Extras - Foetal Malformations Flashcards
What is the neural plate?
What does it go on to form by week 4?
- the neural plate is a thickened section of ectoderm
- the edges of the neural plate elevate, meet in the midline and fuse to form the neural tube
- the anterior neuropore closes on day 25, followed by the posterior neuropore on day 28
- the cranial end of the neural tube develops 3 dilated regions in week 4 - the primary brain vesicles
What are the 3 primary brain vesicles and what do they give rise to?
In what week do the cerebral hemispheres begin to develop?
- the prosencephalon gives rise to the forebrain
- the mesencephalon gives rise to the midbrain
- the rhombencephalon gives rise to the hindbrain
- in week 5, these 3 swellings form 5 secondary vesicles
- the telencephalon forms, which will go on to form the cerebral hemispheres
What are neural crest cells?
What structures do these go on to form?
- a subset of cells that migrate away from the neural folds and all over the body
- they are formed from the region of the neural plate border
- they are involved in the formation of many structures, including:
- adrenal medulla
- conotruncal septum
- sympathetic NS
- CN ganglia
- thyroid gland C-cells
- bones / connective tissue of the face & skull
- GI tract parasympathetic ganglia
- sensory /DRG
- Schwann cells
What is anencephaly and why does it occur?
What is the prognosis of this condition like?
- failure of the anterior neuropore to close leads to absence of the cerebrum and cerebellum
- exposure to amniotic fluid damages the neural tissue and prevents the brain from forming
- the prognosis is very poor with most infants not surviving birth
- those that do survive die within a few hours / days of birth from cardiorespiratory arrest
How can anencephaly be screened for?
- foetal anomaly USS at 20 weeks has a 90% detection rate for NTDs
What NTD is associated with hydrocephalus?
Why does this occur?
- myelomeningocele involves tethering of the spinal cord, which can result in hydrocephalus
- Arnold-Chiari malformation occurs when there is herniation of the cerebellum through the foramen magnum as a result of tethering
- this obstructs the flow of CSF
- there is a build-up of CSF within the ventricles, which puts pressure on the brain
What causes spina bifida?
Why do the symptoms vary from asymptomatic to severe?
- failure of the neural tube to close from the cervical region, running caudally
- in mild cases, there is failure of the vertebral arches to fuse but the defect is covered with skin and neural tissue is not involved
- this is often asymptomatic
- if the vertebral arches do not form, meninges +/- neural tissue can protrude from the spinal canal and be exposed
- this results in severe, irreversible neurological deficits
- the defect is most likely to occur in the lumbar region
What is a meningocele?
- herniation of the meninges through a defect in the skull or spinal cord due to splitting of the vertebral arches
- this creates a CSF-filled cyst
- the protruding sac does NOT contain neural tissue
What is a myelomeningocele?
What symptoms is it associated with and how may it be detected?
- there is herniation of meninges and neural tissue through a defect in the skull or spinal cord
- it is associated with:
- paralysis + sensory loss of the lower limb (problems with mobility)
- bladder + bowel dysfunction
- cognitive dysfunction
- Arnold-Chiari malformation
- hydrocephalus
- it has a 90% detection rate on foetal anomaly USS @ 20 weeks
What are the 10 factors known to increase the risk of NTDs?
- family history of NTD
- previous child with NTD
- high temperatures in early pregnancy
- opioid use in first 2 months of pregnancy
- diabetes
- obesity
- smoking
- vitamin B12 deficiency
- folic acid deficiency
- anti-epileptics
What public health measure has reduced the incidence of NTDs?
What are the problems with implementing this?
- impregnation of non-wholemeal wheat flour with folic acid
- is thought to avoid 200 NTDs annually (20% of UK total)
- it does not apply to gluten-free foods or wholemeal flour
- there is concern about masking of vitamin B12 deficiency and increasing the risk of colon cancer
What marker is raised in NTDs that can be detected prenatally in maternal serum and amniotic fluid?
alpha-fetoprotein (AFP)
- this is part of the quadruple serum test @ 15-18 weeks
- AFP cannot be detected via chorionic villus sampling
What is craniorachischisis?
What causes it and what is the prognosis?
- failure of the neural folds to fuse results in a completely open brain + spinal cord
- there are no meningeal coverings
- the spinal cord region can become completely ossified
- this is incompatible with life
When do the limb buds appear?
What are they composed of?
- the limb buds appear in week 4 as outpouchings from the ventrolateral body wall
- the core is composed of tissue from the lateral plate mesoderm
- this is covered by a layer of ectoderm
- the mesoderm core differentiates into mesenchyme, which will form the bones and connective tissue of the limbs
What are somites formed from?
