Genetics Flashcards
why do we do a karyotype for Down syndrome
important to tell the recurrence risk to parents
if it is due to a unbalanced translocation then one of the parents may be a carrier of a balanced translocation
what is the risk of Down syndrome in any 40 year old woman?
1%
what is the risk of Down syndrome if the mother is a carrier of a balanced translocation
~15%
less if father is the translocation carrier
what are some physical features in a neonate of Down Syndrome
Hypotonia * Poor Moro reflex * Flat face * Upward slanted palpebral fissures * Epicanthal folds Speckled irises (Brushfield spots) Small nose, flat nasal bridge Small dysplastic ears * Joint hyperflexibility * Short neck, redundant skin * Short metacarpals and phalanges Short 5th digit with clinodactyly * Single transverse palmar creases *- impt Wide gap between 1st and 2nd toes- impt Pelvic dysplasia * GI: duodenal atresia and hirschsprung disease- impt
what are the congenital heart defects associated with Down Syndrome
congenital heart defects (50%) atrioventricular septal defects ventricular septal defects isolated secundum atrial septal defects patent ductus arteriosus tetralogy of Fallot
what are brushfield spots? are they pathognomonic for Down syndrome?
Brushfield spots are speckled areas that occur in the periphery of the iris
No! They are seen in about 75% of patients with Down syndrome, but they also are found in up to 7% of normal newborns.
what are some physical exam findings suggestive of Trisomy 18
IUGR microcephaly rockerbottom feet Clenched hands with overlapping fingers Dolichocephaly(condition where the head is longer than would be expected with a prominent occiput) Dysplastic or malformed ears short sternum Shield chest with wide set nipples
what are some physical exam findings suggestive of Trisomy 13
cutis aplasia
holoprosencephaly
midline defects (cleft lip and palate)
post-axial polydactyly (extra digits on the ulnar side of the hand)
hypertelorism
birth weight usually in the normal range (unlike trisomy 18)
what is more of the most common causes of holoprosencephaly
trisomy 13
what is the gold standard test to diagnose Trisomy 13
karyotype
if you need a rapid diagnosis you can do FISH
Family physician calls you about term neonate who weighs 2300 g. Neonate has lymphoedema, low set hair line and wide chest.
1) What test would you send for diagnosis?
Karyotype
what are some physical exam findings suggestive of Turner syndrome
Short stature
Congenital lymphedema
Horseshoe kidneys
Patella dislocation
Increased carrying angle of elbow (cubitus valgus)
Madelung deformity (chondrodysplasia of distal radial epiphysis)
Congenital hip dislocation
Scoliosis
Widespread nipples
Shield chest
Redundant nuchal skin (in utero cystic hygroma)
Low posterior hairline
Coarctation of aorta
Bicuspid aortic valve
Cardiac conduction abnormalities
Hypoplastic left heart syndrome and other left-sided heart abnormalities
Gonadal dysgenesis (infertility, primary amenorrhea)
Gonadoblastoma (increased risk if Y chromosome material is present)
Learning disabilities (nonverbal perceptual motor and visuospatial skills) (in 70%)
Developmental delay (in 10%)
Social awkwardness
Hypothyroidism (acquired in 15–30%)
Type 2 diabetes mellitus (insulin resistance)
Strabismus
Cataracts
Red-green color blindness (as in males)
Recurrent otitis media
Sensorineural hearing loss
Inflammatory bowel disease
Celiac disease (increased incidence)
what are two investigations that should be completed for a patient with Turner syndrome
Congenital heart defects (40%) and structural renal anomalies (60%) are common.
cardiac evaluation for bicuspid aortic valve, coarctation of the aorta, valvular aortic stenosis, and mitral valve prolapse.
renal ultrasound to look for renal anomalies such as horseshoe kidney
physical exam findings of turners syndrome in a newborn
small size for gestational age
webbing of the neck
protruding ears
lymphedema of the hands and feet
what are the most common heart defects seen with turners syndrome
The most common heart defects are bicuspid aortic valves, coarctation of the aorta, aortic stenosis, and mitral valve prolapse.
