MBBS V Paediatrics – Child in Womb (WCS)

Child in Womb (WCS)

Trends
 Low infant mortality rate (Hong Kong – one the lowest)
 Low neonatal mortality rate
o Congenital abnormalities (6% of total births worldwide with birth defects)
 Single gene disorders
 Chromosomal disorders
o Short gestation or unspecified low birthweight
o Respiratory distress syndrome

Genetic and environment (epigenetics) interaction  health, learning, behaviour

 Intra-uterine environment
 Early environment: psychological environment (may not have famine anymore)
 Larger community
 Long term effect

Down’s syndrome: trisomy 21 (expected to know)

 Description of photo
o Karyotype: trisomy 21
o FISH: 3 copies of chromosome 21
o Clinical features
 Palms
 Upslanting palpebral fissure
 Triangular motuh
 Redundant skin fold (pre-natal ultrasound)
o ECHO: ventricular septal defect associated with trisomy 21
MBBS V Paediatrics – Child in Womb (WCS)

 Epidemiology
o Incidence – 1: 600-800 (range: different countries – diff. prenatal dx)
o Life expectancy without CHD: 60 years
o Death due to infections, CHD, malignancy
 Associated with
o CVS: CHD in 40%, AVSD 70%
o IQ: 25-50 (for older patients: 25)
o Dementia: 40-100%
o Short stature
o Hypothyroidism
o Leukemia (15-20 fold increase)
o Male infertility

Patau syndrome: Trisomy 13

 Epidemiology:
o Incidence - 1: 8000 (less common due to pre-natal diagnosis)
o Ex: non-disjunction (80%)
 Clinical features
o Cleft palate
o Abnormal nose shape (flattened, broad)
o Hypotelorism: distance between eyes
o Hands and feet: polydactyly (post-axial type – 5th and 6th digit)

 Associated with
o Congenital heart disease (80%)
 ASD, TOF, TGA
o Pre-natal death (SA or SB): 50%
 Only 5% of live born make it to 1 year
MBBS V Paediatrics – Child in Womb (WCS)

Edward’s syndrome - Trisomy 18

 Clinical features
o Clenched hands (key sign always) (interact with baby) (neuro)
o Rock bottom feet
o Intra-uterine growth restriction
o Corneal clouding
o Micro-ophthalmia
o Malformed and low set ears

 Epidemiology
o Incidence – 1:3000 live born
o 80% females
o Ex: 90% due to non-disjunction
 Associated with
o Cardiac abnormalities (100%)
 VSD, myxomatous changes of valves
o Prenatal death (75%)
 Only 5% of liveborn reach 1 year of life
MBBS V Paediatrics – Child in Womb (WCS)

Prevention methods: involves O&G and family doctors

Primary prevention Folic acid supplement (neuro-tube defect)
Postnatal injection of anti-D immunoglobulin (Rh hemolytic dx)
Immunization of young girls against rubella (infection of
reproductive age women  congenital rubella)
Family planning and prenatal screening (thalassemia)
Genetic counselling for fam hx (Fragile X syndrome)
Secondary prevention Prenatal diagnosis
Tertiary prevention Pediatric surgery
Neonatal screening
Routine antenatal and neonatal care

  Long term neurological deficits

Congenital rubella syndrome

 Visual loss
 Hearing loss
 Thrombocytopenia
 High risk of developmental delay
MBBS V Paediatrics – Child in Womb (WCS)

Fetal origins or Barker hypothesis

 1997 child health cohort in England: in-utero programming change physiology in baby
o Early growth (measured by birth weight and gestational period)  CV health
 Low birth weight linked to cardiovascular disease in women and men
 Low weight gain in infancy linked to CV disease only in men
 Early development and human health
o Sensitive periods and developing brain (early life period  many changes)
 Neurological system: new synapse formation
 Visual following
 Visual fixation
 First words
 Sit
 Stand
 Higher cognitive function
 Endocrine system

o Schizophrenia in early adulthood after prenatal exposure to Chinese Great Leap

Forward Famine (evidence suggest adverse environment in early childhood
leave an impact in long term health effects)
 1960s: urban area vs rural residents correlate with risk of schizophrenia
 increased adult risk of developing schizophrenia
 Fetal origins and epigenetics
o Fetal/maternal environment and modulation of gene expression starts early in
life and can be passed across generation = epigenetics (link between
genetics and environment)
 Genes alone do not determine development
 Epigenetics: “fine tuning” and adjustments to genes (e.g. maximize
extraction of energy due to famine  but environment change 
DM/CVS disease)
 Mechanism: DNA methylation and histone code modification
MBBS V Paediatrics – Child in Womb (WCS)

