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
What teratogenic drugs have been associated with limb defects?
- thalidomide
- warfarin
- phenytoin
- misoprostol
- valproic acid
What is amniotic band syndrome and how can it lead to limb defects?
- fibrous bands of the amniotic sac separate and entangle the foetus
- this leads to deep groves in or amputation of the distal extremities
- there may also be swelling of the extremities distal to the point of constriction
What is chondrodystrophy?
What causes it and what are the most striking features of a foetus with this condition?
- skeletal dysplasia caused by abnormal cartilage development
- it can be caused by many genetic mutations that can be inherited (autosomal recessive)
- in the foetus, the skull and abdomen are the same size
- there is a normal sized trunk with abnormally short limbs + extremities
What is achondroplasia?
What is the mutation / pattern of inheritance and how is the skeleton affected?
- an autosomal dominant inherited condition
- the primary feature is dwarfism (shortened arms / legs with normal size torso)
- there is a mutation in the FGFR3 gene, which is needed for collagen production
- cartilage is not able to fully develop into bone, resulting in shortened bones
From what structure does the primitive gut tube arise?
How is the gut tube formed and what signalling factors are involved?
- it arises from the yolk sac, which is lined with endoderm
- the 4 sections of the gut are sectioned by the concentration of retinoic acid
- high conc RA = hindgut, low conc RA = pharyngeal gut
- interaction between the endoderm and mesoderm is initiated by the action of SHH and activation of HOX genes
- the gut tube is formed during cranial-caudal folding
What substance specifies early patterning of the primitive gut tube?
retinoic acid
- it is important in the development of the endoderm which forms the gut tube
What genes are important for specifying the stomach, duodenum, hindgut, midgut and liver?
- stomach = CSOX2
- duodenum = POX1
- hindgut = COXA
- liver = HOX
- midgut = CDXC
What is the cloaca?
What happens if the cloacal membrane fails to perforate?
- common chamber where the urinary, digestive and reproductive tracts all discharge their contents
- failure of the cloacal membrane to perforate results in a single opening into which the rectum, urethra and vagina enter
How / when is the oesophagus formed?
- the lung bud appears as an outpocketing from the ventral wall of the foregut in week 4
- the tracheo-oesophageal ridges grow towards each other
- this forms the tracheo-oesophageal septum, which divides the respiratory diverticulum from the oesophagus
What is congenital atresia of the oesophagus and when does it occur?
How would a baby with this condition present?
- the oesophagus ends in a blind-ended sac (usually occurs with distal TOF)
- it occurs in week 4 when the tracheo-oesophageal septum should grow to separate the oesophagus from the lung bud
- it presents with:
- aspiration on attempting to feed
- regurgitation of milk
- gastric acid reflux
- upper neck pouch sign
- it is associated with an increased risk of aspiration pneumonia
- the stomach acid can enter the lungs and cause damage
What is the upper neck pouch sign?
- dilation of the blind-ending oesophagus in the upper neck during foetal swallowing
- it is detected on prenatal USS
What are the risk factors for congenital oesophageal atresia?
- part of the VACTERL association
- usually at least 3 are involved of - vertebral column, anorectal, cardiac, tracheal, esophageal, renal and limbs
- diabetes
- gene malformations
- mitochondrial dysfunction
How does the stomach come to lie on the left side of the body?
What factors are important in establishing left-sidedness?
- it rotates 90o clockwise around its longitudinal axis, meaning the left side faces anteriorly
- cellular proliferation occurs much faster in the posterior wall (now on the left), resulting in formation of the greater and lesser curvatures
- rotation about the antero-posterior axis results in the caudal end (pylorus) moving up and to the right
- the cranial part (cardiac part) moves down and to the left
What is pyloric stenosis?
When do symptoms appear and who tends to be affected?
- narrowing of the pylorus of the stomach, which leads to the duodenum
- 4x more common in males
- symptoms appear between 2-12 weeks
What are the symptoms associated with pyloric stenosis?
