Bound for the medical students who seek legal knowledge and for the law students who seek medical knowledge at the interface of two disciplines in teratology litigation.
2. IN THIS ISSUE:
Basics of Human Embryology
- Week 1: Fertilization; Blastocyst Formation; Implantation (7)
- Week 2: The Rule of Twos; Singularities in Embryoblast v.
Trophoblast Divisions (8 -9)
- Week 3: The Rule of Three; Gastrulation and Formation of the
Primitive Streak; Endo-Meso-Ecto-derms; Everything
or Nothing Rule (10-15)
- Week 4: The Rule of Fours; Neural Tube Closure (16 - 19)
- Weeks 5 -8: Organogenesis (20)
- Week 9 +: Fetal Period, Erythropoiesis and Circulation (20 -25)
Twinning: The 3 and 8 Days Rule (zygotic, amniotic,chorionic
divisions) (26 -27)
System Outset: Cardiac (28-34),Vascular (35-36), Neural (37-39), Gastro-
Intestinal (40-43), Renal (44-45), Reproductive (46-50),
Head & Neck (51-60), Ear (61-63), Eye (64-65) Embryology
(continued)
3. Teratogens (66 - 85)
- Illicit Substances; Licit Medications; Radiation; Infectious Agents;
Metabolic Factors; Mechanical Factors; Paternal Factors
Inherited Anomalies (86 - 103)
- Mitochondrial Inheritance; Mendelian Chromosomal Inheritance
(aneuploidy,polyploidy,nondisjunction);Triplet Repeat Expansions;
Hardy-Weinberg Principle, Pedigree Punnett; Heme Synthesis
Disorders; Sphingolipidoses; Histone Modification Disorders
Antenatal Fetal Assessment (104-111)
End of Medical Survey Q & A (112-113)
Malpractice; Fault; Causality (114 -140)
Court Hearings (141 - 142 )
End of Legal Survey Q & A (143 -145)
Disclaimer (146)
IN THIS ISSUE
4. THE OVA
Oögenesis starts in germinal epithelium and is staged of:
Oocytogenesis - formation of oogonium from primordial follicles
through mitosis (diploid/46, two chromatides [2C]) in the 18-22 -
week old female fetus
Ootidogenesis - formation of primary oocyte through meiosis I
(diploid/46, 4C), secondary oocyte through meiosis II (haploid/23,
2C), ootid (meiosis II, haploid/23, 1C) at birth of the female neonate
Oogenesis proper - maturation, formation of the ovum (haploid/23,
1C) in puberty and menarche.
Folliculogenesis (age 11-51 years) starts when the immature ovum
(arrested at metaphase-2 stage, haploid/23, 1C) matures through
follicular phase, ovulation, and luteinization.This includes formation of
the antral follicle, early tertiary,late tertiary and pre-ovulatory follicles,
opening of cumulus oophorus (stigma) at 11-14th
days of menstrual
cycle, release of the ovum (ovulation), atresia (collapse of the follicle),
radical apoptosis,and formation of corpus luteum (the steroidogenic
powerhouse that maintains the endometrium by secretion of large
amounts of progesterone and small amounts of estrogens (E1, E2). 4
6. MATURATION: BATTLE FOR FERTILIZATION
● During menstruation, a cohort of primordial follicles is recruited. The
mechanism and criteria of such recruitment remains nebulous.
● In proliferation phase, the FSH stimulates both mitotic division of the
granulosa cells surrounding the oocyte, and granulosa - cell
aromatization from androgens to estradiol [E2] - the key hormone of
follicular maturation.
● The LH stimulates theca cells' production of androstendione.The latter
is taken by the granulosa cells and under the FSH is aromatized into
estron (E1) and estradiol (E2). (Note, there is no estriol [E3] production
in non-pregnant women).
● The follicle most efficient in E2 production is selected as “the winner ”
or the dominant follicle, with other follicles undergoing atresia.
● In secretory phase, serum progesterone levels peak by day 8-9 after
ovulation.The corpus luteum begins to shrink, unless - at that point -
rescued by the hCG (if the ovum is fertilized).
● With an ideal duration of 28 days and the normal range of 21-35 days,
the length of a menstrual cycle depends (along with non-hereditary or
hereditary factors) on a woman's ethnicity, geographical region
(latitude to the equator, i.e. the yearly average of solar position and
altitude).The closer to the poles, the longer the menstrual cycle. 6
7. WEEK 1: Fertilization, Blastocyst Formation; Implantation
● DAY O: Fertilization. - The head and acrosome of the
spermatozoon(s) enter(s) the egg (usually in the ampullar
fallopian tube), followed by the acrosome reaction (the sperm
releases lysing enzymes to penetrate zona pellucida).
● DAYS 1 -2: Cleavage. - A single-cell zygote (formerly
suspended at metaphase-2) undergoes rapid mitotic divisions
into smaller cells. Each cleavage doubles the cells.
● DAY 3: Morula (“mulberry”) is formed by 16-32 cells.
● DAYS 4-5: Embryoblast & Trophoblast Formation. On day-4
there are 58 cells; on day-4.5 there are 107 cells.The Na+
/K+
-
ATPase pumps deliver sodium, creating an osmotic gradient to
form a fluid-filled cavity inside the morula. Blastocyst is formed
from the embryoblast and trophoblast. Embryoblast seats on the
embryonic pole (Fig 1, page 9).
● DAY 6: Implantation. - The blastocyst implants into the
endometrium (ideally, in the posterior uterine wall). 7
8. WEEK 2: The Rule of Two
8
Cytoblasts are mononuclear. Syncytiotrophoblasts are multinucleated. At this
stage, the blastocyst has already begun to make mRNA for human chorionic
gonadotropin (hCG), the first hormone signal from the early embryo that in turn
will make the trophoblast differentiate into placenta and umbilical cord, and the
epiblast into amniotic sac and bilaminar disk (pre-embryo).
10. The process of gastrulation
starts from the formation of
a primitive streak, a midline
invagination (Fig. 2).The
epiblast cells move through
the streak: the bottom-most
layer becomes endoderm,
the middle layer -
mesoderm, and the top
layer - ectoderm.These
three layers will give rise to
various parts of the
developing embryo and to
organ-systems of the fetus,
and this arrangement of
“three” will remain the
paradigm throughout
gestation.
WEEK 3: Gastrulation, Primitive Streak Formation
10
11. WEEK 3: THE RULE OF THREE
I. ECTODERMI. ECTODERM =>=>
Surface Ectoderm
Neuroectoderm
Neural Crest Cells
II. MESODERMII. MESODERM =>=>
Sclerotone
Myotome
Dermatome
III. ENDODERMIII. ENDODERM =>=>
Auditory
Digestive
Endocrine
Excretory
Respiratory
(continued)
11
12. WEEK 3: ECTODERM
ECTODERM SPLITS INTO THREE PARAXES CLINICAL
SIGNIFICANCE
1) SURFACE ECTODERM1) SURFACE ECTODERM =>=>
Surface layer of some
organs, some glands
(adenohypophysis - the
Rathke pouch, mammary,
sweat, salivary), the skin
epidermis, hair, nails,
olfactory epithelium, oral
and anal mucose.
2) NEUROECTODERM2) NEUROECTODERM =>=>
CNS (brain, spinal cord),
and retina
3) NEURAL CREST CELLS3) NEURAL CREST CELLS =>=>
Peripheral nervous
system, melanocytes,
thyroid parafollicular (C)
cells, chromaffin cells of
the adrenal medulla,
conotruncal endocardial
cushions, some structures
of face (teeth, facial
bones).
This explains why
many congenital
diseases (DiGeorge
Syndrome - a
thymic disorder)
involve both
cardiac and cranio-
facial
abnormalities. 12
13. WEEK 3: MESODERM
13
MESODERM SPLITS INTO 5 PARAXES CLINICAL
SIGNIFICANCE
1) SCLEROTOME1) SCLEROTOME =>=> Bones, cartilages, dura mater
Mesoderm
differentiates via
intercellular signaling
and polarization, to
protect beta-catenin
from degradation.
Mesoderm also has
the capacity to
induce growth of
other structures, like
the neural plate.
2) MYOTOME2) MYOTOME =>=>
Muscles (smooth, cardiac,
skeletal), occipital (the tongue)
muscles, pharyngeal arch
(mastication, mimicry) muscles
3) DERMATOME3) DERMATOME =>=>
The skin dermis, connective
tissue
4) PARENCHOTOME4) PARENCHOTOME =>=>
Gonads, kidneys, adrenal cortex,
spleen. The adrenal medulla
(chromaffin cells) is
from ectoderm. Part
of the urethra,
urinary bladder,
prostate are from
endoderm.
5) CUSTOPOETOME5) CUSTOPOETOME =>=>
Mesenchyme, mesothelium,
peritoneum, endothelium of the
vessels, blood cells (RBC, WBC),
microglia, Kupffer cells (hepatic
macrophages), coelomocytes,
lymph.
14. WEEK 3: ENDODERM
14
ENDODERM SPLITS INTO 5 PARAXES CLINICAL
SIGNIFICANCE
1) AUDITORY1) AUDITORY =>=>
Epithelium of the Eustachian
tube and the tympanic cavity
The epithelium and
parenchyma of the GI
(gut) glands are
derived from
endoderm. The
muscular walls of the
digestive tract (lamina
propria, muscularis
mucosae, submucosa,
muscularis externa,
adventitia and serosa)
are derived from the
splanchnic mesoderm.
2) DIGESTIVE2) DIGESTIVE =>=>
Gut (liver, biliary apparatus,
pancreas, superior and inferior
mesenteric arteries, except
spleen), the entire alimentary
canal (except mouth and distal
1/3 of rectum)
3) ENDOCRINE3) ENDOCRINE =>=>
Glands (thyroid, parathyroid),
thymic epithelium)
4) EXCRETIVE =>4) EXCRETIVE =>
Urinary bladder, part of the
urethra
Kidneys are formed
from mesoderm.
5) RESPIRATORY =>5) RESPIRATORY =>
Trachea, bronchi, pulmonary
alveoli
Pharynx is formed
from mesoderm.
15. WEEK 3: Everything-or-Nothing Rule
During weeks 1-3, teratogens
typically have all-or-none effect:
they either do no harm at all, or
entirely terminate the pregnancy
(spontaneous abortion).
For a bilaterian mammal such as
human being, the rule of 3 of
week-3 also concerns to the
formation of three body axes:
cranio-caudal, medial-lateral, and
dorsal-ventral.
15
The embryonic period covers the days 18 - 55 after the
conception.The complete 8 weeks announce the fetogenesis
and the closure of the neural tube (see further).
16. WEEK 4: The Rule of Fourths
● Week-4 also marks
the rule of fours as
organogenesis starts
taking place:
● Four limb buds begin
to grow (Fig. 3).
● Four cardiac
chambers have
developed and now
begin to beat. Heart
starts beating at the
days 22-23, when it
grows to such a size
that it can't get
adequate nutrition by
diffusion alone. 16
17. WEEK 4
● Week-4 is a critical stage, as teratogenic exposure in this
period is deleterious (see in further chapters), contrasted
to the former period (weeks 1-3) where the principal rule
was “everything or nothing.”
Figure 4 presents Thalidomide exposure in the week-4 period, causing
amelia (agenesia of the limb) in the upper extremities and phocomelia
(shortening) in the lower extremities. 17
18. WEEK 4: Neural Tube Closure
● Although week-3 marks the
beginning of the neural plate
development (which will give rise to
the spinal cord), week-4 marks the
closure of the neural tube.
● This closure can be normal and
abnormal.
18
● Abnormal cranial closure leads to anencephaly (Fig. 5), whereas
abnormal caudal closure leads to spina bifida in one of its three
main forms (Fig. 6-8):
- Spina bifida occulta
- Spina bifida meningocele
- Spina bifida myelomeningocele.