Imprinted genes
 Most of human genes are expressed from 2 copies inherited from both parents
 Imprinted genes are expressed from only one of the parental alleles predominantly in a
parent-of-origin specific manner
o About 60 imprinted genes are found in human genome
o Often (not always) cluster in groups
o Silence by alleic methylation at imprinting control regions (ICRs) in cis
 Imprinting control regions
o Majority are CpG islands with CpG rich sequences
 No human X-linekd imprinted gene is identified up to date

Genetic counselling
MBBS V Paediatrics – Child in Womb (WCS)

 Most genes work in pair (father and mother)

o Usually both turned on and turned off together = bi-alleic expression
 Imprinting genes: control growth and development
o Only one is turned on and one is turned off
o Inherited from father or mother determines which is on and off
 Inter-generational inheritance of disease  Prader Willi syndrome

Prader Willi syndrome

 Features
o Poor development initially
o At a certain point (tilting point)  develop obesity
o Hypotonia: slip through sign
o Hypogonadism
o Almond shaped eyes
 Epidemiology 1 in 10,000

 Molecular mechanism
o Imprinting disorder: chromosome 15 (imprinting region)
 Normal: one copy from father, one copy from mother
 Disease = offset ratio: delete father’s, two mother’s, methylation defect
 One direction: Prader Willi
 Another direction: Angelman syndrome
MBBS V Paediatrics – Child in Womb (WCS)

 Treatment
o Tilting point: reduce risk of obesity through education
o Growth hormone treatment (need monitoring) (lipolytic effect)
o Non-invasive ventilation clinic
o Development assessment
o School placement
o Anticipatory health supervision

 Different underlying mechanisms  different risk of recurrence

MBBS V Paediatrics – Child in Womb (WCS)

Russell Silver syndrome

 Genes: chromosome 11 and chromosome 7 (2 imprinting regions)

 Clinical features
o Extreme failure to thrive (3rd centile): height, weight
 Head sparing (except head circumference)
o Triangular facial appearance (inverted)
o Body asymmetry
o Clinodactyly of 5th finger (curvature of digit)
MBBS V Paediatrics – Child in Womb (WCS)

 Treatment
o Growth chart for Russell Silver syndrome
o Education
o Genetic counselling

Beckwith Wiedemann syndrome

 Clinical features
o Body weight increase
o Body height (may increase)
o Macroglossia (may result in sleep disordered breathing)
o Ear creases and pits
o Birth defect: omphalocele or umbilicus hernia
 Associated with:
o Low glucose: hypoglycemia
o Cardiomegaly and cardiomyopathy
o Embryonal tumour surveillance (e.g. Wilm’s tumour)

Transgenerational responses
 From grandfather/mother to child
 (Re)programming at critical period of development
o Formation of primordial germ cells
 Loss and regain of DNA methylation
 Involves 4 genes in genome
o Before and after fertilization (2nd generation subjected to environmental change
 carries primordial germ cells)
 During fertilization: drastic changes in primordial germ cells
 Loss of DNA methylation
 Fertilization as embryo
 Regain DNA methylation
 Involves all genes EXCEPT imprinting genes
MBBS V Paediatrics – Child in Womb (WCS)

 Childcare behaviour epigenetically programmed

o Left side: good mother mouse
 Kids grow up and take care of kids well
MBBS V Paediatrics – Child in Womb (WCS)

o Right side: bad mother mouse

 Kids grow up to be bad mothers
o Epigenetics marks:
 DNA methylation differences of promoter of glucocorticoid receptors in
the CNS sytem and brain

Multi-generational impact of early environments

 Health of mother
o Pregnancy environments impact multiple genomes
o Pregnancy contains genomes of mother, child and grandchild
 Health of father
o Paternal pre-pregnancy health and wellbeing impacts health and development
infants and children (provide early environment)
MBBS V Paediatrics – Child in Womb (WCS)

Books: Developmental origins of health and disease

Marcus Pembrey
Lars Olov
MBBS V Paediatrics – Child in Womb (WCS)