- palpable pyloric mass
- projectile vomiting (without bile) usually after feeding
- poor feeding
- weight loss
- constant hunger
- dehydration - crying with no tears, less wet/dirty nappies, infrequent urination
What is meant by “physiological herniation” of the midgut?
Why does this occur?
- rapid growth of the liver causes the midgut to herniate into the umbilical cord in week 6 due to reduced space in the abdomen
- the midgut grows faster than the abdominal cavity
- the midgut rotates 90o anticlockwise within the umbilical cord
When do the midgut loops return to the abdomen?
How does the midgut move as it returns?
- during weeks 10-11 when the abdomen enlarges
- the midgut rotates a further 180o anticlockwise as it returns to the abdomen
- the midgut is fixed to the posterior retroperitoneum
- rotation of the midgut is completed by week 12
What is omphalocele and why does it occur?
What conditions is it associated with?
- persistence of the intestine (+/- other viscera) in the umbilical cord as the midgut does not return to the abdomen in week 10
- it is caused by malrotation of the bowels
- associated with trisomy 18 and 13
How is omphalocele screened for?
in what groups is it more common?
- foetal anomaly USS screening @ 20 weeks has a 90% detection rate
- it is associated with raised AFP
- more common in young mothers
What is the prognosis of omphalocele like?
What are the associated risks?
- it has a poor prognosis as it is commonly associated with other congenital malformations
- the prognosis depends on the size of the defect
- potential risks include:
- risk of rupture
- intestinal necrosis
- intestinal atresia
- bowel obstruction
What is gastroschisis?
What causes it?
- the intestines extend outside of the abdomen through a hole next to the bellybutton
- this tends to occur to the right of the midline
- the cause is unknown, but the size of the hole/organs involved is variable
- it is a malformation in lateral body wall folding where it fuses in the thorax, but not in the abdomen
What are the main differences between omphalocele and gastroschisis?
- in omphalocele, the gut is covered by membranes (outpouching of peritoneum)
- in gastroschisis, there is no involvement of the umbilical cord and the intestines are not in a membranous sac (free in amniotic fluid)
- the defect is usually smaller in gastroschisis
How is gastroschisis detected prenatally?
What causes this condition?
- 90% detection rate on foetal anomaly USS
- there are no signs of this condition during pregnancy, so sometimes it is not detected until birth
- the cause is unknown, but risk factors are:
- alcohol consumption
- smoking
- young mothers (<20)
What is the prognosis of gastroschisis like and why?
- it is fatal if left untreated as exposed intestines present a greater risk of infection
- decreased blood flow to the exposed intestines also leads to increased risk of necrotising enterocolitis
- with treatment, survival is up to 90%
What does the urinary system develop from?
What 3 “systems” develop in a sequential, slightly overlapping fashion?
- the urinary system develops from intermediate mesoderm
- the pronephros is rudimentary and does not function - it has disappeared by week 4
- some ducts / tubules contribute to the male genital system
- the mesonephros begins to develop in week 4 and functions for a time
- the metanephros starts to develop during week 5 and will form the definitive kidney
What forms the ureteric bud?
What does this go on to form?
- the ureteric bud is a protrusion from the mesonephric duct
- it will give rise to the collecting duct system of the kidneys:
- collecting ducts
- callyces
- renal pelvis
- ureter
What is polycystic kidney disease and why does it occur?
- it can be autosomal dominant (PKD1, 2 or 3) or recessive (PKHD1)
- multiple cysts develop in the kidneys due to the renal tubules being strucurally abnormal
- cysts are non-functioning tubules that are filled with fluid that can compress adjacent normal tubules, eventually rendering them non-functional as well
- formation of cysts causes the kidneys to enlarge and lose function over time
What are the complications associated with polycystic kidney disease?
- recessive causes kidney failure in childhood, whereas dominant causes kidney failure in adulthood
- hypertension (due to activation of RAAS)
- frequent headaches
- abdominal pain / back pain
- frequent urination / blood in urine
What is horseshoe kidney and why does it occur?
What are the associated complications?
