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CHAPTER 14 Cellular Injury
291
• Tumours produced are basal cell carcinomas, squamous
cell carcinomas and malignant melanomas.
Therapeutic Irradiation
Radiotherapy can be used therapeutically in three ways:
• With a view to a cure (radical radiotherapy).
• Adjuvant.
• Palliative.
Radical Applications
• Basal cell and squamous cell carcinoma of the skin.
• Some head and neck tumours and laryngeal tumours.
• Hodgkin’s disease.
• Lymph node metastases of a testicular seminoma following orchidectomy.
Adjuvant Radiotherapy
is is aimed at clinically undetectable metastases due to
spread locally or into the regional lymph nodes, e.g. carcinoma of the breast giving radiotherapy to the scar, axillary
nodes, supraclavicular nodes and internal mammary nodes.
Palliative Radiotherapy
• Bony metastases: pain relief is oen dramatic.
• Cerebral metastases.
• Ulcerating or fungating breast cancer: controls oozing
and bleeding and allows skin healing.
• Lung cancer to prevent cough and haemoptysis.
Fractionation of Dose
• A higher dose of radiation may be given without increasing side eects if it is divided into a number of fractions
and given on dierent days with a break in between.
• Normal cells are better able to repair than neoplastic cells.
• Results in dierential cell killing of more tumour cells
than normal cells.
Response Modifiers
• Low oxygen tension in tissues reduces sensitivity of
tumours, probably due to fewer oxygen free radicals.
• Compounding this is the fact that tumours may be relatively avascular and the patient may be anaemic: therefore, transfusion may help.
• Radiosensitizers that enter neoplastic tissue may enhance
response to radiotherapy. Experimental work with these
is in progress, but none is in current clinical use.
Injury Due to Burns
• Common form of trauma in the UK:
• approximately 250,000 burns per year, of which 70%
are seen in A&E
• approximately 300 deaths per year.
• Incidence diers between age groups:
• 0–14 years = 30% of burns
• 15–64 years = 60% of burns
• 65+ years = 10% of burns.
• Aetiology diers between age groups:
• children suer more scalds
• adults suer more ame burns
• elderly suer more scald and contact burns.
• Repatriated military burns are an increasing group to
consider.
Types of Burn
Thermal
• Flame – can be associated with inhalation injury.
• Scalds – usually hot drinks or bath water.
• Contact – oen associated with loss of consciousness,
medical conditions or intoxication.
Electrical
• Caused by an electrical current passing through the
body; will have an ‘entry’ and ‘exit’ point.
• If the path of the electricity crosses the chest, it can
aect the myocardium and produce arrhythmias.
• Low-voltage injuries are <1000 volts; usually domestic;
burn the entry and exit points.
• High-voltage injuries are >1000 volts; usually industrial; can burn internal tissue, causing rhabdomyolysis.
• ‘Flash’ injuries occur when an arc of high-voltage electrical current occurs near to the patient, causing thermal
burns, but no electrical current passes through them.
Chemical
• Caused by acids or alkalis in domestic or industrial
settings.
• Can be very deep and can continue to burn unless the
source is removed.
• Particular agents require specic treatments: e.g. hydrouoric acid requires calcium gluconate, as it can cause
lethal hypocalcaemia.
Causes of Burns
• Accidents:
• domestic (most common)
• road trac accidents
• industrial/workplace.
• Intoxication (alcohol/drugs).
• Suicide/self-harm.
• Assault/abuse.
Predisposing Medical Conditions
• Epilepsy.
• Dementia.
292
Epidermis
Dermis
If adequately resuscitated the burn may progress to:
If inadequately resuscitated the burn may progress to:
Zone of necrosis
Zone of stasis
Zone of necrosis
Zone of necrosis
Zone of stasis
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SECTION III Pathology
• Motor/sensory dysfunction, e.g. paralysis.
• Learning disability.
• Mental health issues.
Burn Injury Response
Burn injuries result in both local and systemic responses.
