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Phase 3a > Paeds - Genetics > Flashcards

Paeds - Genetics Flashcards

1
Q

Dysmorphic features of Down’s syndrome

A
  • HYPOTONIA
  • Brachycephaly (SMALL HEAD; FLAT BACK)
  • Short stature + Short neck
  • Upward sloping palpebral fissures (on eyes)
  • PROMINENT EPICANTHIC FOLDS
  • Single palmar crease
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2
Q

When is gneteics usually tested

A
  • Prenetal: MALFORMATIONS detected on scan
  • Paediatric:
    - Developmental delay
    - Seizures
    - Physical malformations
  • CANCER:
    - Early onset
    - Extensive FHx
    - Multiple cancers
  • Adult medicine: cardiomyopathies; kidney disease; neurology
  • Postmortem: Sudden death
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3
Q

Types of genomic tests

A
  • COMPARATIVE GENOMIC HYBRIDISATION
    • chromosome deletion/duplication
    • particularly for intelectual disbility/physical malformations
  • KARYOTYPING (translocation)
  • GENE PANEL/sequencing (for single gene change)
    • NGS panel
    • Exome; Genome
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4
Q

Types of genetic variations

A
  • Single Nucleotide Variant (SNV):
  • Missense (one amino acid for another)
  • Loss of function (STOP, Frameshift)
  • Splice site
  • Short Trinucleotide Repeat (STR)
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5
Q

Down’s syndrome complications

A
  • Congenital heart defects
  • Failure to thrive
  • Physical abnormalities
    - Recurrent Otitis Media + DEAFNESS from Eustachian tube abnormalities
    - VISUAL - myopia, cataracts
    - Atlantoaxial instability
  • Learning difficulties
  • Hypothyroidism
  • LEUKAEMIA
  • Alzheimers
  • INFERTILITY, Stillbirths + miscarriages
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6
Q

Down’s pathophys

A

Non-disjunction in ovaries
- more likely in older mothers but oft due to translocation

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7
Q

Robertsonian translocation

A

One of the chromosome 21s is translocated to chromosome 14 in parent

So baby gets one normal chromosome 21 from mum; one from dad and an extra 21 attached to one of their other chromosomes - overall has 3 21s = Down’s

Test parent’s if baby has translocation

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8
Q

Turner’s Syndrome + Px

A

(45, X)

  • Prenatal: increased nuchal translucency (look at neck on scan)
  • Neonatal: Lymphoedema (SWOLLEN)
  • Cardiac: Aortic coarctation
  • Fertility: dysplastic ovaries (risk of malignancy)
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9
Q

Klinefelter’s

A

47, XXY

Delayed puberty -> oft tall and slim as a result

Results in AZOOSPERMIA - oft found when investigating male INFERTILITY

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10
Q

Reason why some females get x-linked conditions

A

lyonisation (one x chromosome is inactivated)

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11
Q

Modes of genetic inheritance

A
  • Autosomal dominant
  • Autosomal recessive
  • X-linked
  • MITOCHONDRIAL disorders (exclusively from mitochondria from cytoplasm of ova - contain circular chromosome)
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12
Q

Heteroplasmy

A

More than one variant of mitochondrial dna exists within the same cell

  • so can get a mix of normal and abnormal mitochondria esp if cell in question is an ovum
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13
Q

Gonadal mosaicism

A

Condition where the precusor cells to the ova and spermatazoa are a mixture of TWO or MORE GENETICALLY DIFFERENT CELL LINES
- kids can then get mutated gene from one parent

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14
Q

Expressivity

A

Some conditions can present with phenotypes of differing severities even if autosomal dominant

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15
Q

Penetrance

A

The % of individuals carrying a genetic varient who manifest the disease

Can be age related

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16
Q

Antenatal Screening for Down’s

A
  1. COMBINED TEST (11-14 wks)
    • USS = NUCHAL THICKENING >6mm (the measurement checked is ‘nuchal translucency’)
      - Maternal BLOODS:
      - Beta- Human Chorionic Gonadotrophin (high levels = higher risk)
      - Pregnancy Associated Plasma Protein-A (low levels = higher risk)
  2. TRIPLE TEST (14-20 wks)
    - 3 maternal bloods:
    - Beta-HCG
    - Alpha Feto Protein (low = hihger risk)
    - Serum OESTRIOL (should be high in preg - lower = risky)
  3. Quadruple test (14-20 wks)
    - 4 maternal bloods:
    - All of above + INHIBIN-A (higher = riskier)
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17
Q

