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MBBS IV - Junior Clerkship WCS > JC122 (Paediatrics) - Clinical genetics in paediatrics > Flashcards

JC122 (Paediatrics) - Clinical genetics in paediatrics Flashcards

1
Q

Compare entirely genetic and entirely environmental diseases

  • Prevalence
  • Cause
  • Recurrence rate
A 
Entirely genetic
 Rare
 Simple genetics – single gene conditions, Mendelian disorders (dominant/ recessive), chromosomal & mitochondrial disorders
 Unifactorial
 High recurrence rate
Entirely environmental
 Common
 Complex genetics
 Multifactorial
 Low recurrence rate
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2
Q

Example of diseases mostly due to genetic disorder

A

Mostly genetic:
 Duchenne muscular dystrophy
 Phenylketonuria, galactosaemia
 Haemophilia, osteogenesis imperfecta

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3
Q

Example of diseases caused by genetic and environmental factors equally

A

 Club foot, pyloric stenosis, dislocation of hip
 Spina bifida, ischaemic heart disease, ankylosing spondylitis
 Peptic ulcer, diabetes

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4
Q

Definition of rare disease

A

Rare disease is defined as one that affects 1 in 2,000

1 in 17 rate in HK

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5
Q

Classification of abnormal stature

A
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6
Q

Achondroplasia/ hypochondroplasia

  • Genetic defect
  • Classes of mutation
  • Physical sign in newborn
A
  • Genetic defect: fibroblast growth factor receptor 3 gain-of-function mutation
  • Classes of mutation
    1) Achondroplasia
    2) Hypochondroplasia = milder
    3) Thanatophoric dysplasia type I & II (lethal)
  • Physical sign in newborn
    Arm and thighs have a lot of skin folds
    disproportionate: (e.g. body weight 10%, body height 3%, head circumference 75%)
    Rhizomelic shortening (proximal part of long bones)
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7
Q

Achondroplasia/ hypochondroplasia

  • Radiological signs
  • Long-term complications
A

Radiological signs E.g. X-ray:
 Trident hand
 Abnormal spikes on long bones (= classical pattern of achondroplasia)
 Flattened vertebral body, narrowed interpedicular distance

Long-term orthopedic complication
 Spinal canal stenosis
 Lifelong deformity

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8
Q

Achondroplasia/ hypochondroplasia

Management options

A

Management – health supervision

1) CNP analog: acts on bones and damp down overactive FGFR3 pathways

2) Counseling to prevent symptomatic spinal canal stenosis
 Firm back support from birth
 Reclined seating (delayed upright sitting) & reclined handling
 Prone play in older infants
 Trunk-strengthening exercises
 Shock-absorbing footwear
 Good sitting posture

3) Holistic care
- occupational therapist
- psychosocial issues

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9
Q

Turner syndrome

  • Genetic defect
A

proportionate short stature with chromosomal abnormality

phenotypic females lost causing Haploinsufficiency of genes on X chromosome
 Lose an entire sex chromosome (45,X); or
 Lose a portion of the X chromosome that includes the tip of its short arm (Xp; the SHOX gene)/ isodicentric X

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10
Q

Turner syndrome

Morphological features

A 
Body:
 Short stature (98%)
 Micrognathia (60%)
 Cubitus valgus (47%) – elbow deformity, high carrying angles
 Short fourth metacarpal (37%)
 Webbed neck (25%) – fold of skin
 Lymphedema of hands and feet (22%)
 Scoliosis (11%)

Facial:
 Low posterior hairline (42%)
 Short neck (40%)
 High arched palate (38%)

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11
Q

Turner syndrome

Physiological deficits

A 
Multisystem disorder:
Gonadal insufficiency (95%)***
Cardiovascular:
 Bicuspid aortic valve (10-15%)
 Coartation of aorta (10%)
 Aortic dilation (8-28%) & dissection (2.5%)
 Hypertension (20%)

Hearing loss (60%)

Renal anomalies (7-8%)

Autoimmune hypothyroidism (25-30%)

Inflammatory bowel disease (2.5%)

Diabetes mellitus (x 2-4 times)

Osteoporosis

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12
Q

Management of Turner’s syndrome

A

Growth hormone

Monitor pubertal development +/- estrogen replacement

Cardiac referral for structural heart disease

ENT referral for hearing loss

Renal ultrasound for renal abnormalities

Screen thyroid function for autoimmune thyroiditis

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13
Q

List 2 genetic disorders causing neurological developmental delay/ autistic spectrum disorder

A

Fragile X syndrome
(commonest X-linked condition causing intellectual disability in ASD)

Phelan-Dermid syndrome

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14
Q

Fragile X syndrome

  • Genetic defect
  • Clinical manifestation
A

Triple expansions/ trinucleotide repeat disorders in FMR1 gene:
Number of CGG repeats in FMR1:
 Normal (general population): 6-50
 Pre-mutation: 60-200 (clinical problems can occur in adulthood)
 Full-mutation: >200 (triggers promoter hypermethylation and affects transcription&raquo_space; fragile X)

Autism spectrum disorder: difficult in social interaction
No dysmorphic feature

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15
Q

Fragile X syndrome

  • Confirmatory investigations
  • Treatment
A

Investigations:

1) Chromosomal studies: normal (46 XY)
2) Other studies: excessive CGG repeats in FMR1 gene

Genetic counseling:
 Behavioral therapy and counseling

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16
Q

Phelan-Dermid syndrome

  • Genetic defect
  • Confirmatory investigations
A

Genetics:
SHANK3 (22q13) deletion cause abnormal synaptic transmission

Ix:

  • *Chromosomal microarray – array comparative genome hybridization (aCGH):
  • Chromosome imbalance
  • 22q13 deletion syndrome (SHANK3 gene deletion) – 2.3Mb size

