JC122 (Paediatrics) - Clinical genetics in paediatrics Flashcards
Compare entirely genetic and entirely environmental diseases
- Prevalence
- Cause
- Recurrence rate
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
Example of diseases mostly due to genetic disorder
Mostly genetic:
Duchenne muscular dystrophy
Phenylketonuria, galactosaemia
Haemophilia, osteogenesis imperfecta
Example of diseases caused by genetic and environmental factors equally
Club foot, pyloric stenosis, dislocation of hip
Spina bifida, ischaemic heart disease, ankylosing spondylitis
Peptic ulcer, diabetes
Definition of rare disease
Rare disease is defined as one that affects 1 in 2,000
1 in 17 rate in HK
Classification of abnormal stature
Achondroplasia/ hypochondroplasia
- Genetic defect
- Classes of mutation
- Physical sign in newborn
- 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)
Achondroplasia/ hypochondroplasia
- Radiological signs
- Long-term complications
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
Achondroplasia/ hypochondroplasia
Management options
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
Turner syndrome
- Genetic defect
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
Turner syndrome
Morphological features
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%)
Turner syndrome
Physiological deficits
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
Management of Turner’s syndrome
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
List 2 genetic disorders causing neurological developmental delay/ autistic spectrum disorder
Fragile X syndrome
(commonest X-linked condition causing intellectual disability in ASD)
Phelan-Dermid syndrome
Fragile X syndrome
- Genetic defect
- Clinical manifestation
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»_space; fragile X)
Autism spectrum disorder: difficult in social interaction
No dysmorphic feature
Fragile X syndrome
- Confirmatory investigations
- Treatment
Investigations:
1) Chromosomal studies: normal (46 XY)
2) Other studies: excessive CGG repeats in FMR1 gene
Genetic counseling:
Behavioral therapy and counseling
Phelan-Dermid syndrome
- Genetic defect
- Confirmatory investigations
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)
Chromosomal microarray
- Function and procedures
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»_space;> yellow
If deletion: green < red»_space;> red
If duplication: green > red»_space;> green
List mutations that cause Autism spectrum disorders
Fragile X syndrome - FMR1
Phelan-Dermid syndrome - SHANK3
PTEN mutation,
tuberous sclerosis (TSC)
Rett syndrome (MeCP2)
Angelman syndrome (E3A)
Marfan syndrome
- Genetic defect
- Inheritance
Mutation in fibrillin 1 gene (FBN1):
- docking protein for TGFβ: now cannot dock»_space;> systemic increase in TGFβ1 levels (dysregulation of TGF-β activation)
- Weaker connective tissue
- Inheritance: Autosomal dominant
Marfan syndrome
Manifestations
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
Clinical diagnostic criteria for Marfan syndrome
Confirmatory investigation
- Family history
- Aortic root measurement by cardiologist
- Lens dislocation by ophthalmologist (ectopia lentis – displacement/ malposition (pathognomonic))
- Ghent Systemic score
Confirmatory Ix:
molecular/ genetic testing for disease-causing mutation in fibrillin-1 gene (FBN1), TGFBR2
Marfan syndrome
Management options
Only reduce morbidity and mortality of aortic complications:
- Beta blockers (propranolol, atenolol) to reduce aortic wall stress»_space; prevent deterioration of aortic aneurysms & aortic dissection
- Losartan (AT1 antagonist) inhibits TGFβ signaling»_space; preventing aortic aneurysm/ aortic root dilation
List genetic heart syndromes
Noonan syndrome, long QT syndrome, 22q11.2 deletion, Williams syndrome, LDS syndrome
Beckwith Wiedemann syndrome
- Genetic abnormality
Abnormal regulation of imprinted region 11p15 i.e. imprinting gene disorder
Normally:
Paternal allele (methylated on H19) expresses IGF2, KCNQ1»_space; promote growth
Maternal allele (methylated on KCNQ1) expresses H19, CDKN1C»_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)
Beckwith Wiedemann syndrome
Clinical features
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)
Beckwith Wiedemann syndrome
Confirmatory Ix
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»_space; predict recurrence risk to parents of a child with BWS
Subgroups of Beckwith Wiedemann syndrome
Which group is most common
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
Management of Beckwith Wiedemann syndrome
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
List genetic causes of childhood cancer
NF2 syndrome,
Noonan syndrome,
Gorlin syndrome,
X-linked Alport plus diffuse leiomyomatosis
Name one novel technique for detection of undiagnosed genetic disorder
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