When is antenatal testing offered for Down’s + what are the methods

A

Offered if screening risk score > 1 in 150

  • Chorionic Villus Sampling (<15 wks)
    - USS guided placenta biopsy
  • Amniocentesis (only if enough fluid)
    - USS guided amniotic fluid asp w/ needle

Fetal cells from sample are kareotyped

Can also consider - Non-Invasive Prenatal Testing:
- Maternal Blood test; some of the circulating DNA fragments will be from fetus
- not definitive

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18
Q

Management of Down’s

A

MDT management

  • Physio/occupational
  • SALT
  • Dietician
  • SOCIAL SERVICES
  • Additional educational support
  • Charity association
  • Paeds + GP + Health visitors
  • Cardiology (heart defects)
  • ENT if ear problems
  • Audiologist for hearing aids
  • Optician for glasses
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19
Q

What are routinely followed-up in children with Down’s

A
  • 2 yearly THYROID CHECKS
  • ECHO for heart defects
  • Regular AUDIOMETRY
  • Regular EYE CHECK
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20
Q

Prognosis for Down’s

A

Average life expectancy is 60 years but varies depending on complications

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21
Q

Features of Turner’s

A
  • SHORT
  • WEBBED NECK
  • Broad chest with WIDELY SPACED NIPPLES
  • HIgh arching palete
  • Downward sloping eyes + Ptosis
  • Cubitus Valgus (vlgus shape at elbow extension)
  • FERTILITY PROBLEMS
    - Underdeveloped ovaries
    - Late/incomplete puberty
    - Infertility
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22
Q

Conditions/complications associated with Turner’s

A
  • COARCTATION of AORTA
  • Recurrent Otitis Media
  • Recurrent UTI
  • Hypothyroid
  • Hypertension
  • DIABETES, Obesity
  • OSTEOPOROSIS

Learning disabilities

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23
Q

Management of Turner’s

A
  • Growth hormone therapy (for height)
  • OESTROGEN / PROGESTERONE REPLACEMENT
  • FERTILITY TREATMENT

Tx of complications e.g. treating uti, otitis media, surg for coarctation

Monitor for associated conditions + Tx

Oft life expectancy similar to general populace

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24
Q

Kleinfelter presentation

A

Initially looks normal - tends to present at puberty or incidental finding on fertility treatment

  • Taller during puberty
  • WIDER HIPS
  • GYNAECOMASTIA
  • Weaker muscles
  • Small testicles, reduced libido + Infertility

Subtle learning difficulties, esp SALT related

25
Q

Klinefelter Mx

A
  • TESTOSTERONE injections for Sx improvement
  • Advanced IVF for fertility problems
  • Cosmetic surgery (breast reduction)

MDT:
- SALT
- Physio + occupational
- Educational support for any learning disabilities

26
Q

Complications of Kleinfelter

A
  • Infertility
  • Slightly increased breast cancer risk
  • Increased risk of:
    - OSTEOPOROSIS
    - Diabetes
    - Anxiety + Depression

However, life expectancy similar to general populace; affected by complications/associated

27
Q

Fragile X syndrome

A

(Fragile X metal retardation 1) FMR1 gene mutation on X chromosome
- normally codes for Fragile X Mental retardation protein which has role in cognitive development

X-linked but females can be variably affected (males always affected)

Can be through inheritance or de novo mutation

28
Q

Fragile X Px

A
  • INTELECTUAL DISABILITY
  • Long narrow face; BIG ears
  • Large testicles post-puberty
  • HYPERMOBILITY OF JOINTS (esp in hands)

Associated with ADHD, Autism + SEIZURES

29
Q

Fragile X management + prognosis

A

Assistive management

Life expectancy similar to general populace

30
Q

Prader-Willi Pathophys

A

Loss of functional genes on PROXIMAL ARM of chromosome 15 in PATERNAL copy

or because they inherit 2 copies of the chromosomal region from rhe mum and none from the dad

