Embryonic Development and Congenital Malformations

• Embryonic period or period of organogenesis

  • occurs from the 3rd/4th to the 8th week of development
  • is the time when each of the three embryonic primary germ disc layers - ectoderm, mesoderm and endoderm, give rise to definitive specific adult tissues and organs
  • by the end of this period the main organ systems have been established including rendering the major features of the external body form of the developing embryo recognisable
• The ectodermal Layer in general terms Gives rise to organs and structures that maintain contact with the outside world.

  • induced to form neuroectoderm that leads to the formation of the neural tube (via neurulation)
  • also gives rise to the neural crest cells and pituitary gland
  • the sensory epithelium of the ear, nose and eye
  • the epidermis of the skin and other integumentary structures - hair, nails, sweat glands, mammary glands etc.
  • the enamel of the teeth
  • The oral and proctodeal (anal canal) epithelium
• The mesoderm is made up of three parts:

  • Paraxial mesoderm
  • intermediate mesoderm
  • lateral plate mesoderm
• Paraxial mesoderm

  • Form segmental blocks called somitomeres which in the head region is called neuromeres in association with the neural plate
  • the neuromeres contribute to the mesenchyme (connective Tissue) in the head
  • from the neck (occipital) region downwards the somitomeres form segmented pairs of blocks of mesoderm called somites on either side of the developing neural tube
• • the first pair of somites arises in the occipital region of the embryo at about the 20th day of development
  • new somites appear craniocaudally at the rate of about 3 pairs per day
  • at the end of the 5th week about 42 to 44 pairs of somites would have been formed
  • there are 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral and 8-10 coccygeal pairs of somites
  • The age of an embryo can be accurately determined by counting somites numbers during this period of development because somites are formed with a specific periodicity
• Intermediate mesoderm

  • Contribute in the formation of the structures of the urogenital system including the primordial germ cells, gametes and gonads.
• • the parietal layer lines the body (intra embryonic) cavity walls
  • mesoderm from the parietal layer together with the overlying ectoderm, forms the lateral body wall

  also forms

  • The dermis of the skin in the body wall and limbs, bones and connective tissue of the limbs and sternum
  • the costal cartilage, limb muscles and most of the body wall muscles
  • the mesothelioma or serous membranes that line the peritoneal, pleural and pericardial cavities and secrete serous fluid
• Lateral plate mesoderm is split into parietal (somatic) and visceral (splanchnic) layers.
• • Mesoderm of the visceral layer together with the endoderm form the wall of the gut tube.
  • also forms the serous membrane that surrounds organs, and the blood cells and blood vessels
• The main derivative of the endodermal layer is the epithelial lining of the gastrointestinal tract including the pharynx. It also forms:

  • the epithelial lining of the respiratory tract, the urinary bladder and urethra, and the tympanic cavity and auditory tube
  • the parenchyma of the thyroid, parathyroids, liver and pancreas.

  The walls of the GI tract - smooth muscle and other connective tissue are derived from the mesoderm.
• Morphogenesis

  • Form shaping process (arrangements and shaping of body parts) in an embryo, controlled by fundamental cell behaviours that result in differential tissue growth
  • Cellular behaviours include changes in cell shape, size, position, number, migration and adhesivity
  • Interference with differential tissue growth in an embryo, that could be occasioned by genetic mutation, teratogen exposure or a combination of these two processes could result in dysmorphogenesis and the formation of birth defects.
• When responses due to the influence of genetic variations and environmental factors during development (morphogenesis) are considered together, an Abstract norm is defined.

  individuals who develop within a close range of this abstract norm both in form and function are said to have developed normally - normogenesis

  individuals who develop outside this more or less arbitrary range are considered to have developed abnormally - dysmorphogenesis
• Structural Birth Defects involve both Malformations and Deformation resulting from abnormal development (Dysmorphogenesis).

  Birth Defects, Congenital Malformations, and Congenital Anomaly are terms used synonymously to describe structural, behavioural, functional, and metabolic disorders present at birth.
• Malformations consist of primary morphologic defects in an organ or body part and result from disturbance of developmental events or processes directly involved in the formation of a particular structure (e.g. Neural Tube Defects (NTDs) due to none closure of neural folds or Syndactyly due to failure of the digits to fully separate.

  Malformations could be caused by environmental (teratogens) and/or genetic factors acting independently or together.
• Deformation consist of secondary morphologic defects that are imposed upon an organ or body part due to mechanical forces over a prolonged period – an indirect effect.

  Clubfeet due to compression in the amniotic cavity as a result of insufficient amniotic fluid (Oligohydramnios).

  Deformation is common with the skeletal system development.
• Most deformations have a very good and excellent prognosis and very low recurrence risk in contrast with many malformations.

  Disruptions result in morphological alterations of already formed structures due to destructive processes.

  Defects produced by amniotic bands – cleft lip, toe and finger amputations.
• When Dysmorphogenesis occurs as a pattern of well characterised multiple primary malformations appearing together in a predictable fashion in one or more tissues due to a specific underlying single or common cause, it is described as a Syndrome.
• Fetal alcohol syndrome (or Fetal alcohol spectrum disorder).

