Embryology

Question 1

;p0Outline the aetiologies of congenital abnormalities

Answer 1

Causes of mal-development:

1. Genetic – 30%
2. Environmental – 15%
3. Multifactorial – 55%

Question 2

Birth defects: recall the processes leading to congenital abnormalities, including spina bifida, cleft palate and congenital cardiac abnormalities

Answer 2

1. Changes in the numbers of conceptuses or fetuses that develop.

• Twins
• Triplets
• Chimaera

Multiple pregnancy & chimerism

• Identical twins / triplets: one conceptus forms 2 / 3 inner cells masses to form 2 / 3 genetically identical individuals
• Chimerism: 2 genetically distinct conceptuses combine to form one individual

2. Cells and chromosomes

• The distribution of cells and chromosomes can change development.
• Changes to chromosomes can affect gene expression.

Cellular distributions

• Mosaicism (non disjunction) – differences between cells within one individual
• Distribution of cells between inner cell mass & trophectoderm (placenta)
• Chimerism - fused multiple zygotes

–Non-identical zygotes

eg. eye colour

• Human chromosome 15.
• Brown most common colour; others mostly in Caucasians.
• Differentiation of eyes begins about Day 22 PF.
• Event must predate Day 22.

Question 3

Chromosomal abnormalities: too many

Answer 3

Chromosomal abnormalities:

• Too few sex chromosomes – Turner’s syndrome – 45 X0.
• Too many sex chromosomes – Klienfelter’s syndrome – 47 XXX, 47 XYY, etc.

Too few autosomes – non-viability, as does 45 Y0.

Too many autosomes – Downs Syndrome – trisomy 21.

Most risks to the pregnancy occur in the first trimester of pregnancy. The main risks associated with pregnancy in the 3rd trimester is to do with the birth.

There are 4 main organs (lungs, digestive system, immune system and brain) that have limited use in utero so late development is logical but problems developing here become apparent at birth.

This also may cause problems with pre-term birth.

Chromosomal problems

1. Too many, too few, translocations.
2. ALL give rise to syndromes
3. Cross-talk between systems

Chromosome numbers

Too many

XY linked

• –Kleinfelter’s syndrome (XXY). Decreased fertility
• –XXYY, XXXY, XXXYY, etc – severe forms related to KS
• –XYY (XYYY) – very variable (taller, learning problems)
• –XXX. Limited effects, some mental changes
• –XXXX, XXXXX. More severe effects

Chromosomal problems

• Too many
• Autosomal
  
  • Down’s syndrome (ch21) (1 / 1000 live births)
    
    • Heart problems determine survival.
  • Edward’s syndrome (ch18) (1 / 6000 live births)
    
    • Most die before birth, very few live-born, live ≤2 weeks.
  • Patau’s syndrome (ch13) (1 / 15,000 live births)
    
    • Most die before birth, 80% live-born die within 1 year.
    • Others not found in live birth, most detected in some spontaneous pregnancy loss tissues.
    • Ch1 trisomy not found in pregnancy loss tissues.

Question 4

Chromosomal abnormalities: too few

Answer 4

Chromosomal problems

Too few

XY linked

Turner’s syndrome - X0. Female, short stature, infertile

Y0 not viable

Autosomal

No complete losses are viable

Partial chromosome loss syndromes known and characterised

• Altered distribution - translocations
• XY linked

–“XX male” – XY translocation

•Autosomal

–Linked with development of tumours; lymphoma; leukaemia; sarcoma

Question 5

Function of gene product problems

Answer 5

Function of gene product problems

• Mutations
• Altered expression

Many genes are found in both animals and humans.

Holt-Oram syndrome - heart/hand defects

• Phenotype due to mutation in TBX5 (transcription factor) – required as both structures develop.
  
  • Atrial septation defects
  • Range of hand abnormalities

Achondorplasia

• Gain of function mutation in FGFR3
• Achondroplasia means “lack of cartilage”
• Defect is in conversion of cartilage to bone & lack of bone growth

Question 6

Teratogens: summarise how teratogens affect embryo development

Answer 6

Teratology or dysmorphology

• Changes in the PATTERN of development
• •Major abnormalities ~3% of pregnancies (cause 25% of infant deaths.
• •Minor abnormalities ~15% (little health impact)

Teratogen: Any agent that can disturb the development of an embryo or fetus

Infectious agents

• Rubella virus - Cataracts, glaucoma, heart defects, deafness, teeth
• Herpes simplex virus - Microphthalmia, microcephaly, retinal dysplasia
• HIV - Microcephaly, growth restriction
• Syphilis - Mental retardation, deafness
• Zika virus – microcephaly

Physical agents

• X-rays & other ionising radiation - Microcephaly, spina bifida, cleft palate, limb defects

Chemical agents

• Thalidomide - Limb defects, heart malformations
• Lithium - Heart malformations
• Amphetamines - Cleft lip and palate, heart defects
• Cocaine - Growth restriction, microcephaly, behavioral abnormalities
• Alcohol - Fetal alcohol syndrome, maxillary hypoplasia, heart defects

Mal-developements:

1. Limb abnormalities (polydactly - lack of lower limbs)
2. Spina bifida
3. Cleft palate / Cleft lip
   4.

Question 7

Explain limb development in reference to polydaktyly

Answer 7

Limb development

• Forelimb bud appears at d27/8
• Hindlimb bud at d29
• Grow out from lateral plate mesoderm rapidly under control of special signalling regions
• Fully formed and patterned by d56.

Duplication in the whole pattern of the hand = fusion event in the middle fingers with two thumbs

• Sonic Hedgehog (shh) is the polarizing factor for limb development

Question 8

Explain cleft palate, spina abifida, and limb defects secondary to thalidomide

Answer 8

Cleft lip and palate

• Our face starts developing at two separate halves
• The grouves on the righ form and they fill in but if they do not fill in they form a cleft
• Cleft palate is usually centrally placed whereas cleftlip on the side

Spina Bifida

• Neural tissue directs formation of spinal bones
• Bulge of tissue from the spine exptending from the body
• Neurological issues cannot be easily repaired
• Incidence: 1-2 per 1000 pregnancies
• Surgery can help anatomical, but not functional problems
• Folic acid in diet decreases incidence by ~70%
• Folic acid – WHEN should folic acid be given?
  
  • 3 months before conception because the egg starts developing and takes 3 months to fully develop

Anencephaly

• Folic acid (given at the right time) may show benefit
• Implies similar causes to spina bifida
• Anterior neuropore closure incomplete

Thalidomide

• ~10,000 affected infants known, ~50% initial survival rate.
• Limbs affected.
• In addition, deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness.
• Used in some leprosy and cancer treatments at present.
• Thalidomide – affects rapidly developing blood vessels, notably those of upper limbs
• Blood vessel affects can be generic, hence the range of effects observed.

Question 9

Respiratory distress syndrome

Answer 9

Respiratory distress syndrome (RDS), respiratory distress syndrome of newborn (RDSN), surfactant deficiency disorder (SDD); previously called hyaline membrane disease (HMD).

Overall incidence ~1% of all births

~100% at GA 24 weeks

~50% at GA 26-28 weeks

~25% at GA 30-31 weeks

Lung surfactant in the context of labor

Babies are born very preterm: they suffer from low functioning in the lungs – respiratory distress syndorme

No surfactant so lungs are collapsed due to extremely high surface tension

It improves as time goes by

It also gets better with an injection of steroids