● Spina bifida occurs when the neural tube does not close in the L5 -
S1 area.The opening size and related severity manifest in a wide
range of clinical forms: from a completely assymptomatic course to
the permanent paralysis.
19. Spina BifidaSpina bifida occulta (Fig 6), from Latin occulta
(“hidden”), is usually asymptomatic as the
incomplete closure is so minor that the spinal
cord cannot protrude out of the defect.
However, there can be a small tuft of hair or
hyperpigmented skin over the affected area.
The small vertebral fusion defect can be
detected on the spine radiography.
19
Spina bifida with meningocele (Fig. 7)
occurs when the meninges surrounding the
spinal cord protrude through the vertebral
defect, but the spinal cord does not
protrude.The meningeal sac may be visible
at the defective site.
Spina bifida with myelomeningocele (Fig.
8) is a severe defect, where the spinal
cord and meninges both protrude and are
damaged.This typically leads to paralysis
and sensory loss in the legs.
19
20. WEEKS 5 + : Placentation
● The formed placenta is a feto-maternal organ (Fig.9), as part of it
(amnion, chorion) is from the blastocyst, and the other part
(decidua basalis) is from the maternal endometrium.
● The umbilical cord
consists of two
umbilical arteries
and one umbilical
vein.
● The umbilical
arteries will turn to
the medial umbilical
ligaments as they
close at birth.
● Do not confuse this
with the median
umbilical ligament
that forms at the
closure of urachus.
20
21. WEEKS 5 + : Fetal Erythropoiesis
● Fetal hemoglobin (HbF, 2 2) binds oxygen with greaterα γ affinity
than maternal hemoglobin (Hb).Thus, the fetal oxygen
dissociation curve (partial pressure/saturation) is leftward shifted.
● In adult Hb, 2,3-DPG (diphosphoglycerate) is synthesized by the
RBC during breakdown of glucose. 2.3-DPG decreases the Hb-
oxygen affinity.Yet, fetal Hb cannot bind 2,3-DPG which is the
reason of its higher affinity for oxygen.
● The bone marrow of the fetus does not synthesize RBC until the
28th
gestation week.This lack is substituted by other sources in
various stages of gestation (Fig. 10) :
- Yolk sac: weeks 3 - 8
- Liver: weeks 6 – 30
- Spleen: weeks 9 – 28
- Bone marrow: week 28 +
21
22. Fetal Circulation
● The main difference
between the fetal and adult
circulation is in oxygen
concentration and in
presence of physicologic
shunts.
● The oxygen tension is
highest in the umbilical
vein (Fig.11).
● The first physiologic shunt
is in the liver.The ductus
venosus is shunting half of
the oxygenated blood away
from the liver, as the fetal
liver (an erythropoietic
organ) doesn't need all
blood to be properly
oxygenated.The blood
moves to the inferior vena
cava, then into the right
atrium. 22
23. Fetal Circulation Highlights
23
Fetal blood is oxygenated in placenta and flows to the right heart
through the umbilical vein.
The oxygen tension is highest in the umbilical vein as it is the most
proximate to placenta.
Fifty percent (50%) of this oxygenated blood bypasses the liver
through the ductus venosus.
Once in the right heart, there are two possible shunts bypassing the
lung: the foramen ovale and the ductus arteriosus.
Fetal lungs do not oxygenate blood as they do not breathe, rather
they breathe amniotic fluid.
SHUNTS
The first physiological shunt is the (1) liver.The ductus venosus is
shunting away the half of the oxygenated blood from the liver to the
inferior vena cava, then to the right atrium.The pulmonary circulation
is bypassed through the second and third shunts: (2) foramen ovale -
a passageway between the right and left atria, and (3) ductus
arteriosus – a passageway between the pulmonary artery and aorta.
24. Nature's 'engineering tricks' and wisdom
The ductus arteriosus is
distal to the aortic arch
(Fig. 12), which makes the
blood flow to the
descending aorta and to
various end organs, or
back to placenta for
reoxygenation.
On the other hand, the
blood flowing to the left
ventricle can go to the
aortic arch, oxygenating
the upper limbs and
brain.
24
Interestingly, more deoxygenated blood returning from the brain
through the superior vena cava will move to the right ventricle, into the
pulmonary artery, ductus arteriosus, and descending aorta to oxygenate
brain. With such a trick, deoxygenated blood is efficiently moved into
either of two umbillical arteries to be then reoxygenated in placent a.
25. Changes in Fetal Circulation at Birth
Reactive hypoxic vasoconstriction relieved: The low oxygen
tension causes vasoconstriction in the pulmonary vasculature. Once
the newborn makes the first breath, the increased oxygen tension in
the lungs causes vasodilation, consequently dropping the pulmonary
resistance and pressure.
Decreased pulmonary pressure:This in turn decreases the right
heart pressure. As the left heart pressure becomes relatively higher,
the foramen ovale closes.
Closure of the ductus arteriosus: Mechanically closed at birth,
the ductus then obstructs anatomically through fibrosis, turning into
the ligamentum arteriosum.This closure takes place due to the
decreased prostaglandins. In a cardiac pathology, where a patent
ductus arteriosus is needed, prostaglandin E1 (Alprostadil) is
administered to keep the ductus open. In the opposite cases, with the
necessity of closing the ductus, Indomethacin is administered to
prevent prostaglandin production.
Closure of the ductus venosus: At birth, the liver shunt is no
longer necessary.The ductus venosus closes to become the
ligamentum venosum. 25
26. TWINNING: The 3 and 8 Days Rule
● Twinning concerns the zygote (monozygotic, dizygotic), the chorion
(monochorionic, dichorionic), and the amnion (monoamniotic,
diamniotic).
● Dizygotic twins (fraternal twins) are formed from two different ova
and different sperm.They have their own placenta (dichorionic)
and amniotic sac (diamniotic). Monozygotic twins occur when a
single zygote splits and forms two embryos.These are identical
twins. Depending when the split has occurred, they may or may not
share the chorion and amnion.The later the split, the more structures
will be shared.The key marks to remember: the chorion forms on
day 3 and the amnion on day 8.
● Examples below exclusively concern the monozygotic twins:
- Dichorionic, diamniotic:The split has occurred before day 3.
- Monochorionic, diamniotic:The split has occurred between days
3 and 8.
- Monochorionic, monoamniotic:The split must have occurred
after day 8. Examples, conjoined twins, or twin-twin transfusion
syndrome (TTTS). Most cases are fatal. 26
28. Cardiac Embryology: The Loop Formation
● Nearly on days 22-23, the fetal heart starts beating as it has
grown to a size at which diffusion alone fails to fit the nutrition
and oxygenation requirements.
● Although the heart starts pumping, the chambers are not in
proper spatial orientation.“Twisting” of the cardiac loop allows
the chambers to move to the right place.This requires certain
gene coordination and proper distribution of the neural crest
cells of the ectoderm (see Slide 12).That is why there are
congenital syndromes with combined cardiac and craniofacial
anomalies.
● The neural crest cells are responsible for twisting of the
aorticopulmonary septa that divide the truncus arteriosus
(common RV-LV outflow) into the ascending aorta and pulmonary
artery.
● Failure of the proper neural crest cell migration to the truncus
arteriosus region may lead to transposition of the major vessels
and Tetralogy of Fallot. 28
29. Cardiac Embryology: Pivotal Stages
29
Figure 14: Stages of Cardiac Development
(A) Day 15; (b) Day 21; (C) Day 28; (D) Day 50.
A (atria), Ao (aorta), AVV (atrioventricular valves), CT (conotruncus), DA (ductus
arteriosus), LA (left atrium), LCA (left carotid artery), LSCA (left subclavian artery), LV
(left ventricle), PA (pulmonary artery), RA (right atrium), RCA (right carotid artery), RSCA
(right subclavian artery), RV (right ventricle), V (ventricle).
30. Cardiac Embryology: Septation
● The fetal ventricle starts as a single chamber. The muscular interventricular
septum begins as a cardiac apex and grows upward. At this stage, it has an
interventricular foramen. By the end of week-7, the foramen closes when the
membrane of interventricular septum forms by joining of neighboring
tissues (including endocardial cushion and bulbar ridges).
● Below is the interpreting of Figure 15 ( forthcoming Slides 31 – 34).
(A) The foramen primum is the first hole between the atria.The septum
primum is the first septum to form to close the foramen.
(B) The foramen primum is now almost closed by the septum primum with
some perforations in it (the second set of holes).
(C) The perforations coalesce and become the foramen secundum.
(D) The foramen primum is now closed.The septum secundum is developing.
(E) The septum secundum leaves a space between the atria (the foramen
ovale).
(F) The lower limb of septum primum forms the foramen ovale.
(G) Once the left atrial pressure is higher than the right atrial pressure, the
valve shuts the oval foramen.
(H) Failure to close leads to the patent foramen ovale. 30
31. Formation of the Atrial Septum
SAGITAL CUT Fig. 15 (A-B) TRANSVERSE CUT
31
35. Vascular Embryology
Blood vessels develop through two separate ways: vasculogenesis and
angiogenesis.Vasculogenesis involves angioblasts grouping to form the major
vessels (Fig. 16). Angiogenesis involves new vessels growing from existing
ones and is the major array of vascular development.
The aortic arches are six paired embryonic arteries supplying their
corresponding branchial arches and eventually forming major vascular
structures (Table in Slide 36).They emanate from the distal portion of truncus
arteriosus (Fig. 16, A).The aorticopulmonary septum divides the truncus
arteriosus into ascending aorta and pulmonary trunk (Fig. 16, B).The 3rd
aortic
arch forms the common carotid and internal carotid arteries (Fig. 16, C).The
left 4th
forms the aorta.The right 4th
forms the branchio-cephalic artery.The
5th arch regresses early. (Fig. 16, D).
35
35
37. Neuroembryology
- forebrain (prosencephalon)
- midbrain (mesencephalon)
- hindbrain (rhombencephalon).
● The forebrain is later divided into telencephalon (future cranial hemisphere)
and diencephalon (future thalamus/hypothalamus).
● The midbrain develops into limbus,hippocampus,medulla,tectum,tegmentum.
● The hindbrain is divided into two parts: metencephalon (future pons and
cerebellum) and myelencephalon (future medulla).
● Sometimes, primitive masses of paraxial mesoderm flank the neural tube.
37
The
cephalic
portion of
the neural
tube
dilates
into three
structures:
38. Neuroembryological Disorders
PITUITARY GLAND:The posterior pituitary is a neural
structure formed from the downward growth of diencephalon.
The anterior pituitary develops from Rathke pouch (see Slide
12) of oral cavity (derived from the surface ectoderm).
Persistence of Rathke pouch may lead to craniopharyngiomas,
benign suprasellar tumors that compress pituitary (causing
endocrine disorders) or optic chiasm (causing visual
disturbances, like bitemporal hemianopsia).
NOTOCHORD: Longitudinal structure lying ventral to the
neural tube, and polarizing the spinal cord with the help of the
sonic hedgehog homologue protein which induces the
formation of motor neurons along the ventral aspect of spinal
cord. Notochord persists in adults as nucleus pulposus of
intervertebral discs.
HOLOPROSENCEPHALY: A failure of midline formation due
to incomplete cleavage of the prosencephalon into
telencephalon. It can be associated with sonic hedgehog gene
mutations. In severe expressions (cyclopia,absent nose,fused
cerebral hemispheres) it is incompatible with life. In milder
forms, midline structures are affected but two cerebral
hemispheres are developed (the case with a single incisor).
