Extras - Foetal Malformations Flashcards

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
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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
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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:
  1. adrenal medulla
  2. conotruncal septum
  3. sympathetic NS
  4. CN ganglia
  5. thyroid gland C-cells
  6. bones / connective tissue of the face & skull
  7. GI tract parasympathetic ganglia
  8. sensory /DRG
  9. Schwann cells
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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
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5
Q

How can anencephaly be screened for?

A
  • foetal anomaly USS at 20 weeks has a 90% detection rate for NTDs
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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
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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
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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
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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:
  1. paralysis + sensory loss of the lower limb (problems with mobility)
  2. bladder + bowel dysfunction
  3. cognitive dysfunction
  4. Arnold-Chiari malformation
  5. hydrocephalus
  • it has a 90% detection rate on foetal anomaly USS @ 20 weeks
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10
Q

What are the 10 factors known to increase the risk of NTDs?

A
  1. family history of NTD
  2. previous child with NTD
  3. high temperatures in early pregnancy
  4. opioid use in first 2 months of pregnancy
  5. diabetes
  6. obesity
  7. smoking
  8. vitamin B12 deficiency
  9. folic acid deficiency
  10. anti-epileptics
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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
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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
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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
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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
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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:
  1. muscles of the limbs
  2. bones of the limbs
  3. cartilage
  • SHH is important in this process
  • these differentiating cells migrate from the somites into the developing limb bud
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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
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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)
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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
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19
Q

How is thalidomide thought to cause limb defects?

A
  • it interferes with angiogenesis and disrupts FGF signalling at the AER
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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)
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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
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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
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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
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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
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25
Q

What is the incidence of limb defects?

Which limbs are most commonly involved?

A
  • 4.4 per 10,000
  • most defects affect the upper limb, with the hands and fingers most commonly involved
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26
Q

What is phocomelia?

With what drug is it particularly associated with?

A
  • 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
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27
Q

What is amelia?

What gene disturbance is this associated with?

A
  • 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
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28
Q

What is polydactyly?

Why does it occur?

A
  • 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
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29
Q

What is syndactyly and why does it occur?

A
  • 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
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30
Q

What is ectrodactyly?

Why does it occur?

A
  • “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
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31
Q

What are the 4 main environmental factors that can cause limb defects?

A
  • prenatal exposure to teratogenic drugs / toxins
  • tobacco smoke (possibly)
  • amniotic band syndrome
  • some viruses
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32
Q

What teratogenic drugs have been associated with limb defects?

A
  1. thalidomide
  2. warfarin
  3. phenytoin
  4. misoprostol
  5. valproic acid
33
Q

What is amniotic band syndrome and how can it lead to limb defects?

A
  • 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
Q

What is chondrodystrophy?

What causes it and what are the most striking features of a foetus with this condition?

A
  • 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
Q

What is achondroplasia?

What is the mutation / pattern of inheritance and how is the skeleton affected?

A
  • 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
Q

From what structure does the primitive gut tube arise?

How is the gut tube formed and what signalling factors are involved?

A
  • 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
Q

What substance specifies early patterning of the primitive gut tube?

A

retinoic acid

  • it is important in the development of the endoderm which forms the gut tube
38
Q

What genes are important for specifying the stomach, duodenum, hindgut, midgut and liver?

A
  • stomach = CSOX2
  • duodenum = POX1
  • hindgut = COXA
  • liver = HOX
  • midgut = CDXC
39
Q

What is the cloaca?

What happens if the cloacal membrane fails to perforate?

A
  • 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
Q

How / when is the oesophagus formed?

A
  • 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
Q

What is congenital atresia of the oesophagus and when does it occur?

How would a baby with this condition present?

A
  • 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
Q

What is the upper neck pouch sign?

A
  • dilation of the blind-ending oesophagus in the upper neck during foetal swallowing
  • it is detected on prenatal USS
43
Q

What are the risk factors for congenital oesophageal atresia?

A
  • 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
Q

How does the stomach come to lie on the left side of the body?

What factors are important in establishing left-sidedness?

A
  • 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
Q

What is pyloric stenosis?

When do symptoms appear and who tends to be affected?

A
  • narrowing of the pylorus of the stomach, which leads to the duodenum
  • 4x more common in males
  • symptoms appear between 2-12 weeks
46
Q

What are the symptoms associated with pyloric stenosis?

A
  • 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
Q
A
48
Q

What is meant by “physiological herniation” of the midgut?

Why does this occur?

A
  • 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
Q

When do the midgut loops return to the abdomen?

How does the midgut move as it returns?

A
  • 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
Q

What is omphalocele and why does it occur?

What conditions is it associated with?

A
  • 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
Q

How is omphalocele screened for?

in what groups is it more common?

A
  • foetal anomaly USS screening @ 20 weeks has a 90% detection rate
  • it is associated with raised AFP
  • more common in young mothers
52
Q

What is the prognosis of omphalocele like?

What are the associated risks?

A
  • 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
Q

What is gastroschisis?

What causes it?

A
  • 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
Q

What are the main differences between omphalocele and gastroschisis?

A
  • 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
55
Q

How is gastroschisis detected prenatally?

What causes this condition?

A
  • 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
Q

What is the prognosis of gastroschisis like and why?

A
  • 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
Q

What does the urinary system develop from?

What 3 “systems” develop in a sequential, slightly overlapping fashion?

A
  • 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
Q

What forms the ureteric bud?

What does this go on to form?

A
  • 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
Q

What is polycystic kidney disease and why does it occur?

A
  • 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
Q

What are the complications associated with polycystic kidney disease?

A
  • 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
Q

What is horseshoe kidney and why does it occur?

What are the associated complications?

A
  • 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
Q

What is duplicated ureter?

Why does this occur?

A
  • 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
Q

Why are accessory renal arteries common?

Where do they travel?

A
  • 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
Q

What is the crucial factor involved in sex differentiation?

A

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
Q

When do the gonads begin to differentiate as male or female?

How do they first appear and what migrates to this area?

A
  • 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
Q

What are the 2 pairs of genital ducts that are initially present in both males and females?

A
  • mesonephric (Wolffian)
  • paramesonephric (Müllerian)
67
Q

In males, what factors promote development of the of the mesonephric ducts and induce regression of the paramesopnephric ducts?

A
  • 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
Q

What structures do the mesonephric ducts in the male give rise to?

A
  • epididymis
  • vas deferens
  • seminal vesicle
  • ejaculatory duct
  • this relies on testosterone and its androgen receptor
69
Q

What is hypospadias?

A
  • 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
Q

What is epispadias?

What other malformations is this associated with?

A
  • 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
Q

When does inguinal hernia occur?

What are the 2 different types and why is it more common in males?

A
  • 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
Q
A
73
Q

What factors promote development of the paramesonephric duct and regression of the mesonephric duct in females?

A
  • the mesonephric duct regresses in the absence of testosterone
  • the paramesonephric duct persists and develops in the absence of anti-Müllerian hormone
74
Q

What structures does the paramesonephric duct give rise to in the female?

A
  • Fallopian tubes
  • uterus
  • upper part of the vagina
75
Q

What is a bicornuate (bilobed) uterus?

Why does this occur?

A
  • 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
Q

What is a uterus didelphys and why does it occur?

A
  • 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
Q
A
78
Q

What is a septate uterus and why does this occur?

A
  • 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