Extras - Foetal Malformations Flashcards
(78 cards)
1
Q
What is the neural plate?
What does it go on to form by week 4?
A
- 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
2
Q
What are the 3 primary brain vesicles and what do they give rise to?
In what week do the cerebral hemispheres begin to develop?
A
- 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
3
Q
What are neural crest cells?
What structures do these go on to form?
A
- 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
4
Q
What is anencephaly and why does it occur?
What is the prognosis of this condition like?
A
- 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
5
Q
How can anencephaly be screened for?
A
- foetal anomaly USS at 20 weeks has a 90% detection rate for NTDs
6
Q
What NTD is associated with hydrocephalus?
Why does this occur?
A
- 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
7
Q
What causes spina bifida?
Why do the symptoms vary from asymptomatic to severe?
A
- 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
8
Q
What is a meningocele?
A
- 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
9
Q
What is a myelomeningocele?
What symptoms is it associated with and how may it be detected?
A
- 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
10
Q
What are the 10 factors known to increase the risk of NTDs?
A
- 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
11
Q
What public health measure has reduced the incidence of NTDs?
What are the problems with implementing this?
A
- 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
12
Q
What marker is raised in NTDs that can be detected prenatally in maternal serum and amniotic fluid?
A
alpha-fetoprotein (AFP)
- this is part of the quadruple serum test @ 15-18 weeks
- AFP cannot be detected via chorionic villus sampling
13
Q
What is craniorachischisis?
What causes it and what is the prognosis?
A
- 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
14
Q
When do the limb buds appear?
What are they composed of?
A
- 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
15
Q
What are somites formed from?
What factor is important in this process and how does it contribute to limb formation?
A
- 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
16
Q
What 3 axes does the limb develop along?
What factors are important in ensuring this happens correctly?
A
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
17
Q
What is secreted by the mesenchymal core of the limb bud that stimulates proximodistal outgrowth?
A
- 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)
18
Q
What is secreted by the AER and how does this contribute to proximodistal limb growth?
A
- 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
19
Q
How is thalidomide thought to cause limb defects?
A
- it interferes with angiogenesis and disrupts FGF signalling at the AER
20
Q
How is craniocaudal patterning of the limb bud achieved?
A
- 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)
21
Q
How is dorso-ventral patterning of the limb bud achieved?
A
- 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
22
Q
What other gene is involved in dorsoventral patterning?
What syndrome can result if there is a defect in this gene?
A
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
23
Q
How do the digits form from the hand and footplates that appear in week 6?
A
- 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
24
Q
What is synpolydactyly?
What gene mutation is involved?
A
- the combination of syndactyly (fusion of digits) and polydactyly (supernumerary digits)
- mutations in HOX genes result in the formation of new body segments
25
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
26
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
27
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
28
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
29
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
30
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_**
31
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
32
What teratogenic drugs have been associated with limb defects?
1. thalidomide
2. warfarin
3. phenytoin
4. misoprostol
5. valproic acid
33
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
34
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_**
35
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
36
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_**
37
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
38
What genes are important for specifying the stomach, duodenum, hindgut, midgut and liver?
* stomach = **CSOX2**
* duodenum = **POX1**
* hindgut = **COXA**
* liver = **HOX**
* midgut = **CDXC**
39
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
40
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
41
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:
1. **aspiration** on attempting to feed
2. **regurgitation** of milk
3. gastric acid **reflux**
4. **upper neck pouch sign**
* it is associated with an increased risk of **_aspiration pneumonia_**
* the **stomach acid can enter the lungs** and cause damage
42
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
43
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
44
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
45
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**
46
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
47
48
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
49
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_**
50
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**
51
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**
52
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:
1. ***risk of rupture***
2. ***intestinal necrosis***
3. ***intestinal atresia***
4. ***bowel obstruction***
53
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
54
What are the main differences between omphalocele and gastroschisis?
* in **omphalocele**, the gut is **_covered by membranes_** (outpouching of peritoneum)
* in **gastroschisi**s, 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
55
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:
1. ***alcohol consumption***
2. ***smoking***
3. ***young mothers (\<20)***
56
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%
57
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**
58
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:
1. collecting ducts
2. callyces
3. renal pelvis
4. ureter
59
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
60
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
61
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:
1. increased risk of **kidney stones**
2. increased frequency of **UTIs**
3. increased risk of **renal cancers**
4. more frequent **infections**
62
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
63
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)
64
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
65
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_**
66
What are the 2 pairs of genital ducts that are initially present in both males and females?
* mesonephric (Wolffian)
* paramesonephric (Müllerian)
67
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
68
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
69
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**
70
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
71
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*
72
73
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_**
74
What structures does the paramesonephric duct give rise to in the female?
* Fallopian tubes
* uterus
* upper part of the vagina
75
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
76
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
77
78
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_**