What factor is important in this process and how does it contribute to limb formation?
- somites are series of blocks on either side of the neural tube that are formed from paraxial mesoderm
- somites give rise to numerous structures:
- muscles of the limbs
- bones of the limbs
- cartilage
- SHH is important in this process
- these differentiating cells migrate from the somites into the developing limb bud
What 3 axes does the limb develop along?
What factors are important in ensuring this happens correctly?
Proximo-distal:
- from the shoulder to the hand (and from the hip to the foot)
- fibroblast growth factors (FGFs) are important here
Cranio-caudal:
- where the thumb is cranial and the little finger is caudal
- homeobox (HOX) genes are important here
Dorso-ventral:
- where the palm is ventral and the knuckles are dorsal
- WNT proteins (and others) are important here
What is secreted by the mesenchymal core of the limb bud that stimulates proximodistal outgrowth?
- the lateral plate mesoderm forming the mesenchymal core of the limb bud secretes FGF-10
- FGF-10 induces the overlying ectoderm along the tip of the limb bud to thicken and form the apical ectodermal ridge (AER)
What is secreted by the AER and how does this contribute to proximodistal limb growth?
- the AER secretes FGF-4** and **FGF-8
- these cause rapid proliferation of mesenchymal cells underlying the AER
- this proliferating population of undifferentiated cells is the progress zone, which maintains proximodistal outgrowth of the limb
- as the limb grows distally, cells further from the AER differentiate
How is thalidomide thought to cause limb defects?
- it interferes with angiogenesis and disrupts FGF signalling at the AER
How is craniocaudal patterning of the limb bud achieved?
- the craniocaudal axis is determined by a small region of mesenchyme in the caudal part of the limb bud
- this is the zone of polarising activity (ZPA)
- SHH is expressed in the ZPA, which diffuses in a cranial direction
- high concentrations of SHH induces formation of caudal structures (e.g. little finger)
- low concentrations of SHH induces formation of cranial structures (e.g. thumb)
How is dorso-ventral patterning of the limb bud achieved?
- the dorsal ectoderm secretes WNT-7
- the ventral ectoderm secretes Engrailed-1, which inhibits WNT-7
- this explains why humans do not have nails on the pulp of the fingers
What other gene is involved in dorsoventral patterning?
What syndrome can result if there is a defect in this gene?
LMX1B is essential for normal dorsoventral patterning
- defects in LMX1B result in nail-patella syndrome
- this is characterised by absent or small, irregular patellae with abnormalities of the nails
- the thumb is most severely affected, and the little finger the least
- there may also be defects of the bones, kidneys and eyes
How do the digits form from the hand and footplates that appear in week 6?
- AER at the end of each digit encourages proximo-distal outgrowth
- there is apoptosis of cells in regions where the AER is not present
- this leads to the formation of separate digits
What is synpolydactyly?
What gene mutation is involved?
- the combination of syndactyly (fusion of digits) and polydactyly (supernumerary digits)
- mutations in HOX genes result in the formation of new body segments
What is the incidence of limb defects?
Which limbs are most commonly involved?
- 4.4 per 10,000
- most defects affect the upper limb, with the hands and fingers most commonly involved
What is phocomelia?
With what drug is it particularly associated with?
- the arms and/or legs are severely shortened or completely absent
- it is associated with thalidomide
- this disrupts the relationship between the AER and progress zone, which is needed for the proximo-distal outgrowth of the limb bud
What is amelia?
What gene disturbance is this associated with?
- a birth defect resulting in the absence of 1 or more limbs
- associated with a defect in the WNT3 gene, which prevents function of the WNT3 protein
- this is needed for normal limb development
What is polydactyly?
Why does it occur?
- the presence of extra fingers and/or toes
- SHH is usually expressed by the ZPA on the posterior (caudal) limb side
- there can be smaller ectopic expression of SHH on the anterior (cranial) limb side
- this causes cell proliferation that produces the raw material for 1 or more new digits
What is syndactyly and why does it occur?
- this is the most common malformation of the limbs that occurs when 2 or more digits are fused together
- SHH induces apoptosis of the skin between the digits in week 6
What is ectrodactyly?
Why does it occur?
- “split hand” occurring from the absence of 1 or more of the central digits
- there is failure to maintain median AER signalling leading to extensive apoptosis
What are the 4 main environmental factors that can cause limb defects?
- prenatal exposure to teratogenic drugs / toxins
- tobacco smoke (possibly)
- amniotic band syndrome
- some viruses