of genetic disorder
