Congenital Development of Disease Symposium

Question 1

What is Gastrulation?

Answer 1

• when the bilaminar disk of the embryo develops to form 3 distinct layers - usually around week 3
  
  • ectoderm (from the epiblast)
  • mesoderm (invading epiblast cells from the primary streak)
  • endoderm (hypoblast replaced by epiblast cells)

Question 2

What happens during fertilization Day-1 ?

Answer 2

• Sperm and Ovum meet in Uterine Tube (usually in the ampulla) 12-24 hours after ovulation.
• Penetration of Corona radiate and Zona pellucida
• Fusion and 2nd meiotic division
• Acrosome reaction makes ovum impermeable to other sperm
• End- Zygote- has diploid (46 chromosomes)

Question 3

What happens in days 2-3 after fertilization?

Answer 3

• Cleavage occurs- this is the rapid process of mitotic divisions
• The first mitotic division occurs around 30 hours post-fertilization.
• By day 3 the fertilized ovum has become a 16 cell embryo
• Each cell is known as a blastomere.
• forming a solid sphere is known as a morula.

Question 4

What happens day 4-5 post-fertilization?

Answer 4

• Morula develops a cavity and becomes known as a blastocyst.
• The outer layer of the blastocyst thins out and becomes the trophoblast this helps form the placenta
• The rest of the cells move (are pushed up) to form the inner cell mass. This creates an embryonic pole.
• The blastocyst has now reached the uterine lumen and is ready for implantation.

Question 5

What happens day 6-7 post-fertilization?

Answer 5

• the Bilaminar Disc forms- As the embryo starts to implant it forms two layers.
• Inner cell mass differentiates into two layers: epiblast and hypoblast.
• These two layers are in contact.
• Hypoblast forms extraembryonic membranes
• Epiblast forms embryo
• the Amniotic cavity develops within the epiblast mass

Question 6

What happens day 6-8 post-fertilization?

Answer 6

• The Primary Yolk Sac is formed
  
  • it is derived from the hypoblast is the exocoelomic membrane. (aka Extraembryonic hypoblast/membrane)
• The Yolk Sac contains nutrients that supply the embryo before the placenta functions.

Question 7

How has the embryo developed by week 4?

Answer 7

• the flat disc has to fold into 2 directions
• Longitudinal (cephalocaudal) (day 21) begins so that head and tail are brought closer.
• Lateral (transverse) (day 18) brings the amniotic cavity down, creating the future gut tube inside the peritoneal cavity.

Question 8

Describe the structure of the Mesoderm

Answer 8

• formed of three parts
  
  • ​Paraxial mesoderm
  • Lateral plate mesoderm
  • Intermediate mesoderm
• these structures are either side of the notochord
  
  • this is made from the mesoderm
  • remains as the nucleus palposus, the inside part of the vertebrae throughout embryonic development

Question 9

Explain what happens to the Paraxial mesoderm and what its role is in the development

Answer 9

• Paraxial mesoderm undergoes further differentiation into paired blocks of tissue- somites
  
  • 42-44 pairs eventually formed (prep for the vertebral arch)
• Somites undergo differentiation to form dermomyotomes and sclerotomes
• Dermomyotomes: form connective tissue and skeletal muscle
• Sclerotomes: form bone and cartilage- vertebral arch
  
  • _​_the cells from the sclerotome come around the neural tube and form the boney arch (spinous process)
  • if they don’t come around and join completely –> spinabifida

Question 10

Label the structures of this Somite

Answer 10

Question 11

What is the role of the Intermediate mesoderm?

Answer 11

• it gives rise to the urogenital system
  
  • kidneys - from the pronephros then mesonephros then the metanephros
  • gonads
  • urogenital ducts and associated glands
    
    • formed from the degenerating excretory tubules of the mesonephros and pronephros

Question 12

What is the role of the Lateral plate mesoderm?

Answer 12

• creates the parietal and visceral layers
• Continuous with the amniotic sac and yolk sac.
• Amniotic sac mesoderm–> Parietal or somatic layer
• Yolk sac mesoderm–> Splanchnic layer
• Mesodermal cells will become the membranes of the body (pericardium, pleura, peritoneum)
• all cavities are lined with lateral plate mesoderm to form tha parietal layer and the visceral layer
  
  • this then begins to fold to form a horseshoe shape creating an Intraembryoinc cavity which is u shaped
• the bend in the U becomes the pericardial cavity
• limb of U becomes 2 cavities pericardioperitoneal (pleural) and peritoneal cavities.

Question 13

Give an overview of the development of the pharyngeal clefts and pouches

Answer 13

• Clefts separate the arches externally.
• First cleft is the only one that contributes towards the adult structures: external acoustic meatus
• The endoderm of the foregut grows and forms pouches which become: auditory tube, tonsils, thymus and parathyroid gland.
• 1-4 well developed, 5th absent

Question 14

Give an overview of the development of the face week 4-5

Answer 14

• Development begins in week 4 and forms from 5 swellings.
  
