30 terms

Nelson Genetics

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NF 1
- AD mutation in neurofibromin, ch17
- cafe au lait macules, axillary/inguinal freckling, . lisch nodules (pigmented hamartomas of the iris) neurofibromas (schwann cell tumors)
- 10-20% will have: brain tumors (optic gliomas, astrocytomas), HTN, skeletal changes (scoliosis, pseudoarthrosis of tibia), craniofacial disfigurement
- 100% penetrance, variable expressivity
- has pleiotropy: a single mutation causes abnormalities in many different organ systems
- 1 in 3,500
Achondroplasia
- AD disorder of cartilage-derived bone; mutation in FGFR3 on ch4
- short stature, macrocephaly, flat midface w prominent forehead, rhizomelic shortening of the limbs
- 1 in 12,000 births
- as they grow: hydrocephalus and central apnea w narrowing of foramen magnum, bowing of legs, dental malocclusion and hearing loss via middle ear dysfunction, psychological effects, sciatica
- can be DX on amniocentesis or CVS
Marfan syndrome
- AD disorder
- MSK findings: dolichostenomelia (tall, thin body habitus), arachnodactyly, pectus excavatum/carinatum, kyphoscoliosis, pes planus, joint laxity
- Eye findings: high myopia (-> vitreoretinal degeneration), ectopia lentis (via abnl suspensory ligament) - usually dislocates upward and out; cataracts
- Cardiac findings: dilation of aortic root, aortic insufficiency -> aortic dissection
X-linked vitamin D-resistant rickets
- hypophosphatemic rickets
- XLD disorder -> not as severe in females d/t lyonization
- kidney is unable to reabsorb phosphate
Incontinentia pigmenti
- swirling skin pattern of hyperpigmentation that develops after a perinatal skin rash with blistering
- XLD disorder -> affected sons die in utero
Rett syndrome
- XLD disorder -> affected sons die in utero; this primarily a disease of females
- females are normal at birth, but at 6-18 months they develop microcephaly and lose purposeful hand movements
- seizures
mutation in MECP2 gene on chX
Hypertrophic pyloric stenosis
- multifactorial disorder, FHx often seen
- males: females is 5:1
Neural tube defects
- 1/1,000 have myelomeningocele
- genetic component: increased in British Isles
- environmental component: increased in late fall/early winter deliveries
- 20-40X increased risk in subsequent pregnancies for the parents
MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes)
- SSX at 5 years to 15 years old
- episodic vomiting, seizures, recurrent cerebral insults that resemble strokes
Prader-Willi syndrome
- hypotonia of prenatal onset (to the point where NG feeds are required), postnatal growth delay, almond-shaped eyes, small hands/feet, developmental disability, hypogonadotropic hypogonadism, obesity via voracious appetite in later life
- paternal chromosome 15 deletion (= 2 maternal copies)
- deficit of SNRPN (Necdin gene) - present in both chromosomes, but normally is only expressed by the paternally-derived ch15 (methylated and thus blocked on maternal ch15)
Angelman syndrome
- MR, absence of speech, ataxic movements in arms/legs, seizures characterized by laughter
- maternal chromosome 15 deletion (= 2 paternal copies)
- UBE3A is missing - normally expressed by maternal chromosome, present on paternal but methylated and thus not expressed
Fragile X
- MC inherited cause of MR
- SSX: large head, prominent forehead/jaw/ears, macro-orchidism, MVP
- FMR-1 mutation -> failed expression of FMRP (frataxin)
Fetal Alcohol Syndrome
- growth deficiency, microcephaly, developmental delay, skeletal and cardiac changes
- requires pregnant mother to drink 6oz alcohol per day
- "fetal alcohol effect" = when mother starts drinking in second trimester -> no craniofacial or organ changes, but developmental delay still a risk
- fetal alcohol effect is more common than the full syndome
Hyperthermia and pregancy
- avoid hot tubs in the first trimester
consanguinity
- risk of first cousins producing an offspring with AR disorder in 1/64
Ashkenazi Jewish population
- AR disorders
- Tay-Sachs, Niemann-Pick, Bloom syndrome, Canavan disease, Gaucher syndrome, CF, fanconi anemia, familial dysautonomia
Screening
- maternal serum at 16 weeks: AFP (secreted by fetus and would thus be higher than normal; 80% detection rate) to look for NTDs and chromosomal abnormalities (would be lower than normal; use quad screen for this)
- screening ultrasound at 18 weeks
Quad screen