- the inferior poles of the kidneys fuse to form a single horseshoe shaped kidney
- it is usually asymptomatic, but can affect kidney drainage, leading to:
- increased risk of kidney stones
- increased frequency of UTIs
- increased risk of renal cancers
- more frequent infections
What is duplicated ureter?
Why does this occur?
- this occurs when there are 2 ureters draining a single kidney
- it occurs when the ureteric bud splits (or arises twice), which gives rise to the ureter
Why are accessory renal arteries common?
Where do they travel?
- due to persistence of the embryonic vessels that form during ascent of the kidneys
- they arise from the aorta and enter the superior or inferior poles (not hilum)
What is the crucial factor involved in sex differentiation?
presence or absence of a Y chromosome
- the Y chromosome contains a region called the SRY gene
- the SRY gene codes for the protein testes determining factor (TDF)
- in the presence of TDF, male development occurs
When do the gonads begin to differentiate as male or female?
How do they first appear and what migrates to this area?
- the gonads begin to differentiate as male or female in the 7th week
- they appear first as the genital ridges - these are epithelium with underlying mesenchyme
- germ cells migrate to the primitive gonad in week 4 and invade the genital ridges in week 6
- after arrival of the germ cells, the genital ridges proliferate to form the primitive sex cords
- at this stage, the male and female gonad are the same so this is the indifferent gonad
What are the 2 pairs of genital ducts that are initially present in both males and females?
- mesonephric (Wolffian)
- paramesonephric (Müllerian)
In males, what factors promote development of the of the mesonephric ducts and induce regression of the paramesopnephric ducts?
- testosterone is produced by Leydig cells
- this binds to and activates the androgen receptor, which prevents regression of the mesonephric ducts
- anti-Müllerian hormone is produced by Sertoli cells, which induces regression of the paramesonephric ducts
What structures do the mesonephric ducts in the male give rise to?
- epididymis
- vas deferens
- seminal vesicle
- ejaculatory duct
- this relies on testosterone and its androgen receptor
What is hypospadias?
- a birth defect in which the opening of the urethra is not located at the tip of the penis
- 90% are distal, in which the urethral opening is on or near the head of the penis
- 10% are proximal, in which the urethral opening is near or within the scrotum
What is epispadias?
What other malformations is this associated with?
- a malformation in which the urethra ends in an opening on the upper aspect of the penis
- it can occur in females where the urethra exits through the clitoris (too far anteriorly)
- it is part of the exstrophy-epispadias complex, in which the bladder is open and exposed on the outside of the abdomen
When does inguinal hernia occur?
What are the 2 different types and why is it more common in males?
- it occurs when the inguinal canal fails to shut off after 1 year of development, resulting in the intestines protruding through the inguinal canal
- a direct hernia passes through the superficial inguinal ring
- an indirect hernia passes through both the deep and superficial inguinal rings
- in males, the hernias follow the same route as the descending testes as they migrate into the scrotum
- the inguinal canal is much larger in males
What factors promote development of the paramesonephric duct and regression of the mesonephric duct in females?
- the mesonephric duct regresses in the absence of testosterone
- the paramesonephric duct persists and develops in the absence of anti-Müllerian hormone
What structures does the paramesonephric duct give rise to in the female?
- Fallopian tubes
- uterus
- upper part of the vagina
What is a bicornuate (bilobed) uterus?
Why does this occur?
- the upper portion of the Müllerian ducts do not fuse, but the lower portion does and develops as normal
- the lower portion develops into the lower uterine segment, cervix and upper vagina
- this produces a deep indentation at the top of the uterus
What is a uterus didelphys and why does it occur?
- fusion of the Müllerian ducts does not occur, causing a double uterus
- this produces 2 uteri with 2 cervices and possibly a double vagina
- each uterus has a single horn linked to the ipsilateral Fallopian tube
What is a septate uterus and why does this occur?
- the uterine cavity is partitioned by a longitudinal septum
- this can be complete or incomplete
- if it is complete, there is also a double cervix and often a double vagina
- it occurs as the septum formed by the fusion of the Müllerian ducts does not disintegrate