what are some physical exam findings suggestive of Noonan syndrome
short stature low posterior hairline shield chest congenital heart disease: Pulmonary stenosis and hypertrophic cardiomyopathy are generally the most common congenital heart defects found in Noonan syndrome short or webbed neck
what testing should be done for Noonan syndrome
molecular testing or gene sequencing (not seen on microarray)
floppy baby suggest what genetic syndrome
Prader Willi
child with seizures suggests what genetic syndrome
TS
Angelman syndrome
child with regression suggests what genetic syndrome
Rett syndrome
child with autism and intellectual disability suggests what 3 genetic syndromes
Fragile X
22q11 deletion syndrome
NF1
what are some neonatal findings of PWS
hypotonia- hyporeflexia, weak cry, lethargy
feeding difficulties- poor suck, FTT
hypogonadism- cryptorchidism, small testes and scrotum
what are features of prader-willi syndrome
voracious appetite
obesity in infancy
short stature (responsive to growth hormone)
small hands and feet
hypogonadism
intellectual disability (40% have borderline to low average IQ)
behaviour- often challenging due to hyperphagia, compulsivity, resistance to change and OCD tendencies
what causes prader will syndrome
paternal deletion
15q11-q13
what is the genetic test for prader willi syndrome
cytogenetics
MS-MLPA
what causes Angelman syndrome
ALL MAN- don’t have woman’s copy
maternal deletion
15q11-q13
reciprocal of Prader willi syndrome
what are the main clinical features of Angelman syndrome
developmental delay- notable around 6 months of age
severe speech impairment *
acquired microcephaly
gait ataxia and/or tremulousness of the limbs
behaviour: happy demeanour, frequent laughing, smiling, hypermotoric and excitability
microcephaly
seizures
what are common presentations of 22q11.2 (DiGeorge) deletion syndrome
CATCH
Cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus and tetralogy of Fallot) *conotruncal malformations Abnormal facies (squared nasal root) Thymic aplasia Cleft palate and submucosal cleft palate Hypocalcemia/hypoparathyroidism
A child with supravalvular aortic stenosis, small and abnormally shaped primary teeth, low muscle tone with joint laxity, and elevated calcium noted on testing is likely to have what syndrome?
Williams syndrome
what causes William syndrome
microdeletion on chromosome 7
what are associated anomalies with William syndrome
Associated anomalies:
congenital heart defects (~80%)- supravalvular aortic stenosis **
inguinal or umbilical hernias
Hypercalcemia **
feeding difficulties hypertension hypothyroidism developmental delay anxiety*
what is the single best test for 22q11.2 deletion syndrome
FISH or MLPA
also picked up on microarray
if hemivertebrae what workup should you consider?
workup for VACTERL
VACTERL is a diagnosis of exclusion
genetic basis unknown usually sporadic
expect normal intellect
what is Alagille syndrome
Autosomal dominant
complex multi system disorder characterized by the presence of 3/5 major clinical criteria:
- cholestasis with bile duct paucity on liver biopsy
- congenital cardiac defects
- posterior embryotoxon in the eye
- characteristic facial features (broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible)
- butterfly vertebrae
what is the triad of Beckwith-Wiedemann syndrome
OMG
O- ompahocele
M- macroglossia
G- gigantism (hemihypertrophy)
what does VACTERL mean
Vertebral defects Anal atresia Cardiac malformations Tracheoesophageal fistula Renal dysplasia Limb abnormalities
usually at least 1 anorectal or TEF, hemivertebrae can be seen in VACTERL
Newborn with respiratory distress and you are unable to pass an NG through nares. Child with distress, cannot pass NG through nares.
what syndrome?
3 other things you would look for on physical exam?
