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RACP Paediatric Exam - Medstudy edition > Genetics > Flashcards

Genetics Flashcards

1
Q

What is the genetic abnormality in trisomy 21?

A

95% - 3 copies of the whole chromosome 21
3-4% - Robertsonian translocation with Ch 13, 14 or 15
1-2% - mosaicism

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2
Q

What is considered to be the aetiology of trisomy 21?

A

Extra copy of chromosome 21
- nondisjunction during meiosis
Inc risk with increased maternal age

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3
Q

Which screening tests indicate an increased risk of trisomy 21?

A

Decreased aFP
Low unconjugated estriol
Elevated hCG
Elevated inhibin levels

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4
Q

What are the classical findings in trisomy 21?

A 
Hypotonia
Poor moro
ID
Brachydactyly - wide sandle gap
Upslanted palpebral fissures 
Flat midface 
Full cheeks
Protruding tongue
Epicanthal folds 
Single transverse palmar crease
Brushfield spots 
High arched palate 
Hypoplasia of the middle phalanx
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5
Q

What are the common congenital cardiac defects in T21?

A

AVSD - endocardial cushion defect

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6
Q

Which GI defects are associated with T21

A 
Duodenal atresia (double bubble)
Hirschprung disease
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7
Q

Which glandular disorder should you annually screen for in T21?

A

Thyroid function

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8
Q

A 30 year old mother with a child with T21 with three complete copies of ch21. What is her risk of having another child with T21?

A

1%

If parental 21:21 translocation, 100% risk. Mother balanced translocation risk is 10-15%

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9
Q

Is trisomy 18 more common in boys or girls?

A

Girls 4:1

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10
Q

What are the classic features of T18

A 
Edwards:
IUGR
ID
High forehead
Microcephaly
Small face / mouth
Rocker bottom feet
Overlapping fingers
Short sternum
Hypoplastic nails
Structural heart defects - VSD
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11
Q

Most common cause of death in T18

A

Central apnoea

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12
Q

Classic features of T13

A 
Patau:
Midline defects
- orofacial cleft
- microphthalmia 
- postaxial polydactyly of limbs
- holoprosencephaly
- heart malformations
- hypoplastic/absent ribs
- genital anomalies
- abdominal wall defects
- aplasia cutis 
- rocker-bottom feet
- clenched hands
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13
Q

Describe a boy with Klinefelter syndrome?

A

47XXY

  • tall
  • gynaecomastia
  • delayed secondary sexual characteristics
  • azoospermia and small testes, infertile
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14
Q

Describe a girl with Turner Syndrome

A

45XO

  • short
  • web neck
  • hypogonadotropic hypogonadism - ovarian failure/gonadal dysgenesis
  • bicuspid aortic valve
  • coarctation of aorta
  • swollen hands/ feet
  • cubitus valgus
  • shield chest
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15
Q

What are the classic features of a child with 4p deletion?

A

Wolf-Hirschhorn Syndrome

  • Distinctive face - hypertenorism, prominent glabella, frontal bossing, short philtrum, smallness of the jaw
  • Severe growth deficiency
  • microcephaly
  • renal problems
  • hypotonia
  • congenital cardiac abnormalities
  • seizures (90%)
  • variable developmental delay
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16
Q

What are the classic features of 5p deletion?

A

Cru-Du-Chat Syndrome

  • cats cry - abnormal larynx
  • moon face
  • down slanting palpebral fissures
  • hypotonia
  • short stature
  • high arched palate
  • wide and flat nasal bridge
  • ID - severe
  • cardiac manifestations
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17
Q

Classic finding in 18p deletion

A

de Grouchy syndrome

  • microcephaly
  • developmental delay
  • narrowed ear canals
  • froglike position
  • depressed midface
  • protruding mandible
  • deep set eyes
  • everted lower lip (carp like)
  • ID
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18
Q

Which deletion syndrome is associated with trigonocephaly?

A

9p deletion (triangle head)

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19
Q

Describe Angelman and the genetic mutation that caused it?

A

Ch 15
Uniparental disomy - paternal
Maternal deletion

Happy puppet, jerky ataxic movements
Inappropriate laughter 
Microcephaly
Characteristic gait
Hypotonia
Fair hair
Midface hypoplasia
Large chin/mandible
Seizures
Severe ID 
Absent / severely delayed speech
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20
Q

Describe Prader-Willi syndrome and mutation

A

Ch 15
Uniparental disomy - maternal
Deletion of paternal

Infancy
- severe hypotonia and feeding difficulties

Childhood

  • hyperphagia, obesity
  • short stature
  • small hands / feet
  • hypogonadism
  • mild intellectual disability
  • behaviour disorders
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21
Q

Describe child with Williams syndrome

A 
Ch 7 microdeletion (elastin defect) 
Cocktail personality 
Broad forehead 
Elfin facies 
Stellate pattern of iris 
Supravalvular aortic stenosis 
ID
Hypercalcaemia 
Joint laxity
Growth delay / short stature
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22
Q

What characterises WAGR syndrome?