38
39. Neuroembryological Disorders (continued)
DANDY-WALKER SYNDROME: A spectrum of genetic conditions
presenting loss of the cerebellar vermis and eventually dilation of
the fourth ventricle.This can be asymptomatic, yet, the absence of
cerebellar vermis may lead to ataxia, and increased intracranial
pressure.The use of ventral shunt can drain the cerebra-spinal fluid
(CSF), alleviate the hydrocephalus and normalize the intracranial
pressure.
ARNOLD - CHIARI MALFORMATION: Congenital herniation of
the cerebellar tonsils through the foramen magnum.This may
occlude the CSF passage causing hydrocephalus. Always present in
spina bifida, this condition is highly associated with syringomyelia.
SYRINGOMYELIA: Loss of pain and temperature sensation in a
capelike pattern around the back of the arms, due to cystic dilation
of the central canal compressing the spinothalamic tract as it
crosses the midline.Touch/vibration (dorsal columns) and motor
function (corticospinal tract) are intact.
39
41. Gastrointestinal Embryology Highlights
● ALLANTOIS: An outpouching of the hindgut that is nonfunctional and
get obliterated (Fig. 19). It connects to the apex of developing bladder
and moves through the umbilical cord.The proximal portion is known
as urachus, which spans from the umbilicus to the bladder. Once
obliterated, it becomes the median umbilical ligament and is used by
the surgeons as the marker of the abdominal midline.
● VITELLINE DUCT (Omphalomesenteric duct): A tube connecting
the yolk sac to the midgut to nourish the embryo. It gets obliterated in
the 7th
week, and lefts a remnant known Meckel diverticulum.
● CLOACA:Terminal portion of the hindgut. It later divides into the
rectum and urogenital sinus.
● CONGENITAL DIAPHRAGMIC HERNIA: Incomplete formation of
pleuroperitoneal membrane of diaphragm allowing the abdominal
contents to herniate into the thorax.This hernia presses on the lungs
causing pulmonary hypoplasia and hypertension. Neonates experience
respiratory distress. Mortality rate is 50%.
continued
41
42. Gastrointestinal Embryology Highlights (continued)
Fig. 18: A 5-week embryo.Urachus is the
proximal portion of allantois.
Fig. 19: Allantois appears on day -16 as a
tiny, fingerlike outpouching extending from
the caudal wall of the yolk sac.
42
43. Gastrointestinal Embryology Highlights
● OMPHALOCELE: Failure of the GI viscera to enter the abdominal
cavity after physiologic herniation during the early fetogenesis.This
results in a midline, peritoneal-coated sac protruding through the
umbilicus and containing abdominal organs. It is distinguished from
43
the common (benign) umbilical hernia as the
latter is covered by skin. Omphalocele alone is
not lethal. Complications are related to its
severe congenital associations such as heart
and neural tube defects, and chromosomal
abnormalities.
● GASTROSCHISIS: Incomplete fusion of the
body wall leading to protrusion of the GI
viscera. While distinguishing it from
omphalocele or umbilical hernia, consider that
here the protrusion is:
1) lateral to the umbilicus
2) not covered by peritoneum
3) not associated with chromosomal
abnormalities.
44. Renal EmbryologyThere are three distinct stages in
cranial-to-caudal chronology (Fig. 20):
● PRONEPHROS: At week-4, the
formed vestigial nephron-like units
start regressing without ever
functioning.
● MESONEPHROS:The ureteric bud,
developed from mesonephric ducts,
penetrates the metanephrons to form
renal pelvis, collecting duct system,
44
(Wolffian) ducts then persist to form the reproductive
tract.
METANEPHROS: A system of nephron and kidney
parenchyma formation. Metanephric tissue develops
into the organized nephrons (Bowman capsules,
proximal and distal tubules, and the loops of Henle). At
week-12, distal tubules are connected with collecting
ducts (ureteric buds) and the glomeruli are formed.
and ureters (Fig.
21). In males, the
mesonephric
45. Renal Agenesis and Oligohydramnios
● You may wonder why defects of
renogenesis are associated with
oligohydramnios (the scarcity of
amniotic fluid, defined when the
amniotic-fluid index is < 4cm and
where between the fetal body parts
there is no pocket > 1cm in two
perpendicular planes).
● Importantly, it is placenta, not the
kidneys, responsible for removing the
fetal body waste. Fetal urine is
excreted into the amniotic sac, where
it is swallowed and recycled.This
explains why renal agenesis leads to
45
oligohydramnios, as fetal urine is a major component of the amniotic fluid.
● POTTER SEQUENCE: Decreased amniotic fluid may lead to facial
deformities (due to mechanical stress) and pulmonary hypoplasia (due to
decreased nutrients and hydrostatic pressure). Although oligohydramnios is
multifactorial (infections, placentation defects, placenta previa), its causality
chiefly relies on the urogenic anomalies and Potter Sequence shows the
cross-impact (Fig. 22).
46. Reproductive Embryology
Reproductive system emerges at week-5 in the form of paired gonadal
ridges, with migrating primordial germ cells to build sex cords (indifferent
gonad, Slide 48, Fig. 23). Genetic determination of sex begins with fertilization
when the ovum (X) binds the sperm (either X orY). Phenotype determination
of sex begins with the formation of gonads that coordinate the maturation of
the duct system (Wolffian and Müllerian), external genitalia, and secondary
sexual features. Female phenotype is considered as default; male phenotype
requires presence of the testis-determining factor or the SRY-gene.
46
● MALE EMBRYOLOGY
The SRY-gene encodes theY-protein
transcription to turn the indifferent
gonad into the testes.The testes begin
to produce testosterone that makes the
mesonephric (Wolffian) duct turn into
epididymis,vas deferens, and seminal
vesicles.Testosterone is converted to
dihydrotestosterone (DHT) by the
powerful enzyme 5 α-reductase that
also virilizes the genital tubercle.The
antimüllerian hormone causes
regression of the Müllerian ducts.
● FEMALE EMBRYOLOGY
Absence of the SRY-gene allows the
indifferent gonad turn into ovaries by
default. Ovaries start producing
estrogen that turn the Müllerian ducts
into Fallopian tubes, uterus, cervix, and
upper vagina. Estron (E1) also turns the
genital tubercle into lower vagina and
the labioscrotal swelling into vulva. Lack
of estrogens interferes with the descent
of ovaries and gubernaculum, which
leads to the formation of the patent
canal of Nuck (technically, a hernia).
47. Reproductive Embryology Highlights
EMBRYO ADULT MALE ADULT FEMALE NOTES
Indifferent gonad Testicle Ovary
Gender-determining
gene is SRY
Wolffian duct
Urinary collecting
system, Epididymis, Vas
deferens, Seminal
vesicles
Urinary collecting
system
Male structures are
formed under the
influence of testosterone
Müllerian duct Regress
Fallopian tubes,
Uterus, Cervix,
Upper vagina
In males, this duct
regresses under the
antimüllerian hormone
Genital tubercle Penis Clitoris Virilized by DHT
Urogenital sinus
Bladder, Proximal
urethra, Prostate gland
Bulbourethral gland
Bladder, Proximal
urethra, Bartholin
glands, Skene glands
The urogenital sinus is
partitioned off the
cloaca.
Labioscrotal bulge Scrotum Labia majora
Influenced by DHT or E1.
In females they become
posterior labial
commusure.
Urogenital folds Mons pubis Labia minora
In both M and F, the
labioscrotal bulges merge.
47
48. Congenital Gonadal Anomalies
● UROGENITAL SINUS: By the end of
embryonic period (week-8), the ventral
part of cloaca has been partitioned off into
the urogenital sinus, later to form the
bladder and proximal urethra. It will form
the prostate and bulbourethral glands in
males, and Bartholin glands and glands of
Skene in females.
48
● HYPOSPADIA: Incomplete fusion of the urethral folds
leading to the urethral meatus on the inferior portion
of penis (Fig. 24). Surgically curative.
● EPISPADIA: Rare malformation where defective
migration of the genital tubercle results
in the urethral meatus opening on
dorsum of penis.
● MICROPENIS: Insufficient androgen
stimulation from any part of the
hypothalamic-gonadal axis.
48
49. Congenital Gonadal Anomalies (continued)
●
BLADDER EXSTROPHY: Always associated
with epispadia, this is the outcome of incomplete
migration of primitive streak's mesoderm (later
the abdominal wall) around the cloaca
membrane.The bladder extends off the body.
● CRYPTORCHIDISM: 30% of males are born
with undescended testicle(s). Most of those
descend within the first months without any surgical intervention. Of note,
any cause of intrabdominal testicle (androgen insensitivity syndrome) puts
the male at increased risk for testicular cancer.
● UTERINE ANOMALIES: Failure of the paired Müllerian ducts to fuse
results in uterus didelphus (double uterus,double cervix,double vagina).
Partial fusion results in bicornuate uterus (two uterine cavities share a single
cervic and vagina) (Fig. 25, Class 3 and 4, Slide 50).
● NUCK CANAL CYST: A fluctuant, thin-walled, well-defined cyst
(peritoneal hernia) in the labium majus pudendi or inguinal area, due to lack
of E1,E2, and related insufficient descend of the ovaries and gubernaculum.
● MESOPHRIC DUCT REMNANT: Cyst extending up lateral to vagina.
● ACCESSORY BREAST TISSUE: Small non-specific subcutaneous nodule
in vulva, usually unnoticed until pregnancy. 49
51. Head & Neck Embryology
● Six branchial (pharyngeal) arches develop the musculoskeletal compo-
nents of the head & neck region. Each arch contains three layers: ectoterm
(outer), endoderm (inner), and neural crest cells (middle). Separated from
each other by the branchial clefts, each arch is supplied by numerically
corresponding aortic arch and not corresponding cranial nerve. Only the
first cleft contributes to growth and later forms the external acoustic meatus.
● On the endodermal side, between the pharyngeal arches, lie the
pharyngeal pouches that later form the key structures of head & neck (Fig.
26, also see Slides 52, 53).
51
51
53. Head & Neck Embryology: BRANCHIAL POUCHES
POUCHPOUCH ADULT DERIVATIVESADULT DERIVATIVES
1st
Tympanic membrane
Middle ear cavity
Eustachian tube
2nd
Palatine tonsil
Tonsillar fossa
3rd
Inferior parathyroid gland
Thymus
4th Superior parathyroid gland
5th C - cells of thyroid
53
54. Head & Neck Embryology: The Tongue
The tongue formation starts at approximately the same time as the
palate's. The tongue develops of the 1st
to 4th
arches. Per the medial fusion
of the first (mandibular) and second (hyoid) pharyngeal arches, a medial
protuberance (tuberculum impar) appears on the lower edge of the
mandibular arch.Two swellings, lateral lingual prominences, form on
both sides (Slide 55, Fig. 27, 28).
The swellings extend to form the anterior 2/3 of the tongue.This part of
tongue consists of both ectodermic and endodermic portions. At the
caudal end of the tuberculum impar arises the primordium (anlage) of
the thyroid ventral endodermic bud. It further migrates in front of the
larynx and leaves behind the foramen cecum at the invaginated base.
The posterior 1/3 is formed from the fusion of the 2nd
and 3rd
pharyngeal
arches, the copula, and a small portion of the 4th pharyngeal arch. It only
consists of endodermic parts.The 3rd
pharyngeal arch probably grows over
the 2nd
, thus the second has no mesenchymal contribution to the tongue
formation. Between the anterior 2/3 and posterior 1/3 is the terminal
sulcus.The tongue is delimited caudally by the hypopharyngeal
eminence that marks the entrance into the trachea (laryngeal inlet).