Local Response (Fig. 14.11)
Burn injury results in varying degrees of three-dimensional
tissue damage, illustrated by Jackson’s burn wound model:
• Zone of necrosis:
• area of maximum damage
• suers rapid and irreversible cell death due to coagulation of cellular proteins.
• Zone of stasis:
• adjacent to the zone of necrosis
• compromised tissue perfusion due to damaged
microcirculation
• can progress to necrotic tissue if le untreated or
inadequately resuscitated.
• Zone of hyperaemia:
• outermost burn zone, adjacent to zone of stasis
Fig. 14.11 Jackson’s burn wound model and dynamic
changes.
Zone of hyperaemia
Zone of hyperaemia
Zone of hyperaemia
• tissue perfusion is increased due to local inammatory mediator release
• will usually completely recover.
• When referring to the dynamic nature of burns, it is
the changeability of the zone of stasis to which we refer,
i.e. the ability of a burn to progress to a deeper burn or
appear more supercial.
• Factors which can inuence this progression include:
• hypoperfusion
• infection
• oedema.
Systemic Response
Usually seen in burns of over 20%, where massive inammatory mediator release causes changes in the following systems:
• Cardiovascular:
• vasodilatation and increased capillary permeability
cause intravascular protein loss and oedema
• peripheral and splanchnic vasoconstriction
• combined result of hypovolaemia, tachycardia, hypo-
tension and increased systemic vascular resistance.
• Respiratory:
• inhalation of hot gases causing thermal injury to the
upper airways, resulting in inammation and lifethreatening airway oedema
• inhalation of toxic combustion products (carbon mon-
oxide, cyanide, nitrogen and sulfur oxides, etc.), causing severe respiratory compromise or acute lung injury
• circumferential burns to the chest can restrict expan-
sion, furthering respiratory compromise
• inammatory mediators create bronchoconstriction
and oedema, and can lead to adult respiratory distress syndrome (ARDS).
• Metabolic:
• basal metabolic rate can triple, causing massive cata-
bolic changes and inducing muscle wasting
• electrolyte disturbances, including hypo- or hyper-
natraemia, hyperkalaemia and hypocalcaemia.
• Musculoskeletal:
• circumferential limb burns can compromise limb
perfusion due to swelling limb contents not accommodated by inelastic eschar of burnt skin
• compartment syndrome can follow prolonged peri-
ods of immobility due to unconsciousness or electrical injury through a limb/compartment.
• Renal:
• hypoperfusion of kidneys due to hypovolaemia can
result in acute renal failure
• tissue injury releases myoglobin, which produces
rhabdomyolysis and results in acute tubular necrosis
and renal failure.
CHAPTER 14 Cellular Injury
293
• Immunological:
• depression of cellular and humoral immune
responses, increasing risk of sepsis
• systemic inammatory response syndrome and
resulting multi-organ failure.
• Gastrointestinal:
• gut function impairment, leading to barrier breakdown and bacterial translocation
• gastric ulceration due to stress response (Curling’s
ulcer).
• Skin:
• barrier function of skin lost, increasing infection risk
and uid loss.
Carbon Monoxide Effects
• Colourless, odourless gas caused by incomplete oxidation of carbon.
• Detectable in blood of smokers in low levels.
• Produces dierent symptoms at dierent levels
(Table 14.2).
• Has an anity for haemoglobin 250 times that of oxygen and binds strongly to form carboxyhaemoglobin
(COHb).
• Reduces the ability of the blood to transport oxygen,
resulting in respiratory compromise.
• Reduces oxygen available for cytochromes, resulting in abnormal cellular functioning and occasionally
encephalopathy.
• Victims seem confused, disorientated and nauseous,
and can be dismissed as intoxicated.
• Treatment is by displacing COHb with oxygen – COHb
has a half-life of 250 minutes in room oxygen levels and
40 minutes with 100% oxygen.