Only the maternal allele is expressed

31
Q

Prader-Willi Px

A
  • CONSTANT INSATIABLE HUNGER (-> obesity)
  • HYPOTONIA in infants (resulting in poor initial feeding)
  • Hypogonadism
  • Mild-mod LEARNING disability / Developmental delay
  • Mental health - esp Anxiety
  • Softer, fairer skin -> Bruises easily
  • SHORT

Dysmorphic features:

  • Almond eyes
  • Strabismus (SQUINT)
  • Thin upper lip + Downturned mouth
  • Narrow forehead
32
Q

Prader-Willi Management

A
  • Restrict access to food (with dietician advice)
    • Usually requires fewer calories than average individual as they tend to be less active due to poorer muscle tone/strenght
      - educate all care related individuals in child’s life
  • Physio + exercise to improve muscle tone
  • Educational support
  • Behavioural Mx of hyperphagia + developmental delay

GROWTH HORMONE can be used to improve muscle devlopment + body composition

33
Q

Prader WIlli Dx

A

Clinical px + confirmed with genetic testing

34
Q

Genetic imprinting

A

Term describing a mechanism where genes are expressed in a parent-of-origin manner

e.g. Prader-Willi vs Angelman
- In Prader-Willi only maternal allele is presented
- In Angelman only paternal allele is presented

35
Q

Angelman syndrome pathophys

A

Caused by LOSS OF FUNCTION of one copy of the UBE3A gene inherited from the MOTHER

Can be due to chromosome 15 proximal arm; specific mutation in gene; or 2 copies from dad and none from mum

36
Q

Angelman Px

A
  • Developmental delay + learning disability
  • Delayed/absent speech development
  • Ataxia
  • FASCINATION WITH WATER
  • HAPPY DEMEANOUR
  • Inappropriate laughter
  • Hand flapping
  • Abnormal sleep patterna
  • Dysmorphic features
    - Microcephaly
    - Fair skin + hair; Blue eyes
    - Wide mouth with WIDELY SPACED TEETH
37
Q

Angelman’s Mx

A
  • Parental education
  • Social services + support
  • Educational support
  • Physio / Occupational
  • Psych/CAMHS

Treat associated e.g. anti-epilepsy meds

38
Q

Edward’s syndrome

A

Trisomy 18 - most babies die in the perpartum period

Can be complete (trisomy 18 in every cell); Mosaic (trisomy 18 in only some cells): Partial (only part of an extra chromosome 18 in their cells)

Mosaical babies typically live till at least 1 y/o and can live till adulthood

NOT HEREDITARY; more common at older age

39
Q

Screening of Edwards’

A

Done at same time as Down’s + Patau’s in the combined test at 10-14 wks gestation
- Check Nuchal translucency + b-HCG
- USS at 20 wks if first one inconclusive

40
Q

Edwards’ classic presentation

A
  • Small mouth, jaw, neck
  • Prominant occiput
  • Sheild chest / short + prominant sternum
  • Wide set nipples
  • Dysplastic/malformed ears
  • Clenched hands with overlapping fingers
  • Rocker-bottom feet
41
Q

Edwards’ Dx

A

Chorionic villus sampling or amniocentesis - antinatal

If not Dx before birth - Newborn bloods

42
Q

Common complications of Edwards

A
  • Congenital heart defects
  • Impaired lung function
  • Immunocompromise
  • Difficulty feeding
  • Impaired mobility/motor ability as they get older
43
Q

Patau’s syndrome

A

Trisomy 13
- oft miscarry or die perinatally
- low birth weight

Risk increases with maternal age

Typically not hereditary - more commonly hereditary if it is Patau’s sue to translocation
- Can get genetic testing for this reason to plan for future preg
- Also offered to family members

44
Q

Common complications of Patau’s

A
  • Restricted growth in utero -> low birth weight
  • Heart defects
  • Holoprosencephaly (brain doesn’t split into 2 halves)
    - CLEFT LIP + PALATE
    - Microphtalmia (SMALL EYES)
    - Anopthalmia (Absence of eye(s))
  • MICRCEPHALY
  • Ear malformations + deafness
  • Rocker-bottom feet