54
55. Tongue Embryology
TACTILE (touch)
Anterior 2/3 1st
pharyngeal arch N. lungualis (CN V3)
Posterior 1/3 2nd
pharyngeal arch N. glossopharyngeus (CN IX)
Base 3rd
pharyngeal arch N. vagus (CN X)
SENSORY (taste)
Anterior 2/3 4th
pharyngeal arch Chorda tympani (CN VII)
Posterior 1/3 5th
pharyngeal arch N. glossopharyngeus (CN IX)
MOTOR (movement)
Enture musculture 6th
pharyngeal arch N. hypoglossus (CN XII)
55
55
56. Thyroid Embryology
● Thyroid is the first of the endocrine glands to develop nearly
on the 24th
day of gestation. It originates from two main
structures: the primitive pharynx and the neural crest.The
rudimentary lateral thyroid develops from the neural crest cells,
while the median thyroid, which forms the bulk of the gland,
arising from the primitive pharynx.
● Thyroid forms as a proliferation of endodermal epithelial cells
on the median surface of the developing pharyngeal floor.The
site of this development lies between two key structures, the
tuberculum impar and the copula, and is known as the foramen
cecum (see Fig. 27, 29 in Slides 55, 57).Thyroid initially arises
caudal to the tuberculum impar, which is also known as the
median tongue bud.This embryonic swelling develops from the
1st
pharyngeal arch and occurs midline on the floor of the
developing pharynx, eventually helping form the tongue as the
two lateral lingual swellings overgrow it.
56
57. Thyroid (continued)
The foramen cecum begins rostral
to the copula, also known as the
hypobranchial eminence.This
median embryonic swelling
consists of mesoderm that arises
from the 2nd
pharyngeal pouch
(although the 3rd
.And 4th
pouches
are also involved).Thyroid,
therefore, originates from between
the first and second pouches.
An initial thyroid precursor, thyroid
primordium starts as a simple
midline thickening and develops to
form the thyroid diverticulum.This
structure is initially hollow,
although it later solidifies and
becomes bilobed.The stem usually
57
has a lumen, the thyroglossal duct, that does not descend into the lateral
lobes.The two lobes are located on either side of the midline and are
connected via isthmus.
58. Parathyroid Embryology
● Parathyroids originate from the
endoderm (the 3rd and 4th
pharyngeal pouches), with a little
ectoderm (neural crest cells)
involvement.This type of genesis
generates multiple small
parathyroid clusters in addition to
the main parathyroid glands.
● At 6 weeks a diverticulum
elongates from the proliferating
pouch. Fetal parathyroids appear
functional as they respond to the
calcium levels , which eventually
are higher than the maternal Ca.
58
● The inferior parathyroids are also known as parathyroid thirds, because
they arise from the dorsal wing of the 3rd
pharyngeal pouch.The superior
parathyroid glands are known as parathyroid fourths, because they arise
from the dorsal wing of the 4th
pharyngeal pouch. Adult anatomical
position is the opposite of the pharyngeal roster-caudal order.This
occurs due to the 3rd
pharyngeal pouch also giving rise to the thymus.
59. Thymic Embryology
● Thymus has two origins for its lymphoid
thymocytes and epithelial cells.The
thymic epithelium begins as two flask-
shape endodermal diverticula that form
from only the 3rd
pharyngeal pouch (Fig.
30, 31) extending side-ward and
backward into the surrounding
mesoderm and neural crest-derived
mesenchyme (capsule) in front of the
ventral aorta.
59
● The mature thymic epithelium has two main cell types: cortical
thymic epithelial (cTECs) and medullary thymic epithelial cells
(mTECs) or stromal cells.These provide signals for T - cell
differentiation.
● Complex thimyc embryology explains why the thymic medulla
phagocytes negatively select auto-reactive CD4+ and CD8+
thymocytes and eliminate T-cells bearing autoreactive T-cell
antigen receptors (TCRs), and why the thymic cortex positively
selects T-cells in their early stages of development.
60. Pharyngeal Embryology Highlights
● TREACHER COLLINS SYNDROME: Lack of neural cell migration into the
1st
branchial arch causes syndromic facial malformations, including
micrognathia and conductive hearing loss.Originated from the 1st
branchial arch, the Meckel cartilage forms the malleus and incus, and
also guides development of the mandible.
● PIERRE ROBIN SYNDROME: Lack of neural crest migration into the 1st
branchial arch causes syndromic facial malformations, including
micrognathia and cleft palate, as the hard palate is partially of the
maxillary bone - a 1st
arch derivative.
● DiGEORGE SYNDROME: Failure of the 3rd
and 4th
pharyngeal pouch
differentiation results in the absent parathyroid glands (fatal
hypocalcemia) and thymic aplasia (T-cell immunodeficiency).This pesky
syndrome is accompanied by facial (1st arch derived) and cardiac
anomalies (Tetralogy of Fallot). Mnemonic: CATCH-22 (Cardiac anomalies,
Abnormal facies,Thymic aplasia, Cleft palate, Hypoparathyroidism/
Hypocalcemia due to the Chromosome-22 deletion-defect).
● BRANCHIAL CLEFT CYST: Failure of obliteration of one of the branchial
clefts leads to a cystic structure of the lateral neck along the anterior
border of the m.strenocleidomastoid (the 2nd
branchial cleft is involved).
60
61. Ear Embryology
● EAR develops from the 1st
pharyngeal pouch and six small swellings or
otic placodes, which are derived from the ectoderm (Fig. 32) to perform
two functions: hearing and body balancing.
● INNER EAR: Originates from the ectoderm on the 22nd
gestation day. It
derives from two lateral thickenings (otic placodes). Each placode
recedes below the ectoderm and forms the otic pit and otic vesicle.This
entire mass will be surrounded by mesenchyme to form the bony
labyrinth (Fig. 32, Slide 63).
Around the 33rd
day the vesicles begin to differentiate. On the dorsal
side of the embryo they form what will become the utricle and
semicircular canals. On the ventral side of the embryo the vesicles
differentiate into a rudimentary saccule, which will become the saccule
and cochlea. Cochlear duct appears during the 6th
week and connects to
the saccule through the ductus reuniens.
As the cochlear duct’s mesenchyme begins to differentiate, three cavities
are formed: the scala vestibuli,the scala tympani and the scala media.The
first two contain an extracellular fluid perilymph, and the third contains
endolymph.The vestibular basilar membranes develop to separate the
cochlear duct from the vestibular and tympanic ducts. Parts of the otic
vesicle in turn form the vestibulocochlear nerve. 61
62. Ear Embryology (continued)
● MIDDLE EAR: Develops from the ectoderm (neural crest) and endoderm,
in particular from the 1st
and 2nd
pharyngeal arches.The tympanic cavity
and auditory tube develop from the first part of the pharyngeal pouch
between the first two arches in an area (tubotympanic recess) which will
develop to pharynx. The ossicles (malleus,incus and stapes) normally
appear during the first half of fetogenesis.The first two derive from the
1st
pharyngeal arch and the third derives from the 2nd
. All three ossicles
develop from the neural crest. Eventually cells from the tissue
surrounding the ossicles will experience apoptosis and a new layer of
the endodermal epithelial wall constitute the tympanic cavity wall.
● EXTERNAL EAR: Ear canal originates from the dorsal portion of the first
pharyngeal cleft (not pouches, not arches, but cleft). It is fully expanded
in the 18th
week.The eardrum is made up of three layers (ectoderm,
endoderm and connective tissue).The pinna originates as a fusion of six
hillocks.The first three hillocks are derived from the lower part of the
first pharyngeal arch and form the tragus, crus of the helix, and helix,
respectively.The final three hillocks are derived from the upper part of
the 2nd
pharyngeal arch and form the antihelix, antitragus, and earlobe.
The outer ears develop in the lower neck.
62
64. Eye Embryology
● The eye formation begins at 3 weeks and
continues through the 10th
week and involves
both mesoderm and ectoderm (Fig. 33). Eye is
derived from neuroepithelium, surface
ectoderm, and extracellular mesenchyme
which consists of both neural crest and
mesoderm. Eye begins to develop as a pair of
optic vesicles on each side of the forebrain.
Optic vesicles are outgrowing of the brain
which at the end of the 4th
week make contact
with the surface ectoderm to induce changes
necessary for further development (Fig. 33,
34). Specifically:
64
● NEUROPEITHELIUM forms the retina,ciliary body, iris, and optic
nerves;
● SURFACE ECTODERM contributes to the lens, corneal epithelium and
skin of the eyelid;
● EXTRACELLULAR MESENCHYME produces the sclera, the corneal
endothelium and stroma,blood vessels, muscles, and vitreous.
65. Eye Embryology (continued)
NEURAL CREST:
● Sclera
● Cornea (Descemet's membrane and
endothelium)
● Connective tissue and bony structure of the
orbit.
MESODERM:
● Extraocular muscles
● Endothelial lining of blood vessels of the eye
● Blood vessels in sclera and choroid
● Sclera and choroid
● Vitreous
● Suspensory fibres
● Cornea: Bowman's membrane and stroma.
65
66. TERATOLOGY
Teratology is a study about the abnormalities of physiological
development. The term stems of the Greek (“teras”), forτέρας
"monster" or "marvel.”
Such an outcome-oriented epistemology is correct (for including
the word abnormality instead of anomaly), as with that it dismisses
confusions between “teratology” with the “study of human
congenital defects.” Teratology is broader, as it includes all
manifestations of abnormal development that are caused by
environmental insult. These may include growth retardation, delayed
mental development or other congenital disorders with or without
structural malformations.
Teratogens are substances that may cause birth defects.While most
of the congenital birth defects are genetically programmed,
teratogens are potentially avoidable causes of defects.
Where the law of malpractice (torts) or employment law,a careful
distinction is required between defect / deformity/ dysfunction. A
person can have a deformity (structural anomaly), yet have a good
functionality of that body part or region. Defect is the combination
of deformity (anomaly) and dysfunction (abnormality). 66
67. DEFECT = DEFORMITY + DYSFUNCTION
● The short 4th
and/or 5th
finger syndrome (Fig.
33) is multifactorial (idiopathic, or in utero
mechanical trauma,or Turner syndrome - 45 XO,
or pseudohypoparathyroidism, or
pseudopseudohypoparathyroidism, or perinatal
infections such as osteomyelitis,yaws,
tuberculosis causing fetal dactylitis). Person
with such a visible structural deformity of
67
metacarpal phalanges may have a functional hand, may play musical
instruments, sew, type, print, even perform surgeries with those hands.
Thus, this syndrome is not assessed as a defect, as the deformity is not
combined with dysfunction (unless there is Turner syndrome).
● A person with diabetes mellitus or myopia does not have visible
structural or cosmetic anomalies (except histological) but suffers
serious dysfunctions.Yet, diabetes or myopia are viewed as disorders
(not defects) as there are no visible deformities, although a person with
short 4th
phalanges may have a better quality of life than the one with
myopia or diabetes.
● While a rigorous etiological evaluation is the cornerstone of medical
assessment, in the eyes of law the cosmetic defect alone has lesser
value than a dysfunction in assessing teratogenic damages.
68. TERATOGENICITY: GENERAL PRINCIPLES
DEFINITION
Teratogen is an agent extrinsic to the embryo or fetus, and that
increases the risk of the following:
- Malformation
- Carcinogenesis
- Mutagenesis
- Altered function (including mental)
- Growth deficiency (IUGR, SGA, SFS)
- Pregnancy wastage (miscarriage, stillbirth, perinatal death).
EVERYTHING OR NOTHING RULE
Teratogens may exert their effect at any time in pregnancy. Effects
between conception and the 18th
postconceptional day, or during
fertilization and implantation, typically produce spontaneous
abortion. Organogenesis is affected during the embryonic period
(18 to 55 days after conception), while the fetal growth and
maturation are affected thereafter.