TABLE 14.2 Carboxyhaemoglobin
(COHb) and Systemic Effects
COHb %
in blood Systemic effects
0–15 Nil
15–20 Confusion, headache
20–40 Disorientation, nausea, lethargy
40–60 Ataxia, hallucinations, collapse, seizures
9%
Death
Front 18%
Back 18%
9%
9%
1%
18%18%
18%
Front 18%
Back 18%
9%9%
14%14%
60+
Assessing a Burn
Assessment of a burn takes into account:
• the extent of body surface area burnt
• the depth of the burn.
The Extent of Body Surface Area Burnt (Fig. 14.12)
To estimate the percentage of the total body surface area of
the burn (% TBSA) there are two general methods:
• e palmar surface method:
• useful for smaller or patchy burns
• utilizes the principle that the patient's palmar surface
is roughly equal to 1% of their body surface area.
• e ‘rule of nines’ method:
• divides the adult body into areas based on single or
multiple 9% anatomical blocks
• paediatric ‘rule of nines’ slightly altered due to dier-
ent anatomical proportions; charts used
Fig. 14.12 Adult and paediatric rule of 9s.
• useful for larger burns where estimation is essential
for uid resuscitation.
The Depth of the Burn (Fig. 14.13)
• Estimation of burn depth can be dicult, though the
clinical features of the burn can help the decision.
• Diagnostic tools can be useful, such as laser Doppler
imaging to assess areas of skin perfusion.
• In practice, the majority of burns are of mixed depth,
and careful, repeated assessment is needed to ensure
correct depth diagnosis.
• Remember that burn depth can be dynamic, and insufcient resuscitation, infection or oedema can increase
the percentage of a deep burn.
294
Subcutaneous tissue
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Fig. 14.13 Cross-section of skin showing depth of burn.
SECTION III Pathology
Superficial Superficial dermal
Epidermis
Dermis
Burn depth
Deep dermal Full thickness
In general, burns can be classied from supercial to
deep, depending upon the amount of epidermis, dermis
and underlying tissue that has been damaged.
• Supercial epidermal burns:
• involve the epidermis alone and are oen called
erythema
• appear red but with no blistering of the skin
• commonly caused by sunburn, supercial scalds or
‘ash’ burns
• have good capillary rell on examination and intact
sensation
• can be very painful
• will heal within 7 days from the basal epidermis,
with no scarring
• are NOT counted as part of the total body surface
area burn estimation.
• Supercial dermal burns:
• involve the epidermis and the papillary dermis
• appear pink, oedematous and blistered
• commonly caused by minor ame and scald
burns
• have good capillary rell on examination and intact
sensation
• can be extremely painful
• will heal within 10–14 days from the adnexal structures, with little or no scarring
• are counted as part of the total body surface area
burn estimation.
• Deep dermal burns:
• involve the epidermis, the papillary dermis and the
reticular dermis
• appear red and oen have xed staining or petechial
points
• commonly caused by ame, chemical, contact and
scald burns
• have reduced or absent capillary rell on examination and reduced or absent sensation
• oen not as painful as the more supercial burns
• will not heal within 14 days and will leave signicant
scarring
• are counted as part of the total body surface area
burn estimation.
• Full-thickness burns:
• involve the epidermis, the entire dermis and possibly
fat, muscle and even bone
• appear thick and can be either white or black and
charred (eschar)
• commonly caused by signicant ame or chemical
burns
• have absent capillary rell on examination and
absent sensation
• are painless as all nerve endings are gone
• will not heal within 14 days and will leave signicant
scarring
• are counted as part of the total body surface area
burn estimation.
• Circumferential burns:
• on the thorax, may restrict chest wall movement
• on the limbs, may compromise limb vascularity
• escharotomy may be required; escharotomy placement sites and their relevant anatomy are shown in
Fig. 14.14.
Ulnar border of arm
Outer side of leg (beware common fibular [peroneal] nerve, sural
nerve and small saphenous vein)
(beware great saphenous
(beware ulnar nerve)
Chest
CHAPTER 14 Cellular Injury
Radial border of arm
(beware cephalic
vein and radial nerve)
295
Inner side of leg
vein and posterior tibial
artery/vein)
Fig. 14.14 Lines of escharotomy placement.