  • Short palpebral fissure lengths
  • Smooth philtrum
  • Thin upper lip
  • Brain damage
• Down syndrome (Trisomy 21)

  • Flat facial feature with a small nose
  • Reduced muscle tone (Hypotonia)
  • Upward/Downward slant to the eye
  • Enlarge tongue that tends to stick out
  • Single deep crease across the centre of the palm
  • Hyperflexibility (extension) of the joints.
• Teratology is a term used to describe the study of birth defect or congenital malformation or congenital anomaly.

  A Teratogen is any factor or agent that causes birth defect or congenital malformation or congenital anomaly – (see table 9.1 Langman’s Medical Emrbyology 12th Edition).
• The following factors are said to determine the capacity of an agent (teratogen) to produce birth defects:

  Genotype of the conceptus and the maternal genome.

  Developmental stage at the time of exposure to teratogens.

  Dose and duration of exposure to a teratogen.
• The mechanism of action of a teratogen is the specific ways in which it acts on developing cells and tissues to initiate abnormal embryogenesis, - dysmorphogenesis.

  The mechanisms of teratogens may involve inhibition of a specific biochemical or molecular process or pathway.

  Pathogenesis is the abnormal developmental processes that result to Dysmorphogenesis.
• teratology Pathogenesis may involve cell death, decreased cell proliferation, or other cellular phenomena.

  Manifestations of abnormal development are death, malformation, growth retardation, and functional disorders.
• Gastrulation stage in embryonic development – beginning of the third week, is a highly sensitive stage for teratogenic insult.

  Ingressing epiblast cells whose fate has already been determined at or before the time of gastrulation may be damaged by teratogens. E.g.: High doses of alcohol during gastrulation may kill cells of the anterior midline of the germ disc, leading to deficiency of midline in craniofacial structures and results to an abnormality called Holoprosencephaly.

  Child has small forebrain, merged lateral ventricles into one, eyes are close together (hypotelorism).
• Caudal Dysplasia, also called Caudal Regression Syndrome, Caudal or Sacral Agenesis (e.g. Sirenomelia): This is due to mesodermal insufficiency in the caudal-most region of the embryo, which contributes to the formation of the lower limbs, urogenital system and lumbosacral vertebrae.

  Affected child exhibits a variable range of defects including:

  Hypoplasia and fusion of the lower limbs, vertebral abnormalities, renal agensis, imperforate anus, and abnormalies of the genital organs.

  Caudal dysplasia or regression syndrome is associated with maternal diabetes in human.
• Situs inversus: a condition with transposition of the viscera in the thorax and abdomen.

  Laterality sequences: Patients with these conditions do not have complete situs inversus but are predominantly bilaterally either left-sided or right-sided.

  Those with left-sided bilaterality have polysplenia.

  Those with right-sided bilaterality have asplenia or hypoplastic spleen.

  Patients with laterality sequences are also likely to have other malformations, especially heart defects.
• Sacrococcygeal teratomas: a condition where remnants of the primitive streak persist in the sacrococcygeal region to form tumours.

  Sacroccygeal tumour is the most common gastrulation associated tumour in newborn.

  These tumours commonly contain tissues derived from all the three germ layers.
• Trilaminar Germ Disc

  A) ectoderm

  B) mesoderm

  C) endoderm

  D) notochordal canal

  E) notochordal process

  
• the study and treatment of fetus - prenatal paediatrics or fetology
• Maternal Serum Screening (MSAFP+)

  • maternal serum alpha-feto-protein, produced by fetal liver, level increases steadily during pregnancy
  • human chorionic gonadotrophin, produced by placenta, levels peak about 14 weeks of gestation and then drop
  • unconjugated estriol, produced by placenta
  • inhibin-A, produced by fetus and placenta
• • Maternal serum AFP are high when compared to normal levels at the same week of gestation in a fetus with neural tube defects
  • Maternal hCG and inhibin-A levels are high, and estriol levels are low in a Down syndrome fetus.
• Ultrasonography: used to examine the fetus and could detect a variety a fetal anomalies.

  • fetal echocardiography detects abnormalities of the fetal heart and heart beat
  • also used for nuchal translucency screening. Measures the thickness of the clear area at the back of the neck
  • fetuses with down syndrome and other chromosomal and major heart anomalies accumulate fluid in the back of the neck during the first trimester of pregnancy
• amniocentesis: analyses the amniotic fluid aspirated from the amniotic cavity between 14-16 weeks of gestation
• chorionic villus sampling: analyses chorionic tissue sample
• • birth defects are leading cause of infant mortality and a major contributor to disabilities
  • birth defects account for about 25% of infant deaths
  • major structural anomalies occur in approximately 3% of live born infants and about additional 3% recognised by age 5
  • birth defect frequencies are non-discriminatory - mortality rates due to birth defects are the same in most parts of the world
• • about 40-45% cases of birth defects have unknown aetiology
  • genetic factors account for about 28% cases of birth defects
  • environmental factors account for about 3-4% cases of birth defects
  • about 20-25% cases of birth defects are of multifactorial aetiology
• • minor anomalies (microtia - small ear, pigmented spots, short palpebral fissures) occur in about 15% of newborns
  • infants with minor anomaly have a 3% chance of having a major malformation
  • infants with 2-3 or more minor anomalies have 10% and 20% chance respectively of having a major malformation
  • minor anomalies serve as clues for diagnosing more serious underlying birth defects