A

Wilms tumour
Aniridia
Genitourinary malformations - male
Mental retardation

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23
Q

Describe the classic features of Alagille syndrome. What are the most common cardiac manifestations?

A 
AD inheritance, JAG1 gene
Triangular face, pointed chin
Long nose, broad midface
Bile duct paucity with cholestasis
- presents first 3/12 with cholestasis, jaundice, pruritus 
Peripheral pulmonary stenosis, PV stenosis
Ocular defects - posterior emrbryotoxon 
Butterfly vertebrae

Cardiac:List
Peripheral and branch pulm stenosis (67%)
Tetralogy of fallot

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24
Q

List common findings in 22q11.2 deletion syndrome

A 
CATCH22
Cleft palate
Absent thymus
Congenital heart disease 
- TOF>interrupted aortic arch>VSD>truncus arteriosus

Short stature
Behaviour problems
Hypocalcaemia - absent parathyroid gland
ID

Diagnosis with FISH / microarray

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25
Q

Differentiate AD pedigree

A

Mutation in 1 gene only
Both sexes equally affected
Both sexes transmit to offspring
Present in all generations
Every affected child has a parent with the disorder
Fathers can transmit to sons (this excludes XLR and mitochondrial)
High spontaneous mutation

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26
Q

Differentiate AR pedigree

A

Only disease phenotype when both alleles carry mutations
No history of disease in prior generations
Males and females equally affected
Males and females can each transmit the altered allele
Risk for 2 heterozygotes is 1/4
Consanguinity increases risk

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27
Q

Differentiate X-linked pedigree

A

Dominant or recessive
Recessive - more common, mostly affects males
Never male to male transmission
If a generation has only females, will appear to skip generation
Affected father transmits to all daughters and no sons
Carrier females have 50% change of transmitting disease to each son

28
Q

What is germline mutation?

A

Parent carries the gene mutation in gonadal tissue and germline cells, but not in somatic cells - so no signs of disease.
Future offspring are at increased risk to inherit condition

29
Q

Which form of classic Mendelian inheritance does not have male-male transmission?

A

X linked disorders

30
Q

Which form has father passing to all daughters and no sons

A

X linked disorders

31
Q

What is an example of genetic imprinting?

A

Differences in gene expression depending if disease inherited from father or mother
Angelman - maternal deletion
Prader-Willi - paternal deletion

32
Q

How is mitochondrial inheritance unique?

A

Egg, not sperm, tramsits all mitochondria
Mother passes to all children
Father does not pass it on

Myoclonic epilepsy and ragged-red-fibres
Mitochondrial encephalopathy, lactic acidosis, stroke like episodes
Leigh syndrome (basal ganglia defects, hypotonia, optic atrophy in infancy/early childhood)
33
Q

Are dizygotic twins more likely, less likely or equally likely to have traits similar to those of a nontwin sibling?

A

Dizygotic twins are no more similar than nontwin siblings

34
Q

Name 4 diseases or abnormalities that are more likely to be concordant in monozygotic than dizygotic twins?

A

Autism 60% mono, 0% di
Cleft lip/palate 38% vs 8%
Clubfoot 32% vs 3%
Spina bifida 72% vs 33%

35
Q

A positive prenatal quad screen indicates an increased risk of what 4 disorders? (aFP, bHCG, estriol and inhibi A)

A

T21, T18, neural tube defects, abdo wall defects

36
Q

What diagnostic testing method is used to detect single gene defects?

A

Sanger method

37
Q

Chromosomal instability syndromes most commonly have what pattern of inheritance?

A

Largely autosomal recessive
Increased freq of chromosomal breaks
eg. ataxia telangiectasia, Bloom syndrome, Fanconi syndrome, xeroderma pigmentosum

38
Q

What is Pierre Robin sequence?

A

Mandibular hypoplasia
Displacement of tongue -> U shaped cleft -> displacement of tongue into the airway -> resp distress and feeding problems
No macroglossia!

39
Q

Anomalies in hemifacial microsomia

A

External ear anomilies - microtia, anotia, canal atrasia
Maxillary and/or mandidular hypoplasia
Cervical vertebral anomalies 33%
Renal 15%

Goldenhar = hemifacial microsomia with epibulbar lipodermoids, VSD

40
Q

What type of head growth is seen with early closure of the sagittal sutures?

A

Excessive anterior/posterior growth
Long, narrow head , occipital prominence
Dolichocephaly

41
Q

What type of head growth is seen with early closure of the coronal and sphenofrontal sutures?

A

Unilateral flattening of forehead
Elevation of ipsilateral orbit and eyebrow
Prominent ear on affected side
Frontal plagiocephaly

42
Q

What type of head growth is seen with early closure of the metopic sutures?

A

Keel shaped forehead and hypotelorism

Trigonocephaly

43
Q

What is positional plagiocephaly?