296
e
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SECTION III Pathology
OSCE SCENARIOS
OSCE Scenario 14.1
A 77-year-old female presents to your clinic with a suspicious-looking lesion on her temple.
1. Outline your history, examination, investigations and
management plan.
2. Draw around the lesion on the diagram (Fig. 14.1Q) to
indicate your surgical margins and direction of incision.
e pathology report of the lesion indicates an incompletely excised, poorly dierentiated squamous cell
carcinoma with ulceration. A multi-disciplinary skin
cancer meeting suggests re-excision of the scar with a
1 cm margin.
3. Outline your options for closing this defect.
4. Explain the pathological ndings and management plan
to the patient, including her follow-up.
OSCE Scenario 14.2
You are the A&E doctor in a district general hospital at 3
am. A 33-year-old male has been trapped in a re in his
home, and had to be rescued from the house by the re
brigade, who think the re started at around 1 am. He
has supercial non-blistering burns to his face with soot
around his nose, and blistering burns to the whole of his
le leg and arm, including his hand. He appears confused
and the ambulance crew think he may be intoxicated.
1. Approximately what percentage is this man's burn?
What features would you use to assess the depth of the
blistered burn?
Lesion left templ
2. Assuming that his facial burns are epidermal and his
arm/leg burns are full-thickness, calculate this man's
uid resuscitation requirements and detail how this
should be administered.
3. What acute injuries and pathology specic to burns
would this man be at risk of from the above description?
4. Which allied medical sta would you like to involve?
OSCE Scenario 14.3
You see a 63-year-old male in clinic who describes a 2-year
history of an ulcer on his leg. He has been self-managing
the wound with dressings from the pharmacy, but recently
it has become malodorous and his children encouraged
him to seek medical advice.
1. What salient features from this gentleman's history
would you like to know?
2. What is your dierential diagnosis?
3. Describe the factors aecting wound healing.
On further questioning the patient tells you he has previously had radiotherapy to this limb for a ‘kind of skin
c an c e r ’.
4. What eects does radiotherapy have on the body? How
does this change your dierential diagnosis?
OSCE Scenario 14.4
A 79-year-old diabetic has neglected a foot infection and is
admitted extremely unwell. e whole forefoot is black, wet
and malodorous.
1. What type of necrosis has occurred in the foot?
2. What clinical term is used for this type of tissue loss?
3. What would be the clinical management of this patient?
OSCE Scenario 14.5
A 53-year-old female is in the breast cancer clinic following
surgery for a right-sided breast tumour. As you are taking
a history she tells you she has also had ovarian cancer and
that a close relative had a brain tumour and a rare muscle
tumour.
1. Do you know of any inherited condition that relates to
all these tumours?
2. What does p53 normally do and how does it lead to neo-
plasia when genetic abnormalities occur?
Answers in Appendix pages 461–464
Fig. 14.1Q Indicate surgical margins and direction of
incision.
Please check your eBook at https://studentconsult.inkling.com/ for more self-assessment questions. See inside cover for
registration details.
15
Disorders of Growth,
Morphogenesis and Differentiation
GROWTH
Growth is the process of increase in size resulting from the
synthesis of specic tissue components.
Physiological growth takes place by several mechanisms:
• multiplicative: increase in number of cells, e.g. in all tissues during embryogenesis
• auxetic: increase in size of cells, e.g. in growing skeletal
muscle
• accretionary: increase in intercellular tissue component,
e.g. growing bone
• combined patterns, e.g. in embryological development.
Cell Turnover
Growth depends on the balance between an increase in cell
numbers due to proliferation and the decrease in cell numbers due to cell death. Regeneration is covered in Chapter 14.
Cell Cycle
• Cells proliferate by undergoing mitosis.
• Mitosis is only a small part of the cell cycle.
• e length of the cell cycle determines the cell kinetics
of a tissue.
Phases of the Cell Cycle (Fig. 15.1)
Four main stages to the cell cycle are:
• M phase: comprising nuclear division (mitosis) and
cytoplasmic division (cytokinesis).