68
69. TERATOGENS: BASIC PRINCIPLES
CLASSES
- Licit medications (prescribed, over-counter)
- Illicit substances
- Infectious agents
- Paternal exposures
- Radiation
- Food / metabolic
- Mechanical compression, deformation, disruption of fetal growth.
MECHANISM OF TERATOGENESIS
Cell death or reduced proliferative rate (viral infections)
Altered biosynthetic pathways (chromosomal or gene disorders)
Abnormal cellular or tissue interactions during crises (diabetes)
Extrinsic factors (hypoxemia, cell hypoxia, or tissue compression)
Threshold interaction of multiple genes with known or unknown
environmental factors (drugs, radiation). 69
70. GENERAL RULES OF TERATOGENICITY
TERATOGENIC EFFECT DEPENDS ON:
Dose exposed/administered
Gestational age at the exposure
Duration of exposure
Maternal genotype, fetal genotype
Maternal-fetal circulation
Placentation defects
Maternal and fetal immune response
Simultaneous exposure to other teratogenic agents
(1) Agent A = Defect A
(2) Agent B = Defect B
(3) Agent A + B + C = No defect
(4) Agent A + B at different gestational age = No defect
INTERPRETING:
A given defect may result from several different agents.
A given agent may have multiple effects.
Proof of teratogenicity is very strenuous.
70
71. TERATOGENIC AGENTS
● (I) SUBSTANCES
Alcohol: Fetal alcohol
syndrome represents the most
common birth defect caused
by a teratogen. Along with
mental retardation, newborns
have the typical smooth
philtrum, epicanthal folds, a thin
upper lip, a saddle-shape
nose(flat nasal bridge) and
maxillary hypoplasia (Fig. 36).
Cocaine: By preventing the
71
reuptake of catecholamines, cocaine is a potent sympathomimetic. Increasing
vasoconstriction (through 1-agonist effect ofα catecholamines), it decreases
the placental circulation which is an obstetric emergency.The sequential
perinatal hypoxia may lead to mental retardation and number of birth defects.
● Opioids:These are not teratogenic, however, their use leads to the fetal
opioid withdrawal syndrome, and sudden infant death syndrome (SIDS). Heroin
leads to intrauterine growth retardation (IUGR), premature rupture of the
membranes, and chorioamnionitis.The 75% of newborns show clinical signs
of withdrawal within the first 48 hours after birth: diarrhea, tremors,
respiratory distress.
72. TERATOGENS (continued)
Methadone, along with producing fetal dependence and withdrawal in the
majority of exposed infants, is associated with higher rates of neonatal
morbidity and mortality; yet the average birth weight for methadone-addicted
neonates is higher than that for heroin-dependent infants. Neonatal withdrawal
from methadone may be treated with 1 - 2 mg of methadone given twice daily.
● Marijuana: Greater than 25% of women admit to marijuana use. Although
marijuana exposure in pregnancy has been associated with few short-term or
long-term effects on fetus, its risks are dose-dependent, with an increased
incidence of IUGR and SIDS.
● Illicit Hypnotics/Sedatives: Maternal use of sedatives/hypnotics leads to
physical dependency in the fetus characterized by the neonatal
abstinence/withdrawal syndrome (NAS): behavioral and autonomic nervous
system dysfunction plus gastrointestinal, respiratory, and central nervous
system involvements.Women using sedatives/hypnotics during pregnancy
may need to be hospitalized during detoxification because the risk for
seizures and other CNS symptoms is high.
● Tobacco: No distinct birth defects are related, yet smoking causes damage to
the vascular endothelium in the entire body which leads to fetal hypoxia,IUGR,
and prematurity. In average,nicotine reduces birth weight on 300 g. Significant
associations with neonatal respiratory distress and scrotal skin cancer are
described.
72
73. (II). TERATOGEN MEDICATIONS
AGENT INDICATION FETAL EFFECTS
SAFER
ALTERNATIVES *
Acne medication
(Accutane,
Isotretinoin, Retin-A)
Hair follicle blockage
with sebum,
Propionibacterium
Hox-gene distruption,
Spontaneous abortion,
IUGR, Cleft palate
Salicic acid or
Hydroquinone belong
to the FDA Category-C
Alcohol injected
chronically
Binge Fetal alcohol syndrome
(Slide 71)
Abstinence
Aminoglycoside
antibotics
Maternal infecions
Ototoxicity, Deafness
Nephrotoxicity,
Sensory (cranial n. VIII
damage)
Macrolides
Androgenes
(Diethylstilbestrol)
Morning after
abortifacient
Adenosis, Clear cell
adenocarcinoma of the
fetal vagina
-
* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or
recommend therapy. All drugs must be assessed, prescribed, and supervised by your health
provider. Remember: the benefit must outweigh the risk.
73 continued
74. TERATOGEN MEDICATIONS (continued)
74
AGENT INDICATION FETAL EFFECTS
SAFER
ALTERNATIVES *
Angiotensin -
converting enzyme
(ACE) inhibitors
Hypertension,
Congestive heart
failure
Renal agenesis,
Oligohydramnios,
Bone malformations,
Pulmonary hypoplasia,
IUGR, Death,
Acebutolol,
Chlorthalidone Pindolol
Anticonvulsants
(Valproic acid,
Phenytoin for grand
mal, Trimethadione
for petit mal)
Epilepsy, Anxiety,
Bipolar disorder
Fetal hydantion
syndrome, Facial
defects, Mental
retardation
Neural tube defects
Monotherapy with
Carbamazepine,
Lamotrigine,
Phenobarbital
Antidepressants
(Lithium, 2nd
SSRIs)
Unipolar and bipolar
depression
Ebstein's anomaly
Therapy sessions,
Exercise, Tricyclis,
2nd
generation SSRI
* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or
recommend therapy. All drugs must be assessed, prescribed, and supervised by your health
provider. The benefit must outweigh the risk.
continued
75. TERATOGEN MEDICATIONS (continued)
75
AGENT INDICATION FETAL EFFECTS
SAFER
ALTERNATIVES *
Antimetabolics
(Methotrexate,
Arava, Pevalite,
Kineret ) - FDA
Category-X
Cancer, Rheumatoid
arthritis, Lupus,
Misdetected ectopic
pregnancy,
Antiphospholipid
syndrome (AFS)
Combined anomalies
Death
Tumor necrosis factor
(TNF) inhibitor,
Certolizumab pegol
(Cimzia) does not cross
the placenta
Antythyroid drugs
(Carbimazole,
Thiouracil)
Myxedema,
Grave's disease,
Hyperthryroidism
Aplasia cutis, Choanal
atresia, Tracheal -
esophageal fistulae,
Facial anomalies,
Psychomotor delay
Iodine-modified diet,
Selenium supplement,
Coleus Forskohlii
Anticoagulants
Warfarin, Coumadin)
Facial and bone
dismorphism, Cranial
hemorrhage, Abortion
SQ Heparin, Aspirin
(before 30 weeks, and
less 100mg/day)
* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or
recommend therapy. All drugs must be assessed, prescribed, and supervised by your health
provider. Remember: the benefit must outweigh the risk.
continued
76. TERATOGEN MEDICATIONS (continued)
76
AGENT INDICATION FETAL EFFECTS ALTERNATIVES *
Acetylsalicylic acid
(FDA category-C)
Various (pain, fever,
migraine headache,
preeclampsia**)
Pulmonary
hypertension,
Premature closure of
ductus arteriosus,
Renal failure,
Oligohydramnios
Acetaminophen
(Tylenol)
Sulfa antibiotics A wide range of
infections
Bilirubin binding,
Jaundice
Penicillin Macrolides
Tetracycline antibiotics
(FDA category-D)
Infections
Tooth staining, Bone
malformations
Penicillin, Macrolides
Thalidomide Sedation, Hypnosis Phocomelia Tryptophan
Tranquilizers
(Diazepam, FDA
category-D)
Anxiolysis, Hypnosis,
Anticonvulsant, GABA
enhancement
Delayed
neurobehavioral
adaptation
Tricyclics, Hydroxizine
* Note: Information in the “Safer Alternatives” column is NOT intended to endorse drugs or
recommend therapy. All drugs must be prescribed by your health provider.
** The use of Aspirin for tocolysis or in preeclampsia is erroneous, because Aspirin: (1)
unselectively blocks both COX-1 and COX-2; (2) isn't an alpha-1 blocker; and (3) decreases platelet
alpha 2-receptor affinity for both agonists and antagonists.
77. (III). INFECTIOUS AGENTS AS TERATOGENS
AGENT CONGENITAL DEFECTS, OBSTETRIC COMPLICATIONS
B-streptococcus
Premature rupture of membranes, Preterm birth, Low birth
weight, Sepsis
Chagase disease
(Trypanosoma cruzi)
Cardiac or gastrointestinal symptoms in mother transmittable
to the fetus.
Chlamydia trachomatis
Premature rupture of membranes, Preterm birth, Low birth
weight, Cardiac anomalies
Cytomegalovirus (CMV)
Blindness, Cerebral calcification, Chorioretinitis, Deafness,
Hydrocephalus, IUGR, Microphthalmia (transmission risk
33%)
Hepatitis B, C
Fulminate hepatic failure in mother in peripartum,
Prematurity (transmission risk 10 - 34%)
Listeria
Spontaneous abortion, Prematurity, Low birth weight,
Chorionamnionitis, Increased perinatal mortality (10x)
Lymphocytic
choriomeningitis virus
(LCMV)
Chorionitis, Hydrocephalus, Macrocephaly, Retinopathy,
Increased risk of perinatal mortality (7x)
continued
77
79. (IV). RADIATION AS A TERATOGEN: Basic Concepts
TYPES OF RADIATION
Radiation is fast-moving energy emitted as particles or waves. It is
commonly divided into two categories: nonionizing and ionizing radiation.
- Nonionizing is low-frequency radiation that disperses energy through
heat and increased molecular movement. It includes visible light,ultraviolet
rays, microwave, ultrasound,radio waves, and infra waves.
- Ionizing radiation includes particles (alpha and beta) and electromagnetic
waves (gamma rays, x-rays, terahertz).The higher electromagnetic wave
frequency, the increased is ionizing effect.
In average, the Americans are exposed to approximately 0.001 Gy (0.1 rad)
of annual radiation/per capita, from cosmic rays, environment, medical
procedures, and naturally occurring radiation in the human body.
RADIATION TYPES IN MEDICINE:
Ionizing Radiation: Gamma rays (Nuclear Medicine, Positron Emission
Tomography, Single Photon Emission CT); X-rays (CT, Computed
Radiography, Digital Subtraction Angiography, Pulsed-field Gel
Electrophoresis [PFGE], Duel-energy X-ray Absorptiometry, Fluoroscopy,
Mammography; Radiography; Radiation Therapy).
Nonionizing Radiation: Radio FrequencyWaves (Magnetic Resonance
Imaging [MRI]), UltrasoundWaves (Ultrasonography). 79
80. RADIATION (continued)
GENERAL MECHANISMS OF ACTION:
● Nonionizing radiation interacts with tissue through the generation of heat. A
causal linkage is found between prenatal exposure to electromagnetic fields
and birth defects, miscarriage, or childhood leukemia. Ultrasound and MRI
should be performed only per medical indications.
● Prenatal exposure to ionizing radiation can be teratogenic,carcinogenic,or
mutagenic. Ionizing radiation acts directly with biochemical structures in
tissue (proteins,DNA) or indirectly by causing the formation of free radicals,
which in turn break the cell structures (mitochondria).The effects of
exposure may be classified as deterministic or stochastic.
Deterministic effects result from radiation-induced cellular injury or death,
and are characterized by a threshold dose. For a given threshold dose, there
is loss of organ/tissue functionality leading to pregnancy loss,congenital
malformations, neurobehavioral abnormalities, and fetal growth restriction.