FISH

(Karyotype: normal (46 XY): does not show submicroscopic changes)

17
Q

Chromosomal microarray

  • Function and procedures
A

Function:
Recommended as first-tier testing in patients with unexplained** developmental delay, ASD, multiple congenital anomalies

Procedure:
1. Produce probes complementary to different areas of genome
2. Print all the probes presenting the whole gnome onto the glass slide (the chip)
3. Prepare control DNA & patient DNA in same quantity and mark with different colored probes
4. After hybridization (mix patient DNA with control DNA):
If balanced (no duplication/ deletion): green = red&raquo_space;> yellow
If deletion: green < red&raquo_space;> red
If duplication: green > red&raquo_space;> green

18
Q

List mutations that cause Autism spectrum disorders

A

Fragile X syndrome - FMR1
Phelan-Dermid syndrome - SHANK3
PTEN mutation,
tuberous sclerosis (TSC)
Rett syndrome (MeCP2)
Angelman syndrome (E3A)

19
Q

Marfan syndrome

  • Genetic defect
  • Inheritance
A

Mutation in fibrillin 1 gene (FBN1):

  • docking protein for TGFβ: now cannot dock&raquo_space;> systemic increase in TGFβ1 levels (dysregulation of TGF-β activation)
  • Weaker connective tissue
  • Inheritance: Autosomal dominant
20
Q

Marfan syndrome

Manifestations

A

revised Ghent criteria (scoring of systemic features):

Skeletal features:
Arachnodactyly – Walker-Murdoch wrist sign and thumb signs
Pectus carinatum/ pectus excavatum deformity
Hindfoot deformity
Protrusio acetabuli
Scoliosis/ thoracolumbar kyphosis
Low upper-to-lower segment/ high arm span-to-height ratio

Facial: dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia

Eye: Myopia, diopters

CVS: Skin striae, Mitral valve prolapse

Lung: Pneumothorax

Others: Dural ectasia

21
Q

Clinical diagnostic criteria for Marfan syndrome

Confirmatory investigation

A
  1. Family history
  2. Aortic root measurement by cardiologist
  3. Lens dislocation by ophthalmologist (ectopia lentis – displacement/ malposition (pathognomonic))
  4. Ghent Systemic score

Confirmatory Ix:
molecular/ genetic testing for disease-causing mutation in fibrillin-1 gene (FBN1), TGFBR2

22
Q

Marfan syndrome

Management options

A

Only reduce morbidity and mortality of aortic complications:

  • Beta blockers (propranolol, atenolol) to reduce aortic wall stress&raquo_space; prevent deterioration of aortic aneurysms & aortic dissection
  • Losartan (AT1 antagonist) inhibits TGFβ signaling&raquo_space; preventing aortic aneurysm/ aortic root dilation
23
Q

List genetic heart syndromes

A 
Noonan syndrome, 
long QT syndrome, 
22q11.2 deletion, 
Williams syndrome, 
LDS syndrome
24
Q

Beckwith Wiedemann syndrome

  • Genetic abnormality
A

Abnormal regulation of imprinted region 11p15 i.e. imprinting gene disorder

Normally:
Paternal allele (methylated on H19) expresses IGF2, KCNQ1&raquo_space; promote growth
 Maternal allele (methylated on KCNQ1) expresses H19, CDKN1C&raquo_space; suppresses growth

Offset in this balance resulting from mutated genes/ failure in imprinting will cause under-/ overgrowth, e.g.:
Paternal disomy (2 copies of father)
 Single gene mutation
 Epigenetic dysregulation (e.g. hypermethylation of H19, hypomethylation on KCNQ1)

25
Q

Beckwith Wiedemann syndrome

Clinical features

A 
 Premature birth
 High body length, weight
 Macroglossia (hypotonic)
 Abnormal ear pits (creases)
 Omphalocele (abdominal organs protrude through belly button but covered in a thin sac)
26
Q

Beckwith Wiedemann syndrome

Confirmatory Ix

A

Methylation-specific multiplex ligation- dependent probe amplification (MS-MLPA):
 Shows abnormal methylation pattern: loss of methylation in DMR2 region of KCNQ1- extra expression of KCNQ1 which promotes growth

Deduce de novo/ sporadic/ inherited&raquo_space; predict recurrence risk to parents of a child with BWS

27
Q

Subgroups of Beckwith Wiedemann syndrome

Which group is most common

A

Paternal UPD - sporadic

Hypomethylation on DMR2 (most common) - Usually sporadic

Hypermethylation on DMR1 - Usually sporadic

11p15 chromosome translocation/ inversion - Inherited or sporadic

11p15 chromosome duplication - Inherited or sporadic

CDKN1C mutations- Inherited or sporadic

28
Q

Management of Beckwith Wiedemann syndrome

A

Monitor for hypoglycemia in neonatal period (increase cellular demand due to overgrowth

Surveillance for embryonal tumor development:

  • Abdominal ultrasound examination every 3-6 months until eight years of age - Wilm’s tumor
  • Serum alpha-fetoprotein (AFP) concentration measurement for hepatoblastoma until age 4
29
Q

List genetic causes of childhood cancer

A

NF2 syndrome,

Noonan syndrome,

Gorlin syndrome,

X-linked Alport plus diffuse leiomyomatosis

30
Q

Name one novel technique for detection of undiagnosed genetic disorder

A

whole-exome sequencing - sequence all protein-coding part of the genome

 Size of the human genome = 6 billion bp
 Size of the human exome = 30 million bp (1% of genome)
~85% disease-causing mutations occur in the exome

MBBS IV - Junior Clerkship WCS (131 decks)

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