• G1 phase (gap 1): duration varies between cell types.
• S phase: DNA synthesis occurs.
• G2 phase (gap 2).
Other factors involved in the cell cycle
• G0 phase: cells can leave the cell cycle temporarily and
re-enter later; said to be in the G0 phase.
• Cells can leave the G1 phase permanently, lose the ability
to undergo mitosis, and become terminally dierentiated cells.
• Dierences in cell cycle times that characterize dierent tissues are related to the G1 duration, which may last
days or even years.
• Once a cell has passed out of G1, the cell cycle proceeds
to completion.
• S, G2 and M phases of the cycle are remarkably constant
and independent of the rate of cell division.
Control of Cell Division
• e cell cycle requires activating signals.
• Activating signals are provided by cyclins, which activate a number of proteins involved in various phases of
the cycle, e.g. DNA replication, spindle formation.
• Inhibitory signals come from tumour suppressor genes,
e.g. p53 and cyclin-dependent kinase inhibitors.
• Removal of the growth-inhibiting action of the retinoblastoma gene allows growth to proceed.
• Protein growth factors direct the proliferation of dierent
types of cell, regulating cell population densities, e.g.:
• epidermal growth factor (EGF)
• platelet-derived growth factor (PDGF)
• insulin-like growth factor (IGF-1).
• Growth factors act on cells in G0 phase, leading to DNA
synthesis followed by cell division.
Therapeutic Interruptions of Cell Cycle (Fig. 15.2)
• Various cancer chemotherapeutic agents act at specic
parts of the cell cycle.
• Attack rapidly dividing cancer cells.
• May attack rapidly dividing normal cells, e.g. bone marrow, lymphoid tissue, resulting in anaemia, thrombocytopaenia and immunosuppression.
Factors Affecting Growth
Normal growth requires a number of factors whose absence
may result in limited or abnormal growth. ese include:
• genetic factors
• hormones
• nutrition
• blood supply
• oxygen supply
• nerve supply
• growth factors.
297
298
2
kinases
New cell
Cytosine arabinoside
Vincristine
CyclophosphamideVincristine
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SECTION III Pathology
enters cycle
M
s
i
o
i
v
n
i
D
G
2
G
1
I
n
t
e
e
r
s
p
a
h
S
Stimulated by growth
factors: PDGF, EGF, IGF1 &
Inhibited by pRb, p53
Inhibition removed
by cyclin-dependent
Terminal
differentiation:
no further division
G
0
Fig. 15.1 The cell cycle. The four main stages of the
cell cycle are the M phase (mitosis and cytokinesis,
i.e. cell division) and the interface stages G1 (gap 1),
S phase (DNA synthesis) and G2 (gap 2). Cells may
enter a resting phase, G0, which may be of variable
duration, followed by re-entry into the G1 phase.
Some cells may terminally differentiate from the G1
phase, with no further cell division and death at the
end of the normal lifetime of the cell. The sites at
which growth factors and inhibitors act are shown.
(From Underwood JCE (ed). General and Systematic
Pathology, 4th edn. Churchill Livingstone, Edinburgh,
2004, with permission.)
Genetic Factors
• Achondroplasia (dwarsm): a primary disturbance of
endochondral ossication occurring in early fetal life.
An autosomal dominant condition.
• Beckwith–Wiedemann syndrome: increased growth due
to duplication of short arm of chromosome 11 where the
genes for insulin and somatomedin IGF-2 reside, resulting in excessive growth.
Hormones
• General body size is controlled by growth hormone
(GH) from the anterior pituitary gland.
M
G
2
Cyclophosphamide
Methotrexate
G
1
S
Cyclophosphamide
Corticosteroids
L-asparaginase
G
0
Fig. 15.2 Pharmacological interruption of the cell
cycle: the sites of action in the cell cycle of drugs
that may be used in the treatment of cancer. (From
Underwood JCE (ed). General and Systematic
Pathology, 4th edn. Churchill Livingstone, Edinburgh,
2004, with permission.)