CHARGE Coloboma Heart defects choanal Atresia Retarded growth and development Genital abnormalities Ear anomalies
what are the major physical exam findings for BWS
Macrosomia (traditionally defined as weight and length/height >97th centile)
Macroglossia
Hemihyperplasia (asymmetric overgrowth of one or more regions of the body)
Omphalocele (also called exomphalos) or umbilical hernia
Embryonal tumor (e.g.,Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood
Visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and/or pancreas
Cytomegaly of the fetal adrenal cortex (pathognomonic)
Renal abnormalities including structural abnormalities, nephromegaly, nephrocalcinosis, and/or later development of medullary sponge kidney
Anterior linear ear lobe creases and/or posterior helical ear pits
Children with Beckwith-Wiedemann syndrome are at increased risk of which childhood cancers?
Wilm’s tumor- is the most common
95% of Wilms’ tumors occur by age 7.
Hepatoblastoma- is the second-most common cancer in patients with Beckwith-Wiedemann syndrome.
Typically develops by age 2.
what screening is required for BWS
Screen for embryonal tumors by abdominal ultrasound examination every three months until age eight years
Monitor serum alpha-fetoprotein (AFP) concentration every two to three months in the first four years of life for early detection of hepatoblastoma.
Annual renal ultrasound examination between age eight years and mid-adolescence to identify those with nephrocalcinosis or medullary sponge kidney disease
how do patients with achondroplasia present?
typically manifest at birth with short limbs, a long narrow trunk, and a large head with midfacial hypoplasia and prominent forehead.
The limb shortening is greatest in the proximal segments, and the fingers often display a trident configuration
dominant condition
due to 1 or 2 specific gene changes in a specific gene (FGR3 mutation)
TS major criteria
At least 2 major or 1 major and 2 minor A La Grass Hut A- facial angiofibromas ≥ 3 or forehead plaque L- lymphangiomyomatosis A- Ash leaf spots (hypo pigmented macules ≥ 3, >5mm in diameter) G- giant cell subependymal astrocytoma R- rhabdomyoma in heart A- angiomyolipoma of the kidney S- shagreen patch S- subependymal nodules H- hemaratomas of the retina U- ungal fibromas ≥ 2 T- tubers
periventricular calcification- can change into giant cell astrocytoma
what is the inheritance pattern of TS and NF1
Autosomal dominant
how is TS diagnosed
molecular testing
NOT microarray or cytogenetics
what are 3 common brain imaging findings in TS
subependymal nodules (90%) cortical tubers (70%) SEGAs- subependymal giant cell asytrocytoma (5-15%0
rett syndrome presentation
x linked
females only
Development may proceed normally until 1 yr of age, when regression of language and motor milestones and acquired microcephaly become apparent. An ataxic gait or fine tremor of hand movements is an early neurologic finding.
The hallmark of Rett syndrome is repetitive hand-wringing movements and a loss of purposeful and spontaneous use of the hands; these features may not appear until 2-3 yr of age. Autistic behaviour is a typical finding in all patients.
Generalized tonic-clonic convulsions (up to 90%) occur in the majority but may be well controlled by anticonvulsants.
what gene is associated with Rett syndrome
MECP2
what is the classical presentation for Fragile x syndrome
male with moderate intellectual disability or a female with mild intellectual disability macrocephaly long face protuberant ears post pubertal macroorchidism* joint laxity flat feet MVP seizures- complex partial most common
how is fragile x diagnosed
DNA testing or molecular testing
CGG repeats in FMR1 gene on x chromosome
what clinical features are associated with a female who has a permutation for fragile x
premature ovarian failure, early menopause
Fragile X-associated tremor/ataxia syndrome (FXTAS)
learning problems
chance to have more children with fragile x syndrome
NF1 criteria
CROPLAND
Marfan is similar to what metabolic condition
homocystinuria
How can you distinguish Marfan from homocystinuria
Marfan- have cardiac manifestations (aortic dilatation) whereas homocytinuria patients present with learning issues and have increased risk of thromboembolism
Homocytinuria- autosomal recessive
Marfan- autosomal dominant
how is Duchenne muscular dystrophy diagnosed
molecular testing of dystrophin gene