A

Postnatal flattening of the skull - caused by infant’s preference of sleeping/resting position

44
Q

Describe findings in achondroplasia

A

Autosomal dominant! most de novo mutation FGFR3 (fibroblast growth factor receptor 3) on Ch 4p16.3
Disproportionately short stature
Rhizomelic shortening
Lumbar lordosis
Trident hands
Macrocephaly
Characteristic craniofacial findings, flat nasal bridge, prominent forehead (frontal bossing) and midface hypoplasia

45
Q

What is brachio-oto-renal syndrome?

A 
AD inheritance
Brachial cleft fistulas
Preauricula pits
Cochlear and stapes malformation
Mixed conductive/sensorineural hearing loss
46
Q

What is rhizomelic shortening?

A

Short lengths of most proximal “root” segment of upper arms and legs compared to distal segments

47
Q

What skull structural abnormality can occur in infants with achondroplasia?

A

Foramen mangum stenosus and/or craniocervical junction abnormalities
Compression of upper cord - apnoea, quadriparesis, growth delay, hydrocephalus

48
Q

What is the most commonly affected bone in Caffey disease ?

A

Mandible - 95% of cases (helps differentiate NAI)

Infantile cortical hyperostosis, AD, incomplete penetrance
Irritability, fever, anotexia, soft tissue swelling

49
Q

Describe a child with osteogenesis imperfecta type 1

A

OI Type 1: classic nondeforming OI with blue sclerae

AD - brittle bone disease
Mildest form, most common
Decrease synthesis of Type 1 collagen

Multiple fractures - before puberty
Blue sclerae 
Delayed fontanella closure
Hyperextendable joints
Hearing loss
decreased stature
Dentinogenesis imperfecta - discoloured, weak teeth
Osteopenia  long bones
Wormian dones (multiple small bones in cranial sutures)
50
Q

Which type of osteogenesis imperfecta is the most severe and usually results in death in infancy?

A

OI Type 2 = perinatally lethal OI

Type 2 = most severe
Respiratory insufficiency = death in infancy

De novo AD mutation of COL1A1 - no normal function of Type 1 collagen

51
Q

Which type of osteogenesis imperfecta has the highest risk of neurologic complications?

A

OI Type 3 = progressively deforming OI

Type 3 - hydrocephalus and basilar skull invagination
Present as newborn - multiple fractures

52
Q

What are the classic scleral findings in osteogenesis imperfecta type 4?

A

OI Type 4 = common variable OI with normal sclerae

Milder form
White / near white sclerae
Tibial bowing = hallmark

53
Q

What causes the most deaths in Marfan syndrome?

A

Cardiovascular complications, aortic root dilatation and rupture

Dx criteria:
Ectopia lensis (upward)
Aortic dilatation or dissection
FHx

54
Q

Describe the typical findings in classic Ehlers-Danlos syndrome

A 
AD, connective tissue disorders
Hyperextensible skin
Hypermobile joints
Easy bruising - normal coags
Dystrophic scarring 
Skin:
Texture - doughy, wet chamois, fine sponge
Extra on hands/feet/stomach
Stretchy like rubber band 
Fragile skin 
Bruising 
Wrinkled palms/soles

MV prolapse
Proximal aortic root dilatation

55
Q

What are the classic skin findings in NF1?

A

Cafe au lait spots (6 or more, >5mm prepub, >15mm post pub)
Neurofibromas >2 (or >1 plexiform neurofibroma - of peripheral nerve)

Lisch nodules - benign iris hamartoma 75% prepub

56
Q

How frequently is NF1 due to a new mutation?

A

50% are sporadic, or de novo AD mutations

57
Q

Describe how NF2 differs from NF1

A

AD disorder
Essentially no clinical overlap with NF1
Bilateral vestibular schwannomas (acoustic neuromas)

58
Q

What abnormalities do vestibular schwannomas cause in NF2?

A
  • SNHL
  • tinnitus
  • imbalance
  • facial weakness
59
Q

Describe the skin findings in tuberous sclerosis

A

Hypopigmented macules (ash leaf spots) - 90%
Shagreen patches - oval nevoid plaque on trunk/lower back
Facial angiofibromas
Forehead plaques
Nail / gingival fibromas

60
Q

What cardiac tumours are common in infants with tuberous sclerosis?

A

Cardiac rhabdomyosarcomas - 50% infants

Infantile spasms also common in TS - treat with vigabatrin

61
Q

What tumours are commonly seen in patients with von Hippel-Lindau syndrome?

A

Cerebellar hemangioblastoma in adolescence
OR
Retinal angioma by 10yo

Mutation VHL tumor supressor gene Ch3

62
Q

Noonan syndrome has what type of inheritance pattern?

A

Autosomal dominant

63
Q

Beckwith-Wiedemann syndrome has what type of inheritance pattern?

A

Autosomal dominant 11p15.5 deletion

64
Q

What are the features of Beckwith-Wiedemann syndrome?

A 
LGA
Generalised overgrowth
Macroglossia
Ear lobe creases
Posterior auricular pits
Omphalocele
Wilms tumour
Cryptochidism
Hemihypertrophy
65
Q

What syndromes have cafe au lait spots?

A

NF1
McCune Albright Syndrome
Russell-Silver

RACP Paediatric Exam - Medstudy edition (9 decks)

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