• GH release is stimulated by hypothalamic growth
hormone releasing factor (GHRF) and inhibited by
somatostatin.
• GH stimulates release of somatomedin IGF-1 and IGF-2
from the liver; these act on target tissue such as muscle
and bone.
• Reduced growth may be due to:
• reduced GH production resulting in proportion-
ate dwarsm, which is corrected by GH injections
prior to puberty (when skeletal growth arrests due to
epiphyseal fusion)
• reduced GH receptors (Laron dwarsm): circulating
GH is high but the liver is insensitive to GH; treatment with GH does not increase growth rate
• reduced thyroid hormone secretion causes reduced
hepatic IGF-1 secretion. Dwarsm results with stunted
limbs because bone ossication is reduced. GH injections do not help, but thyroxin given before puberty is
corrective.
• Increased growth may be due to:
• increased pituitary GH. Before puberty this results
in gigantism; aer puberty (aer epiphyseal fusion),
acromegaly results.
Nutrition
• General catabolic states may cause poor growth.
CHAPTER 15 Disorders of Growth, Morphogenesis and Differentiation
299
• Starvation in the form of kwashiorkor (protein deprivation) or marasmus (protein and total calorie deprivation) disturb growth.
Blood Supply
• Maldevelopment of a vessel can lead to non-development of the organ it should supply.
• Epidermal atrophy occurs in the skin of the lower limbs
with chronic ischaemia due to arterial disease.
• Increased blood ow, e.g. arteriovenous stula, may
cause increase in size of a limb.
Oxygen Supply
• Infants born at altitudes of 15,000 feet have a 16%
lower birth weight due to reduced intrauterine oxygen
availability.
Nerve Supply
• Loss of muscle innervation causes muscle atrophy, e.g.
poliomyelitis, nerve injury.
• Loss of whole limb innervation causes disuse atrophy of
bone.
Growth Factors
• PDGF, EGF and IGFs act locally in healing skin by stimulation of basal cell division.
Increased Growth
Growth may occur in relation to physiological or pathological stimuli by the following mechanisms:
• Hypertrophy: increase in cell size without cell replication.
• Hyperplasia: increase in cell number due to cell division.
• A combination of the two.
• e stimuli for hypertrophy and hyperplasia are similar.
• In permanent cells, hypertrophy is the only adaptive
option as the cells cannot divide.
• A decreased cell loss by apoptosis is an important component of hyperplasia.
• Hyperplasia and hypertrophy are reversible when the
stimulus is removed.
• Hyperplasia and hypertrophy may be physiological or
pathological.
Physiological Hypertrophy and Hyperplasia
Examples include:
• muscle hypertrophy in athletes
• hyperplasia of bone marrow at high altitude
• hyperplasia of breast tissue, e.g. puberty, pregnancy,
lactation
• hypertrophy and hyperplasia of uterus in pregnancy
• thyroid hyperplasia as result of increased metabolic
demands at puberty and pregnancy.
Pathological Hypertrophy
• Myocardial hypertrophy and hypertension.
Pathological Hyperplasia
• Grave’s disease.
• Endometrium exposed to excess oestrogen.
Atrophy
Atrophy is a decrease in size due to loss of cells or reduction in size of individual cells. It may be reversible when
stimulus returns, with certain exceptions, e.g. heart muscle,
neurons. Organ atrophy may be due to:
• reduction in cell size
• reduction in cell numbers
• both of these.
For atrophy to occur there must be:
• cessation of growth
• reduction in cell size and/or cell numbers mediated by
apoptosis.
Atrophy may be physiological or pathological.
Physiological (Box 15.1)
• Occurs any time from early embryological life to old age.
BOX 15.1 Tissues Involved in
Physiological Atrophy and Involution
Embryo and fetus
Branchial clefts
Notochord
Thyroglossal duct
Müllerian duct (males)
Wolffian duct (females)
Neonate
Umbilical vessels
Ductus arteriosus
Fetal layer adrenal cortex
Early adult
Thymus
Late adult and old age
Uterus, endometrium (females)
Testes (males)
Bones (particularly females)
Gums
Mandible (particularly edentulous)
Cerebrum
Lymphoid tissue
300
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SECTION III Pathology
Pathological
• Decreased function, e.g. muscle atrophy of limb aer
immobilization for fracture treatment.