  • Frontonasal
  • Maxillary X2
  • Mandibular X2

By week 5 two events occur:

• Maxillary prominences enlarge in the medial direction
• Nasal placodes appear and form medial and lateral processes

Question 15

Give an overview of the development of the face week 6-8

Answer 15

• Maxillary prominences enlarge in the medial direction
  
  • the maxillary prominences fuse with the lateral and medial nasal processes to form the upper lip
• Nasal placodes appear and form medial and lateral processes
  
  • medial nasal processes merge towards each other and form intermaxillary segments

Question 16

How is the Palate formed?

• consequences fo improper formation?

Answer 16

• Develops from the fusion of the primary and secondary palate
• Grows obliquely down and then elevates
• Fuses in the midline at palatine raphe
• At the same time frontonasal process and medial nasal processes form nasal septum
• if this doesn’t occur properly this results in a cleft palate/ lips

Question 17

Give an overview of Ear formation

Answer 17

• Eyes and ears arise from ectodermal placodes
• Placodes are thickened areas of ectoderm which have interacted with the neural tube.
• External and middle ear derived from first 2 pharyngeal arches and cleft and pouch
• Inner ear develops at day 22 into otic placode.
• Otic vesicle enlarges and forms 2 parts: Dorsal vestibular portion- semicircular canals and Ventral cochlear portion- cochlea

Question 18

Give an overview of Tongue formation

• anterior
• posterior (pharyngeal)

Answer 18

Anterior Tongue

• 3 tongue buds form from 1st arch
• The distal buds (lateral lingual swellings) expand and fuse and overgrow the median bud to form the anterior tongue.

Pharyngeal tongue (posterior)

• Two swellings from 2nd, 3rd & 4th arches.
• V-shaped line represents the line of fusion, with a midline depression (foramen caecum- the origin of the thyroid gland)
• Hence different innervation of the tongue

Question 19

What is the innervation for different parts of the tongue?

Answer 19

• CN V3 - oral sensation (1st arch) blue
• CN VII - oral taste (2nd arch) red
• CN IX - pharyngeal taste/sensation (3rd arch) green

Question 20

What does LKA stand for?

• what is it, when is it used

Answer 20

• Leukotriene receptor antagonist
• this is a low dose ICS
• used in under 5’s

Question 21

Why is a specific diagnosis of disease important?

Answer 21

• can lead to a specific treatment
• allows you to counsel the parents more accurately
  
  • genetic counselling for future pregnancies
• estimate recurrence risk
• prenatal diagnosis & intervention where possible

Question 22

How do you classify Single defects?

• examples
• recurrence risk

Answer 22

• Defect involves just a single structure
• Child otherwise “Normal”
• Examples - CDH, CTEV, Cleft lip/palate, CHPS, cardiac septal defects, neural tube defects
• Multi-factorial (?unknown)
• Recurrence risk: 2 to 6%

Question 23

How can single defects present?

Answer 23

• Malformation
  
  • localised defect during differentiation
  • CHPS, cardiac septal defects
• Deformation
  
  • structural alteration after ‘normal’ differentiation
  • CDH, CTEV
• Disruption
  
  • ​Structural destruction of a previously ‘normally’ formed part
  • due to entanglement, disruption of blood supply

Question 24

What is Pyloric Stenosis?

• prevalence
• management/treatment

Answer 24

• constriction of the pyloric sphincter
• occurs in 3 per 1000 live births
  
  • usually in Males 4:1, first born
• presents with Non-bilious projectile vomiting at the 2nd week
• feeling Pyloric ‘tumor’ after a test feed. You can also see parelstlatic waves when they swallow
  
  • this is in 60-80% of cases
• Hypochloremic (hypokalemic) metabolic alkalosis
  
  • due to excess fluid loss when vomiting
• Treatment –> Pyloromyotomy
  
  • small incision in the pylorus muscle - not too deep.
  • allows baby to feed soon after the surgery

Question 25

What is a Dysplastic Hip?

• presentation/ diagnososis
• management/treatment

Answer 25

• a Dislocated or dislocatable hip
• occurs more frequently in female 9:1, 1 in 1000 / 100 and Breech births
• can present with asymmetric skin folds
• Barlow test – try to dislocate
• Ortolani test – try to relocate the dislocated hip
  
  • Clunk vs Click when the hip is relocated
• Early diagnosis –> Conservative treatment (Pavlik Harness)
• Late diagnosis –> Surgical correction, more specialist the later the diagnosis

Question 26

What is Intestinal Atresias?

• presentation/diagnosis
• managment/treatment

Answer 26

• Obstructruction of the intestinal tract
• Oesophageal atresia (with/out TO fistula)
• Duodenal atresia
• Jejunal / Ileal atresia
  
  • (incomplete – stenosis)
• Polyhydramnios
• Intestinal obstruction
• Emergency that needs surgery

Question 27

What is a sequence single defect?