Thus, in deterministic theory the dose matters.
Stochastic effects are caused by radiation-induced changes in cells that
maintain their capability for replication. Over time, these cells can become
malignant. Unlike deterministic effects, stochastic effects do not have a
threshold dose.Their effect probability depends on simple, linear models,
which are the basis for current radiation protection standards and practices.
This model theory suggests that any exposure dose to ionizing radiation may
be harmful. 80
81. RADIATION (continued)TIME OF EXPOSURE:
(a) From day 1 to day 18 after conception, there is “everything or nothing
rule” (the conceptus either dies, or does not sustain any teratogen effect).
(b) Between days 18 – 55, the most sensitive period (organogenesis), the
risk of teratogen, growth-retarding or lethal effects of radiation is the highest.
(c) Between weeks 9 – 40 (fetal period) there is decreased radio-sensitivity
for the organ systems, but overall fetal growth retardation (symmetric), CNS
dysfunction, or postnatal neoplastic effects may occur.
BASIC CONSIDERATIONS IN RISK ASSESSMENT:
● Gestation age at time of exposure.
● Type of radio-diagnostic exam (X-ray, radionuclide, PFGE). Does the isotope
concentrate on the fetal side of placenta?
● Is the radiation dosage estimated by an expert radiologist or physicist?
● Radiation exposure from a single diagnostic imaging procedure does not
increase the risk of fetal anomalies or pregnancy loss.
● Prenatal ultrasonography may only be performed if medically indicated and
when the lowest possible exposure setting is used.
● A dosimetry specialist should be consulted for calculation of the estimated
fetal radiation dose when a patient is undergoing multiple diagnostic
procedures. Single procedure estimates are provided in Slide 82. 81
82. MEDICAL PROCEDURES & RADIATION DOSES
TARGET, PROCEDURE Average Uterine Dose (mrad) Reported Range (mrad)
Dental exam 0.06 0.03-1.0
Head & Neck 0.5 0.5- 3.0
Extremities 0.5 0.5-1.8
Thorax, Thoracic Spine 11.0 10.0 - 55.0
Lumbosacral Spine 721.0 20.0 - 2900.0
Cholecystogram 78.0 14.0 - 1600.0
Intravenous Pyelogram 588.0 50.0 - 4000.0
Abdomen 221.0 18.0 - 1400.0
Pelvimetry 600.0 160.0 - 4000.0
Barium Enema 900.0 20.0 - 9200.0
- Table shows the range of fetal radiation doses from common procedures (not
including fluoroscopy).
- The data are modified from the National Council on Radiation Protection and
Measurements (NCRP Rep N 54).
- The presented estimates cannot be used for individual calculations of fetal
irradiation without counseling with a radiologist.
82
83. PRENATAL RADIATION RISK
Common Risk Measures (including carcinogenic)
● Less than 5 rad (5000 mrad): no increased risk for malformations, but other
teratogen effects (mutation, carcinogenesis) may occur.
● 5 to 10 rad: no increased risk for malformations.
● 25 rad > : definite risk for malformations.
● 100 rad >: definite IUGR, malformations
● There is no threshold dosage for the risk of carcinogenesis, mutagenesis, and
miscarriage.
Non-carcinogenic Risk of the Acute Fetal Irradiation
83
ACUTE DOSE BLASTOGENESIS ORGANOGENESIS WEEKS 8 -15 WEEKS 16-36
0.05 Gray (Gy)
or 5 Rad
- - - -
0.05 – 0.5 Gy
5-50 Rad
Implantation
failure
Higher risk of
malformations, IUGR
IUGR, Severe
mental
retardation (25%)
-
0.5 Gy > Implantation
failure
Miscarriage, Major
malformations, IUGR
IUGR, Major
malformations
Increased risk for
neonatal death
Note: A fetal dose of 1 Gy (100 rad) will likely kill 50% of embryos. The dose necessary to kill
100% of human embryos before 18 weeks' gestation is about 5 Gy (500 rad).
84. (V). MECHANICAL TERATOGENS
● Mechanism of action
- Deformation: Mechanical molding of tissues (oligohydramnios, uterine
structural anomalies and tumors,corsages)
- Disruption: Destruction of normal tissue (amniotic band syndrome)
● Amniotic Band Syndrome (ABS):
A congenital disorder caused by entrapment of fetal parts in fibrous
amniotic bands. Defects are usually asymmetric, do not follow the
sequence of embryonic development, are often associated with annular
constrictions or congenital amputations of fetal limbs or digits (Fig. 37).
Torpin et al propose the following stages of the ABS:
84
Rupture of the amnion => Fetus enters
chorionic cavity => Oligohydramnios
=> Clubbing => Spinal deformities =>
Mesodermic band formation => Days
28-45: Craniofacial defects,Visceral
defects,Abortion.// Day 45-Week 18:
Limb constriction,Digital constriction,
Amputations.
85. TERATOGENS (continued)● (V). PATERNAL EXPOSURE
- Effects of paternally-mediated factors are dual: fertility (sperm kinetics
alteration), and fetal anomalies (sperm genome alteration).
- Agent Orange is a common concern of the Vietnam War veterans.
- Other concerns: Chemotherapy, Smoking, Illicit substance ab/use, Ionizing
radiation, Cryopreservation, Occupational hazards (lead, arsenic,mercury,
heat,vibration).
- Due to bioethical rules, experimental studies or randomized controlled
trials on human reproductive toxicity are unfeasible. Existing data are based
on the observational, epidemiological,retrospective studies.
There are three main mechanisms of male reproductive toxicity: non-genetic
(presence of drugs in seminal fluid), genetic (gene mutation or chromosomal
abnormality), and epigenetic (effect on gene expression, genomic imprinting,
DNA methylation).
Some common occupational exposures (1,3-butadiene) are linked to
increased risk of leukemia in offspring.
● (VI). MULTIFACTORIAL
Defects result from Mendelian,chromosomal,and teratogen causes. For
example, congenital cardiac anomalies may be drug induced (Lithium),
infection related (Rubella), or chromosomal (Trisomy 21).
Other multifactorial conditions: Cleft lip/Cleft palate, Neural tube defects,
Renal anomalies, Müllerian fusion defects, GI anomalies, Orthopedic
anomalies (club foot, hip dysplasia, scoliosis).
85
87. (I). MITOCHONDRIAL INHERITANCE
Mitochondrial inheritance is related to two basic principles:
- all mitochondria in the offspring are from the mother's ovum (female gamet)
- the smermatozoid (male gamet) does not contain mitochondria.
Therefore, affected females (mothers) with mitochondrial diseases will have
100% of their offspring affected; yet, the affected males (fathers carrying
mitochondrial diseases from their mothers) will have 0% of their offspring
affected. (See specifics in Slide 88).
Examples of mitochondrial hereditary diseases:
– Leber hereditary optic neuropathy (LHON)
– Mitochondrial encephalopathy with lactic acidosis and stroke-like
episodes (MELAS)
– Myoclonic epilepsy and ragged red fibers (MERRF).
Primary Mitochondrial Diseases: Are caused directly by mutated,damaged,
or deleted mitochondria. The mutated genes can be inherited or sporadic (when
disease occurs for the first time in a family, or is an isolated episode due to an
unknown cause - a spontaneous mutation).Sporadic occurrences are less
common and often correlated with actual deletion of mitochondria.
Secondary Mitochondrial Diseases: Occur when mitochondria are damaged
or under stress due to other diseases, like Parkinson's or Alzheimer's. 87
88. Are mitochondrial diseases always inherited?
Mitochondria has two types of genomes: Mitochondrial DNA Genome and Nuclear
DNA Genome.
- Mitochondria DNA Genome appears as double stranded organelle, a very
small piece of DNA that makes only 13 proteins which are part of the electron
transport chain.They continue to mix in a mosaic-like pattern in zygote formation.
Mitochondrial DNA may also sustain a deletion (due to injury/trauma/physiologic
stress).This type of deletion disease is not familial,not inherited.The loss of
specific Mitochondrial DNA may result in very specific problems/symptoms.
- Nuclear DNA Genome,which we link to the chromosomes,is what we
commonly (erroneously) associate with inherited diseases through maternal line.
Yet,if problems occur in the Nuclear DNA,the transference to the next generation
would not be just through the mother (egg) but would follow standard Mendelian
laws of inheritance. Currently there are 55 identified Nuclear Genes (there may
be as many as 1200),occurring primarily in electron transport chain,and which
cause very complex Nuclear DNA Mitochondrial syndromes.
- In summary, mitochondrial disease may be inherited from the (1)
mitochondrial DNA (strictly maternal inheritance), (2) nuclear DNA (standard
Mendelian inheritance), or may (3) occur as spontaneous mutations.
88
MITOCHONDRIAL (continued)
89. BASIC MENDELIAN INHERITANCE
Chromosomal abnormalities are single-gene disorders and can be:
Numerical – chromosomes are either missing or in excess than the
regular pairs.
Structural – fragments of chromosomes are excessive or missing.
● NUMERICAL
- Occur from nondisjunction that may take place in both meiosis -I (leading
to monosomy) and meiosis-II (leading to trisomy) (see Slide 90).
- May involve autosomes (chromosomes 1-22) or sex chromosomes (X,Y).
- A chromosomal complement that is not the multiple of the haploid number
23 is aneuploidy (see Slide 90).
- A chromosomal complement that involves an entire haploid set of 23 is
polyploidy (see Slide 91).
● STRUCTURAL
1) Rearrangement of chromosomes may or may not produce phenotypic
abnormality, depending where the excessive or missing genetic info is.
2) Balanced rearrangements yield phenotypically normal individuals
who have an increased risk of producing unbalanced gametes, which
leads to reproductive loss or abnormal children. 89
90. Nondisjunction during Meiosis I and II90
● A): Nondisjunction occurs in meiosis-I.A pair of homologous chromosomes fails to
separate which leads to formation of four affected eggs.Taken Down Syndrome as an
example, two eggs will have an additional 21st
chromosome and will produce
trisomy-21 child from a non-affected father.The other two eggs will produce
monosomy-21 child from a non-affected father. Autosomal monosomies are lethal and
are miscarried. X-linked monosomies survive (Turner, monosomy X). Most autosomal
trisomies are also lethal (except Down -21, Patau -13, and Edwards -18 syndromes).
● B): Nondisjunction takes place in meiosis-II.The first division is appropriate,
producing two unaffected eggs which will then divide normally.Thus, out of four
gametes, two will be normal, one will have trisomy 21, and the other - monosomy 21.
92. NUMERICAL ANOMALIES (continued)
● Pedigree analysis helps deduce whether a condition is autosomal
dominant, autosomal recessive, X-linked dominant, or X-linked recessive.
● In Punnett square, the alleles of each parent are drawn in a 2 x 2 table.The
main principles of pedigree assessment are these:
X – linked Disorders:
(1) There can't be father-to-son transmission.
(2) Dominant:
a) Both males and females may be affected.
b) An affected male will have normal sons,
yet all daughters will be affected.
c) Offspring of an affected female will be
normal or carrier, with 1:1 ratio.
d) Example: D-resistant rickets.
(3) Recessive:
a) Only males are affected (there's a room for a rare homozygous female)
b) An affected male will have all normal sons, and all daughters-carriers.
c) Examples: Duchenne's/Becker muscular dystrophy,Hemophilia-A and B.
92
93. ● Autosomal Disorders
(1) Both sexes are equally affected.