• Loss of innervation, leading to muscle and bone
atrophy (osteoporosis), e.g. poliomyelitis, spinal cord
injuries.
• Loss of blood supply, e.g. following tissue hypoxia, epidermal atrophy is seen in the skin of lower limbs in
chronic ischaemia.
• Pressure atrophy, e.g. destruction of skin and subcutaneous tissue as in bed sores.
• Lack of nutrition, e.g. cachexia in severe starvation, gut
atrophy in starvation.
• Loss of endocrine stimulation, e.g. hypophysectomy
results in adrenal atrophy due to lack of stimulation
from ACTH.
• Hormone-induced atrophy, e.g. oestrogens and testicular atrophy, corticosteroids and adrenal atrophy (via
‘negative feedback’ reduction of ACTH).
Decreased Growth (Hypoplasia)
Hypoplasia is the failure of an organ to attain its normal
size. It is a failure of morphogenesis, although closely
related to atrophy and pathogenesis. Examples include:
• congenital adrenal hypoplasia associated with anencephaly or pituitary hypoplasia (no ACTH)
• failure of lower limb development in spina bida.
DIFFERENTIATION
is is the process whereby a cell develops a specialized function that was not present in the parent cell. Dierentiation is
an important part of morphogenesis; growth also plays an
important part in morphogenesis.
Control of Differentiation
In the fetus, dierentiation is controlled by:
• genes
• systemic hormones
• local growth factors
• position within the fetus
• matrix proteins.
Dierentiation and morphogenesis may be disturbed by
environmental factors, e.g. teratogens, such as:
• irradiation
• drugs
• infections.
During embryonic development, cell determination and
dierentiation occur by transcriptional modications to
genomic expression. ere is no increase or decrease in the
number of genes present.
MORPHOGENESIS
Morphogenesis is a highly complex process of development
of structural form and shape of organs, limbs, etc., from
primitive cell masses during embryogenesis. It involves cell
growth and dierentiation and relative movement of cell
groups. Unwanted features are removed by apoptosis.
Congenital Disorders of Differentiation and
Morphogenesis
Chromosomal Abnormalities Affecting Whole
Chromosomes
• Autosomal chromosomes, e.g. trisomy 21 (Down’s
syndrome).
• Sex chromosomes, e.g. Klinefelter’s syndrome (47 XXY),
Turner’s syndrome (45 X).
Chromosomal Abnormalities Affecting Parts of
Chromosomes
• Cri-du-chat syndrome (46 XX 5p–, or 46 XY 5p–, i.e.
deletion of short arm of chromosome 5).
Single Gene Alterations
• Enzyme defects:
• decreased enzyme synthesis
• defective enzyme synthesis, e.g.
• accumulation of phenylalanine, causing mental
retardation due to phenylalanine hydroxylase deciency (phenylketonuria)
• albinism caused by absent melanin production
due to tyrosinase deciency.
• Defects in receptors or cellular transport, e.g.
• insensitivity of tissues to androgens due to loss of androgen receptors can lead to pseudohermaph ro ditism
• cystic brosis in which there is a defective cell membrane transport system across exocrine secretory
cells.
• Non-enzyme protein defects, e.g.
• abnormal haemoglobin in sickle cell disease
• defective collagen in Marfan’s syndrome and Ehlers–
Danlos syndrome.
• Adverse reaction to drugs, e.g.
• G6PD deciency and haemolysis aer administration of the antimalarial drug primaquine.
Functional Aspects of Developmental Disorders
• Embryo division abnormalities, e.g. Siamese twins, fetus
in fetu.
• Exposure to teratogens: organ development occurs in
rst 4–8 weeks of intrauterine life and teratogens have
major eects at this time (Box 15.2).
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