• give examples of the two main sequences

Answer 27

• Single defect, but it’s multiple anomalies
• due to a cascade of secondary & tertiary errors in differentiation
• Examples
  
  • Breech deformation sequence (not a deformation in itself but causes a sequence of events that cause deformation)
    
    • Barthrocephaly, torticollis, facial asymmetry, dislocated hip, valgus deformities of the foot
  • Amniotic band disruption sequence
    
    • craniofacial and limb defects

Question 28

What are Multiple defects and what are there cause?

Answer 28

• Several structural defects (at least 2 systems)
• Chromosomal abnormalities
• Single Gene mutations
• Teratogens

Question 29

Give an overview of chromosomal abnormalities

• types of abnormalities
• types of syndromes caused
• causes of specific syndromes

Answer 29

• Abnormalities of Chromosomal number
  
  • Trisomy – 21, 18, 13
  • Monosomy – Mostly lethal; (Turner Syndrome)
• Abnormalities of chromosomal structure
  
  • Deletions, micro-deletions, duplications, invertions – 4p-, 5p- etc
• Sex chromosome abnormalities
  
  • 45XO, 47XXY, 47XYY
• Mosaicisms - more than two cell lines from a single zygote- associated with structural defects
  
  • germline mosaicism is transmittable to offspring
• Fragile sites / Breakage syndromes
• Imprinting / Uniparental disomy:
  
  • Prada-willi syndrome: paternal deletion of 15q11
  • Angelman syndrome: maternal deletion of 15q11

Question 30

What is Downs syndrome?

• common presenting features

Answer 30

• caused by Trisomy 21 (translocation)
  
  • 1 in 660
• Typical facies
  
  • Clinodactyly, Simian crease
  • Congenital Heart Defects
  • Duodenal atresia
  • Hypotonia
  • Delayed Development
• common facial features are
  
  • Epicanthic folds, upslanting & narrow palpebral fissures, hypertelorism,
  • flat nasal bridge, small chin, protruding tongue, low set ears,
  • relatively small mouth and large forehead and sometimes microcephaly
• Good Social skills

Question 31

Give an overview of Single Gene mutations

• what types are there
• what diseases are they associated with?

Answer 31

• Mutations or ‘pathologic’ variants
• For example
  
  • Autosomal Dominant - Marfans, neurofibromatosis
  • Autosomal Recessive - Phenylketonuria (PKU)
  • X-linked Recessive - Haemophilia
  • X-linked Dominant – Hypo Phosphataemic Rickets
  • Maternal Inheritance – Mitochondrial diseases
• having an extended family history can be helpful with diagnosis

Question 32

What is Neurofibromatosis Type 1?

-

Answer 32

• tumour formed on a nerve cell sheath, frequently symptomless but occasionally malignant.
• 1 in 4000; Autosomal Dominant defect - 17q11.2
  
  • Variable penetration
• Neural crest cells – differentiation/migration
• Café-au-lait spots, neurofibromas, freckling, lisch nodules, bone lesions, optic glioma, must have a family history of NF1
• Disfiguring & varied features
• associated with Non-cancerous CNS tumours
• Health surveillance

Question 33

Give an overview of Tertagoens that can cause defects

• what defects do they cause

Answer 33

• Infections
  
  • Congenital Rubella causes:
    
    • cataracts, blindness, deafness, IUGR, microcephaly, CVS anomalies and developmental delay
• Chemicals
  
  • Foetal alcohol syndrome
    
    • IUGR, facial features - short palpebral fissures, epicanthal folds, small jaw, thin upper lip, long philtrum
    • cardiac defects, joint & limb anomalies and delayed development
  • Maternal Phenylketonuria (PKU)
    
    • miscarriage, microcephaly, dev. delay, cardiac defects
• Drugs
  
  • Thalidomide
  • Valproate ( used to treat epilepsy and bipolar disorder)
    
    • neural development disorders

Question 34

What is PKU?

Answer 34

• phenylketonuria
• a genetic disorder that causes increase levels of the amino acid phenylalanine in the body

Question 35

What are the two main Non-random grouping defects (Associations) to be aware of when diagnosing defects?

Answer 35

• VATER association
  
  • ​Vertebral
  • Ano-rectal
  • Tracheo-Oesophagal fistula
  • Renal/Radial anomalies
• CHARGE association
  
  • ​Coloboma
  • Heart defects
  • Atresia Choanae
  • Retarded growth
  • Genital anomalies
  • Ear anomalies

Question 36

What is the diagnostic process when presented with Cafe au lait spots?

What are differentials for Cafe au lait spots?

Answer 36

Diagnostic process

• Look for other features
• Special examinations
• Imaging
• Blood tests
• Genetic testing
• Consult databases
• Consult specialists
• Review in few years

Differentials

• “Normal”
• Neurofibromatosis
• McCune Albright Syndrome
• Ataxia telangiectasia
• Tuberous sclerosis
• Gauchers disease
• Russell Silver syndrome