(2) Dominant:
a) Penetrance and expressivity may vary from one individual to
another.
b) Affected individuals will produce either normal or affected
offspring, in a ratio of 1:1.
c) The affected individual either has an affected parent or
represents a new mutation.
d) The affected parent poses a 50% risk.
e) An affected child born to unaffected parents presents a new
mutation and there is no increase in the recurrence risk.
f) Older father ( > 50 years) form the risk group for the new
mutations involving autosomal-dominant inheritance.
g) Examples: Achondroplasia,Huntington's Disease,Tuberous
Sclerosis, Marfan Syndrome,Polycystic Kidnet Disease,Acure Intermittent
Porphyria, Osteogenesis Imperfecta (some types).
93
NUMERICAL ANOMALIES (continued)
94. Autosomal Disorders(3) Recessive:
a) Both parents of affected infant must be carriers.
b) Offspring of two carrier parents will be either unaffected, or
carrier, or affected in 1:2:1 ratio.
c) Siblings may be affected; however, affected relatives are
uncommon unless there is consanguinity in the pedigree.
d) The couple with an affected child has 1:4 chance of recurrence in
each next pregnancy.
e) Birth of a child with rare or bizarre anomalies should always
prompt consideration of an autosomal recessive disorder.
f) For women with other affected relatives, the risk depends on
frequency of gene population.
Hardy-Weinberg equation
is used to estimate gene frequency from incidence of disease:
p2
+ 2pq + q2
=1
where p2
is the frequency of noncarriers (almost always <1), q2
is the frequency
of the affected individuals, and 2pq is the frequency of carriers.
g) Examples: Cystic Fibrosis, Sickle Cell Anemia,Tay-Sachs,Meckel-
Gruber Syndrome,Thrombocytopenia-absent Radius (TAR) and other single-
gene defects. 94
95. Structural Chromosomal Anomalies
The two major chromosomal mutations are: (1) insertion, (2) translocation.
Chromosome aberration or mutation is a missing, extra, or irregular
portion of chromosomal DNA. It can be from an atypical number of
chromosomes or a structural abnormality in one or more chromosomes.
While missing or extra DNA mutations take place during the meiotic
phases of the ova, some anomalies can happen after conception, resulting in
Mosaicism (where some cells have anomaly and some do not). Such
anomalies are “de novo,” not inherited from a parent.
Rearrangement of chromosomes may or may not produce phenotype
abnormality, depending where the excessive or missing genetic information
is. Balanced rearrangements yield phenotypically normal individuals.
● Examples of structural anomalies:
- Most cancers, either with formation of hybrid genes and fusion proteins,
deregulation of genes and over-expression of proteins, or loss of tumor
suppressor genes.
- Malignant Paraganglionic Neoplasm - chromosome-11 deletion.
- Pallister Killian syndrome, part of the chromosome-12 is duplicated with
elements of mosaicism.
- Cri du Chat or "Cat Cry” syndrome - deletion of chromosome 5p.
95
96. Some genetic conditions are caused by expansion of a DNA segment that
contains a repeat of three nucleotides (triplet repeat), such as
VAT.VAT.VAT.
Healthy individuals have a variable number of triplet repeats, but there is
a threshold beyond which a high number of repeats causes disease.This
threshold varies from one disorder to another.
The triplet repeat expansion (TRE) is also known as dynamic or unstable
mutation because the number of triplet repeats may increase as the gene
is passed from a parent to offspring. In this way, the condition may
worsen or have an earlier onset from generation to generation (genetic
anticipation).
Where there is a number of repeats in normal range,TRE is not expected.
However, when the number of repeats falls in the premutation range
(normal, but unstable number of repeats), the repeats may or may not
expand upon transmission to the next generation.Therefore, normal
individuals with premutation are at risk of having an affected child with a
triplet repeat in full mutation range.
Sometimes the premutation range and the affected range overlap. In this
gray area, someone may or may not express symptoms of disorder.
The premutation size and source matter in inheritance. For example, the
Myotonic Dystrophy triplet repeat is most likely to expand when inherited
from mother.The Huntington Disease triplet repeat is most likely to
expand when inherited from father.
TRIPLET REPEAT EXPANSION
96
97. HEME SYNTHESIS DISORDERS
Heme is composed of a tetrapyrrole ring (4 linked pyrrole rings)
of protoporphyrin IX, with one coordinating ferrous (Fe 2+
) iron ion
in the center. Heme is found not only in hemoglobin and
myoglobin but also in cytochromes and catalase. Synthesized
primarily in liver (cytochrome P-450 protein) and bone marrow
(delta-aminolevulinic acid and protoporphyrin), the first and the
three last stages of heme formation occur in mitochondria.The rest
occur in cytosol.
That explains why some of the heme-synthesis disorders
(porphyrias, both hepatic and erithropoetic) are hereditary. All are
autosomal dominant except the erythropoietic porphyria which is
autosomal recessive. Some of these are photosensitive and
accumulate deleterious free radicals from tetrapyrrole
intermediates.
continued
97
98. The Best Known Types of Porphyrias:
TYPE of DISEASE DEFICIENCY H/E CLINICAL FEATURES
Acute intermittent
porphyria (AIP)
Uroporphyrinogen I
synthetase
Hepatic
CNS effects, Abdomonal
pain
Congenital erythropoietic
porphyria
Uroporphyrinogen III
synthetase
Erythropoietic
Hemolytic anemia,
Photosensitivity
Porphyria cutanea tarda
Uroporphyrinogen
decarboxylase
Both
Red-brown urine,
Photosensitivity
Hereditary coproporphyria
Coproporphyrinogen
oxidase
Hepatic
CNS effects, Abdominal
pain, Photosensitivity
Porphyria variegate
Protoporphyrinogen
oxidase
Hepatic
CNS effects, Abdominal
pain, Photosensitivity
Erythropoietic
protoporphyria
Ferrochelatase Erythropoietic
Liver dysfynction,
Photosensitivity
Crigler-Najjar syndrome
Bilirubin
glucoronyltransferase
Hepatic
CNS effects, Kernicterus,
Jaundice, Death
Gilbert (zheel BAR)
syndrome
Bilirubin
glucoronyltransferase
Hepatic
Common in females,
Nonhemolytic jaundice,
No treatment is required
98
99. GLYCOGEN STORAGE DISEASES
● IN DEFAUT:
The substrate for glyconeogenesis is uridine diphosphate
(UDP) glucose. Glycogen synthase adds to the nonreducing
ends of chains in (1=>4) linkages.Yet, branches of theα
(1=>6) linkages are facilitated byα amylo- (1=>4)-α α
(1=>6)-transglucoside. Glyconeogenesis is stimulated by
insulin and is inhibited by glucagon and epinephrine.
Glycogenolysis starts from the cleavage of (1=>4) bondsα
between glucosyl residues' nonreducing ends, and forming
of glucose-1-phosphate.The latter converts to glucose-6-
phosphate,then to glucose by releasing (1=>6) bondsα
under the debranching enzyme. Glycogenolysis is
stimulated by glucagon, epinephrine, and is inhibited by
insulin.
continued
99
100. Six Glycogen Storage Diseases
(all are autosomal recessive):
TYPE of DISEASETYPE of DISEASE DEFICIENCYDEFICIENCY GLYCOGEN INGLYCOGEN IN
AFFECTED CELLSAFFECTED CELLS
CLINICAL FEATURESCLINICAL FEATURES
Von Gierke (type I)
Glucose-6-
phosphatase
Increased - with
normal structure
Hepatomegaly,
Hypoglycemia
Pompe (type II) α-1,4-glucosidase
Increased - with
normal structure
Cardiac and respiratory
failure, Early death
Cori (type III)
Debranching
enzyme
Increased, shortened
branches
Similar to Von Gierke, but
in midler forms
Anderson (type IV) Branching enzyme
Increased, prolonged
branches
CNS effects, Abdominal
pain, Photosensitivity
McArdle (type V) Phosphorylase
Slightly increased, with
normal structure
Muscle cramps while
exercising
Hers (type VI) Phosphorylase Increased
Similar to Von Gierke, but
in milder forms
100
101. SPHINGOLIPID STORAGE DISEASES
Sphingolipids are derived from ceramide, a molecule formed by
coupling a fatty acid and sphingosine:
Fatty Acid + Sphingosine = Ceramide
● Sphingolipids are found in the white matter of CNS. Lysosomal
enzymes degrade those to sphingosine through several hydrolytic
reactions.
● SPHINGOLIPIDOSIS are a group of hereditary lysosomal enzyme
deficiency diseases with defects of one of above noted hydrolytic
enzymes in degrading pathways. Deficiencies of sphingolipid-
degrading enzymes in lysosomes lead to the accumulation of
substrates therein, which results in lysosomal storage diseases.
● All are autosomal-recessive, except Fabry Disease which is X -
linked. In most of these diseases neurological deterioration and
early death occur.
continued
101
102. Sphingolipid Degradation Disorders 102
SPHINGOLIPIDOSISSPHINGOLIPIDOSIS DEFICIENT ENZYMEDEFICIENT ENZYME ACCUMULATEDACCUMULATED
MATERIALMATERIAL
CLINICAL FEATURESCLINICAL FEATURES
Tay - Sachs disease Hexosaminidase-A GM2
gangliosides
Developmental regression,
Muscle weakness, Blindness,
Cherry-red macular spot,
Deafness, Absence of Hepato-
splenomegaly, Death
Gaucher disease β -Glucosidase Glucocerebrosides
Joint and limb pain,
Hepatosplenomegaly,
Macrophages look like “crinkled
paper”
Niemann-Pick
disease
Sphingomyelinase Sphingomyelin
Failure to thrive, Hepato-
splenomegaly, Cherry-red spot
in retina, Developmental delays,
Macrophages look like “bubbly”
Fabri disease α - Galactosidase
Ceramide
trihexosides
Cataract, Kidney and heart
failures, Paresthesia
Krabbe disease β - Galactosidase Galactocerebrosides
Progressive psychomotor
retardation, “Globoid bodies” in
brain white matter, Death
Metachromatic
Leukodystrophy
Arysulfatase -A Sulfatides
Mental retardation, Peripheral
neuropathy
103. HISTONE MODIFICATION DISORDERS
Histones are highly alkaline proteins found in eukaryotic cell nuclei that package
and order the DNA into structural units, nucleosomes.The chief protein
components of chromatin, they act as spools around which DNA winds, and
participate in gene regulation.
● The linkage between histone methylation pathways and immune and neuronal
signaling explains the greater genetic basis of neuropsychiatric disorders than
previously recognized.
● Whole exome screens of lymphoma,multiple myeloma, renal carcinoma and other
malignancies identify genes encoding diverse histone modifiers as targets of
somatic mutation.
- Wiedemann-Steiner syndrome (autosomal dominant) – IUGR, psychomotor
tardiness, hypotonia, facial dysmorphism (flat, assymetric face, dolichocephaly,
telecanthus, thick eyebrows, short nose, hypertelorism, long philtrum, heavy jaw,
ptosis, low-set ears, epicanthal folds, mild clinodactyly), short stature, sacral
dimple short and thick limbs.
- Kabuki syndrome (X-linked) – mental retardation, postnatal dwarfism, facial
dysmorphism (reminiscent of Kabuki make-up), scoliosis, short 5th
finger.
- Cornelia de Lange syndrome (autosomal dominant) – facial dysmorphism
(synophrys), intellectual deficit, IUGR, digital defects and splanchnic malformations.
- Other:Weaver syndrome, Sotos syndrome, Coffin-Siris syndrome, Nicolaides-
Baraitser syndrome. 103
104. ANTENATAL FETAL ASSESSMENT: ERRORS
Challenges in assessing fetal condition are often related to type-1 and type-
2 errors which may be analytic (timing, interpreting) and technical (i.e.
sensitivity and specificity of the chosen method).
Type-1 error (false positive result, Fp)
Type-2 error (false negative result, Fn)
Sensitivity (given the disease/anomaly is present, the probability that the
test will be positive)
Specificity (given the disease/anomaly is absent, the probability that the test
will be negative).