Less common:
- Omphalocele (intestines outside body)
- Kidney cysts
- Polydactyly

45
Q

Muscular dystrophy types

A

Duchenne and Becker

Duchenne is OUT-OF-FRAME Dystrophin deletion
- virtually none of the protein is expressed
- More severe at earlier age

Becker muscular dystrophy: IN-FRAME Dystrophin deletion
- Protein expressed at lower levels or dysfunctional
- Can retain mobility into adulthood

46
Q

Muscular dystrophy epidem

A

Duchenne is most common form

Typically affects males as it is X-LINKED RECESSIVE

47
Q

What causes muscular dystrophy

A

Mutations (deletions) in the DYSTROPHIN GENE

Dystophin is required for MUSCLE CONTRACTION + STABILITY

48
Q

Muscular dystrophy presentation

A

DUchenne:

  • Presents in early childhood
    • GOWER’S SIGN
    • Difficult to pick the child up (too floppy)
  • Usually wheelchair-bound before puberty
  • Tend to die from resp failure in early 20s
    (calves may be hypertrophic - broken down muscle is replaced with fat)

Becker:

  • Later childhood muscle wasting + weakness
  • Wheelchair bound by teens
  • Survive well into adulthood (at least 30s usually)

PROXIMAL MUSCLES prominantly affected

49
Q

DDx for muscle weakness

A
  • X-linked recessive muscular dystrophy
  • Limb-Girdle Musc Dystrophy
    - (AUTOSOMAL INHERITANCE + later onset than Duchenne/Becker)
  • Spinal Muscular Dystrophy
    - (caused by ANTERIOR HORN CELL DEGENERATION not dystrophin loss)
  • Myopathies (NON-PROGRESSIVE)
50
Q

Muscular dystrophy Ix

A
  1. CK in blood - HIGH if muscle dystrophy
  2. Gold = GENETIC test

Can do muscle biopsy (also GOLD) but as it is more invasive, genetic testing is prefered

51
Q

Muscular dystrophy Mx

A

Supportive treatment

  • GLUCOCORTICOIDS - slows muscle breakdown
  • Physio/occupational
  • Tx heart/breathing problems

Genetic counselling for families (HEREDITARY CONDITION)

52
Q

Main complications of muscular dystrophy

A
  • Loss of mobility
  • RESPIRATORY COMPLICATIONS due to muscle weakness
    - nocturnal hypoventilation
    - poor cough - can’t clear airways well
  • DILATED CARDIOMYOPATHY
53
Q

Noonan syndrome

A

Number of genetic causes

Usually AUTOSOMAL DOMINANT

54
Q

Noonan Px

A

Varies depending on underlying cause but commonly:

  • SHORT
  • Broad forehead
  • Downward sloping eyes + Ptosis
  • Hypertelorism (wide space between eyes)
  • Prominent nasolabial folds
  • Low set ears
  • WEBBED NECK
  • Widely spaced nipples
55
Q

Associated complications of Noonan’s

A
  • HEART DEFECTS - particularly PS + LVH; ASD
  • CRYPTORCHIDISM (-> infertility in males)
  • LEARNING DISABILITY
  • BLEEDING DISORDERS
  • Lymphoedema
  • Leukaemia + Neuroblastoma risk
56
Q

William syndrome

A

Deletion of genetic material on ONE copy of chromosome 7
- typically random - not hereditary

57
Q

William syndrome Px

A
  • WIDE MOUTH + WIDELY SPACED TEETH
  • STARBURST EYES
  • Happy, sociable personality
  • Mild learning disabilty
  • Broad forehead
  • Flattened nasal bridge + long philtrum
  • Small chin
58
Q

Associated complications of William syndrome

A
  • SUPRAVALVULAR AORTIC STENOSIS (need ECHOs)
  • HYPERCALCAEMIA (low calcium diet)
  • Hypertension (BP monitoring)
  • ADHD

Phase 3a (26 decks)

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