- AFP, unconj-Estriol 3, inhibin A, hCG
- increased chromosomal abnormality detection rate to 80%
- Trisomy 18: all 4 will be decreased
- Trisomy 21: hCG will be elevated, all others are low -> perform amniocentesis if increased risk is found on quad screen
Down syndrome
- 1/800
- nondisjunction in 92.5%; meiosis 1 nondisjunction is MCC
- can have mosaicism
- hypotonia, facies (brachycephaly, flattened occiput, hypoplastic midface, fattened nasal bridge, upslanting palpebral fissures, epicanthal folds, large protruding tongue), transverse palmar crease, wide gap between toes 1 and 2, cutis marmorata (velvety, loosely adhering mottled skin)
- congenital heart dz in 40% (endocardial cushion defects - AV canal, VSD, ASD)
- GI disease in 10% (duodenal atresia, annular pancreas, imperforate anus)
- congenital hypothyroid in 1%; MC to have acquired hypothyroid
- common to have polycythemia > 70% at birth
- cataracts risk
- atlanto-axial instability and increased 1 - 2 vertebrae distance
Trisomy 18
- SGA, hypertonia, prominent occiput, receding jaw, low-set malformed ears, short sternum, rocker-bottom feet, hypoplastic nails, clenched fists (2nd overlaps first, fifth overlaps fourth)
Trisomy 13
- SGA, microcephaly, cyclopia, cebocephaly (single nostril) cleft lep/palate, alobar holoprosencephaly, small/malformed ears, microphthalmia, polydactyly of hands, clubfeet or rocker-bottom feet
- congenital heart disease
- aplasia cutis congenita (punched-out scalp lesion over the left or right occiput
Klinefelter syndrome
- increased number of X chromosomes (in mosaics) = increased risk MR
- DX at 15-16 YOM
- pubertal hair w/o increase in testicular volume, gynecomastia, low T = no facial hair, no deepening voice, decreased libido
- tall, long arms and legs
- adults: osteoporosis, infertility (IVF can isolate fertile sperm, however)
Turner syndrome
- short stature, low-set, mildly malformed ears; triangular-appearing face, flattened nasal bridge, epicanthal folds, webbed neck (w or w/o cystic hygroma) shieldlike chest with widened internipple distance, puffiness of hands and feet
- congenital heart defects (coarctation, bicuspid AV, risk of aortic aneurysm during pregnancy), horseshoe kidney
- risk hypothyroidism
- streak gonads (gonadal dysgenesis) -> estrogen deficiency: amenorrhea, lack of secondary sex characteristics
Cri du Chat syndrom
- deletion of short arm of ch5
- catlike cry in infancy (via tracheal hypoplasia), LBW, FTT, hypotonia, developmental delay, microcephal, craniofacial dysmorphism (ocular hypertelorism, epicanthal folds, downward obliquity of palpebral fissures, low-set malformed ears)
Wolf-Hirschhorn syndrome
- growth retardation, MR, abnormal facies ("greek helmet" = frontal bossing, high anterior hairline, hypertelorism, ptosis, epicanthal folds)
- upward slanted palpebral fissures, large low-set ears with preauricular pits/tags, coloboma of iris
- seizures
- partial ch4p deletion
Williams syndrome
- small deletion in ch7q11
- short stature, abnormal facies ("elfin facies" = median flare of eyebrows, fullness of perioral and periorbital region, blue irides with stellate pigment pattern, depressed nasal bridge), MR with strong personal social skills
- personality: loquacious and gregarious ("cocktail party personality"), remarkable musical ability
- congenital heart disease (supravalvar aortic/pulmonic stenosis)
WAGR syndrome
- Wilms tumor, aniridia, genitourinary anomalies, mental retardation
- deletion in ch11p13
- GU = cryptorchidism and hypospadias
- parents are short and may have microcephaly
Miller-Dieker syndrome
- lissencephaly, abnormal face (bitemporal narrowing, high forehead, small upturned nose, upward slanting palpebral fissures
- ch17p13.3 deletion (LIS-1 gene)
Chromosome 22q11 deletions
- Velocardiofacial syndrome: cleft palate with velopharyngeal insufficiency, conotruncal cardiac defects, face (large prominent nose, broad nasal root), T cell immunodeficiency, psych disorders
- DiGeorge syndrome: neonatal onset of symptoms with conotruncal cardiac abnormalities, hypocalcemia, hypoplasia of thymus and parathyroid glands, micrognathia, cleft palate, low-set ears, hypertelorism, MR
Pierre Robin sequence
- failed growth of mandible -> micrognathia -> forces tongue to an unusual position and blocks fusion of palatal sheves -> U-shaped cleft palate; airway obstruction and sleep apnea