Marking true-positive (Tp) and true-negative (Tn) as well, we can then
define sensitivity as Tp/(Tp + Fn).
A highly sensitive test, therefore, can rule-out the disease. Consider the
mnemonic SN-N-OUT – for a test that is SeNsitive, a Negative result rules
OUT a disease.
Specificity s defined as Tn/(Tn + Fp).
Thus, tests with high specificity rule-in the disease. The corresponding
mnemonic, SP-P-IN, stands for – a test that is Specific, a Positive result rules
IN a disease.
104
105. FETAL ASSESSMENT: PREDICTION
Positive predictive value (PPV) – given the test is positive, the
probability that the disease/anomaly is present.
PPV = Tp/(Tp + Fp)
For example, if the amniocentesis has 78% specificity for
cystic fibrosis, then given a positive finding of cystic fibrosis
the offspring will truly have the disease in 72% of the time.
Negative predictive value (NPV) – given the test is negative,
the probability that the disease/anomaly is absent.
NPV = Tn/(Tn + Fn)
For instance, if a mid-pregnancy scan (ultrasound) has a 67%
NPV for the fetal limb defect, then given the negative result,
the fetus will truly not have a limb defect in 67% of the
time.
105
106. FETAL ASSESSMENT: BASIC MEASURES
The red-line between miscarriage (including late miscarriage) and
preterm birth, as well as between stillbirth or perinatal death is the 22nd
gestation week (formerly, before the ICPD of 1995, it was the 28th
week).
At the end of 22nd
gestation week, a regularly growing fetus weighs ~ 453
g (1 pound) and is ~ 28 cm (11-inches) long.
Intrauterine growth retardation (IUGR) is when the estimated fetal weight
(EFW) is at least 10% lesser than the expected normal. IUGR can be
symmetric (fetal head and body are equally affected), and asymmetric (a
milder form, where head is less affected than the torso).
Table below shows ultrasound-assigned parameters for the:
106
GESTATIONAL AGE FETAL GROWTH
● Biparietal diameter
● Head circumference
● Femur length
● Crown-rump length
● Outer orbital diameter
● Transcerebellar diameter
BPD
HC
FL
CRL
OOD
TCB
EFW
HC /AC
FL /AC
EFW
● Estimated fetal weight assessed by
nomograms that combine AC and either FL or
BPD.
● > 95% is an asymmetric IUGR
● > 0. 24 is IUGR
● > 90% I macrosomia - if dates are
population- adjusted and accurate.
107. ANTENATAL FETAL ASSESSMENT: ULTRASOUND
Lateral Ventricular Width (LVW) /
Hemisphere Width (HW) ratio is used
in detection of ventriculomegaly and
fetal hydrocephalus (Fig. 39). Bilateral
indentations of the fetal skull in the
frontal region (“lemon sign”) before 24
weeks of estimated gestation age (EGA)
are suggestive of neural tube defect.
107
Occipitofrontal Diameter (OFD) is
used (Fig. 40) for estimating Cephalic
Index (CI).
CI = BPD / OFD
CI < 0.75 - dolichocephaly
CI > 0.85 - brachycephaly
(OFD + BPD) / 2 x 3.14 = Head
Circumference (HC).
HC is used to estimate gestation age in
settings with abnormal CI.
108. CRANIAL ULTRASOUND (continued)
Outer Orbital Diameter (OOD),
Interorbital Distance (IOD), and
Ocular Diameter (OD) are used for
estimating gestational age (Fig. 41).
The abnormal IOD suggests
hypertelorism or hypotelorism.An
abnormally small OD suggests
microphthalmia.
108
Transcerebellar Diameter
(TCD) is used for estimating
gestational age (Fig. 42). It is
spared to some degree in the
IUGR. Abnormal shape of
cerebellar hemisphere (“banana
shape,” instead of regular round
shape) is associated with neural
tube defects.
109. THORACIC ULTRASOUND
Fig. 43: Four-chamber Heart
View
Cross section of fetal chest
shows four-chamber view of the
fetal heart and the spine – to
assess cardiac anatomy and
measure thoracic circumference
(TC).
A normal four-chamber image
rules out most (81%) cardiac
anomalies. Absence of fetal
head motion is an irrefutable
indicator of the intrauterine
109
fetal demise.
TC = (D1 + D2)/2 x 3.14
TC helps predict the presence or absence of pulmonary hypoplasia --
together with the AC/TC ratio.
110. ABDOMINAL ULTRASOUND
Fig. 44: Fetal Abdomen
This cross section view at
the level of liver and
stomach shows ductus
venosus in the liver and
is the adequate place for
measuring abdominal
circumference (AC).
AC= (D1 + D2)/2 x 3.14
AC can be used for
estimating gestational
age but it's more
sensitive to the fetal
growth disorders.
Common measures:
● Higher than normal HC/AC – asymmetric IUGR
● Lower than normal HC/AC – macrosomia or microcephaly
● Higher than normal FL/AC – IUGR, lower than normal FL/AC – macrosomia
● Lower EFW but normal HC/AC - symmetric IUGR.
110
111. AMNIOTIC FLUID, DOPPLER, FETAL VESSELS & PLACENTAL PERFUSION
● Qualitative Amniotic FluidVolume – is ultrosonographically observed after
30-32 gestation weeks and is the pocket of the fluid that measures at least
1 cm in two perpendicular planes.
● Amniotic Fluid Index (AFI) – is the sum of 4 quadrant vertical
measurements. It is one of the 5 biophysical profile metrics.
● Oligohydramnios – there is no pocket > 1cm in two perpendicular planes,
and AFI is < 4cm. Polyhydramnios - largest pocket is > 8cm in two
perpendicular planes.
● Angle-independent Doppler indices: S/D = systolic/diastolic ratio; (S-D)/S
= resistance index, (S-D)/Mean =pulsation index (Fig. 45).
● Uterine and Arcuate Arteries: S/D is normally < 2.6 after 26 weeks.
● Umbilical Arteries: S/D decreases with advancing gestation and normally
111
is less 3.0 after 30 weeks.
● Fetal Descending Aorta: Peak velocity of
flow is decreased with fetal hypoxia.
● Carotid Artery & Cerebral Circulation: In
hypoxic states, blood flow to fetal head
increases, PI decreases, and S/D of
umbilical artery increases.
112. END OF MEDICAL SURVERY: Questions
● Q1: During a well-child exam, a 4 year-old male is found to have a cyst on the
lateral side of the neck along the m.sternocleidomastoid border. What is the
embryological origin of this condition?
● Q2: A man with Leber hereditary optic neuropathy consults for the odds of his
condition being passed to his sons or daughters. What is your advice?
● Q3: An increase in the uterine artery PI or S/D is always indicative of:
a) IUGR
b) Fetal compromise
c) Increase in vascular resistance
d) None of the above.
● Q4:What is involved in the classic triad of congenital rubella syndrome?
● Q5:True or false? The IUGR may be detected by measuring HC/AC and
FL/AC, and by estimating the fetal weight (EFW).
112
113. END OF MEDICAL SURVERY: Answers
● A1. A branchial cleft cyst has likely been growing because of the 2nd
branchial cleft's obliteration failure (see Slides 35, 36, 58).
● A2: Mitochondrial disease such as Leber hereditary optic neuropathy,
mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
(MELAS), or myoclonic epilepsy and ragged red fibers (MERRF) are
transmitted only from the affected females to their offspring.The egg has
mitochondria, not the sperm.The chance of passing on the male patient's
condition to his offspring is 0% (see Slides 87, 88).
● A3: Correct answer is D. Not necessarily. In this case, increased PI and S/D
are more indicative of preeclampsia (see Slide 111).
● A4:The classic triad consists of (1) Cataracts, (2) Congenital cardiac
defects, (3) Sensorineural deafness. Other complications include: Autism,
Chorioretinitis, Hepatosplenomegaly, Microcephalus, Mental retardation,
Osseous defects (see Slide 78).
● A5:True (see Slides 106, 110).
113
114. TERATOLOGY & MALPRACTICE LAW
At the interface of two disciplines, Teratology and The
Law of Torts, at least three challenges manifest in
relation to the:
Recognition of the purpose of Teratology as a science
related to a measurable human problem.
Communication and conflicts between Teratology and
other sciences (obstetrics, perinatology, occupational
health, oncology, radiology, mental health, genetics,
toxicology, environmental health, others) in addressing a
legal inquiry.
Assessment of Teratogenesis beyond the frames of the
cause-and-effect relationship, by recognizing alternative
consequences that could take place under the same
causation.
114
116. 4 IMPERIOUS ELEMENTS OF PRIMA FACIE SHOWING OF
MEDICAL NEGLIGENCE
To recover on a theory of negligence or malpractice, the injured party (with
standing) carries the burden of proving that:
(1) defendant had duty to conform his conduct to a standard of care;
(2) defendant failed to conform his conduct to the requisite standard of care
required by the relationship;
(3) defendant's negligent act was the proximate cause of injury, and
(4) damage was transferred.
Where congenital anomaly is the matter of a legal dispute, the roles of
plaintiff and defendant are intricate.
● PLAINTIFF – can be parent(s) petitioning on behalf of the affected child, or
the affected child filing after his/her 18th
birthday, or the state (ex patre, on
behalf of the unborn fetus) against the negligent pregnant woman.
● DEFENDENT - can be the healthcare provider (GP, obstetrician, any other
specialist in charge of a woman's medical or mental conditions in
pregnancy), radiologist, toxicologist, nutritionist, pharmaceutical company,
pharmacist, medical educator, trial researcher, employer, landlord, spouse;
simply anyone or any entity with linkage to the cause-effect chain.
116
117. DUTY
In general, there are two key aspects of physician-
patient relationships:
● voluntary agreement (there is no obligation
without consent),
● once created, such a relationship raises
unwaivable obligations.
The voluntary relationship doctrine has sprung
from Hurley v.Eddingfield. [1]
The issues were: (1)
whether the licensed doctors were obligated to
help patients in dire medical need; and (2) whether
there was an affirmative duty to be a good citizen
and help others in peril without a predicament?
117
The Montgomery Circuit Court of Indiana ruled that:
a physician has no duty to enter into relationships with a patient;
the license permits, but does not require provision of medical services;
a physician can't be forced to practice at all,or on terms he may choose to
accept.
(1) Hurley v. Eddingfield, 156 Ind. 416, 59 N.E. 1058, 1901 Ind
NOTE: In obstetrics or antenatal care,the voluntary relationship doctrine does
not apply. A pregnant woman applying for care can't be rejected.
118. THE INTRAUTERINE VICTIM
● In malpractice law, the three forms of liability (intentional torts, negligent
torts, and strict liability) may merge in assessment of damages. Where
there is a gross medical error, absence of intent or but-for rules are
unimportant and plaintiff may be awarded for punitive damages in
addition to simple compensation.
● If the case involves maternal-fetal conflicts (a pregnant woman smokes or
uses illicit substances, or knowingly/unknowingly exposes herself to
toxic hazards, employment hazards, or radiation), the wrong act may
potentially be prosecuted as criminal offense in the states with fetal
custody laws, where the government represents the “unborn victim.”
● In 2004, President G.W.Bush signed into law the UnbornVictims of
Violence Act, which - coded in two sections [2, 3]
- recognizes a child in
utero as a legal victim if s/he is injured or killed during the commission
of any of over 60 federal crimes of violence listed in the Model Penal
Code [2, 3].
(2) Title 18, Chapter 1 (Crimes), §1841
(3) Title 10, Chapter 22 (Uniform Code of Military Justice), Article 119a.
● Slides 119 -120 list the states that have “offense against the unborn”
statutes and jurisdiction: 118