Download DOGP STUDY GUIDE FOR EXAM 3

PATHOLOGY GUIDE FOR EXAM 3
Chapter 7 Genetic and Pediatric Disease
7.A. Review all of the laboratory case studies, understand diseases shown in each and be
able to recognize and understand the pathologic lesions shown in them. In addition, be
familiar with photographs shown in lectures that describe specific and characteristic
syndromes.
Please review on your own.
7.B. Explain what is meant by the term “Mendelian Disorders” and be able to recognize
examples of diseases that are included in this classification.
Mendelian disorders are those conditions produced by single gene defects/mutations that follow mendelian
patterns of genetics. There are more than 5000 known Mendelian disorders. Each is
rare, but these total 1%
of all adult hospital admissions and 6-8% of child admissions. These disorders can be grouped into 3
categories--(a) autosomal dominant, (b) autosomal recessive or (c)
X-linked. Here are some examples to be
familiar with (the ones mentioned in Dr. Faye-Petersen's
lecture are starred.*)
Autosomal Dominant
 Familial hypercholesterolemia
 polycystic kidney disease*
 Huntington disease
 Hereditary spherocytosis
 Marfan syndrome*
 Tuberosclerosis*
 Neurofibromatosis*
 Osteogenesis imperfecta*
Autosomal Recessive
 Sickle cell anemia
 Cystic fibrosis
 Tay-Sach's Disease*
 Phenylketonuria
 Mucopolysaccharidoses *
 Glycogen Storage Diseases
 Galactosemia
 Niemann-Pick*
 Gaucher's*
 Pompe's*
X-Linked
 Fragile X syndrome*
 Duchenne muscular dystrophy
 Hemophilia
7.C. Understand the clinical features and mechanism of disease for the following
autosomal dominant genetic diseases and explain the general features of autosomal
dominant disorders.
Autosomal Dominant (ADD):
Manifest in the heterozygous stage: at least one parent of index case is usually affected)
Transmitted in males and females
Risk of recurring in 50% of offspring
Not always do affected individuals have an affected parent, could acquire from new mutation in egg
or sperm from which they were derived in one gamete or could be in entire germ line affecting
siblings
Occurs on chromosomes 1-22, only requires one copy of the gene
Clinical Characteristics of ADD:
Reduced penetrance: gene defect present but individual phenotypically normal
Variable expressivity: all carriers of gene defect have phenotypic manifestation but severity and
constellation of signs differ
Often delayed age of onset (adulthood) of clinical manifestations
Affect regulators of complex pathways or structural proteins (usually not enzymes)
7.C.1. Neurofibromatosis.
Neurofibromatosis (5 types; 1 and 2 most common)
Type 1: occurs on locus 17q11.2 tumor suppressor gene (encoding neurofibromin); also know
as Recklinghausen Disease and “peripheral NF”
3 distinct features of NF-1:
1. Café au lait spots > of 1.5 cm; axillary freckle highly informative
2. Iris hamartoma/tumor(Lisch nodule) pathognomonic, present in 94% > age 6yr
3. Large plexiform neurofibromas and risk for malignant change in 3-15% of individuals
- Can see optic gliomas, ependymomas, meningiomas; and unilateral acoustic neuroma in
the CNS
Mechanism: NF1 gene mapped to chromosome 17, and it encodes a protein
(neurofibromin) that acts as a negative regulator of the RAS oncogene.
Type 2: occurs on locus 22q12.2 encoding the tumor suppressor merlin
Features:
1. Distinguishing characteristic is bilateral acoustic schwannomas and multiple
meningiomas
2. No café au lait spots, peripheral NF, or Lisch nodules
3. Central NF with mean onset age of 21.6 years
4. Causes blindness due to damage to optic pathways, juvenile posterior subcapsular
cortical lenticular cataracts, and retinal harmartomas
7.C.2. Tuberous Sclerosis
Tuberous Sclerosis Complex (TSC) (4 types, but 1 and 2 most common)
50% new mutations
Mechanism: tumor suppressor gene affected as second hit of two-hit process: 1st hit germ
cell mutation, then neural precursors abln, then disperse, and 2 nd hit, then release trophic,
neurotransmitters, then tumorgenesis at multiple sites
TSC1 on 9q34 (harmartin); TSC2 on 16p13 (the tuberin, GTPase activating protein)
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Features: triad of MR, epilepsy, adenoma sebaceum, but only in 30%; now criteria 1, 2, 3
Craniofacial/CNS: subependymal calcifications, seizures, MR, and olfactory harmartomas
Skin: hypopigmented Ashleaf and confetti macules; adenoma sebaceum, shagreen patches,
and ungula fibromas
Visceral: cardiac rhabdomyoma, renal angiomyolipoma, renal cysts, pulmonary cysts and
lymphangiomyomatosis, and liver harmartomas
Oral/ Dental: gingival fibromas and enamel hypoplasia and numerous pits
Ocular: retinal hamartomas
7.C.3. Osteogenesis Imperfecta
Osteogenesis Imperfecta (OI) : Abnormal development of Type I collagen
Variable group of bone disorders with osteopenia resulting in osteoporosis and skeletal
deformity
50% decrease in collagen I; decrease in amount and stability; codon termination of Proa1(I) allele transcription
OI types I-IV genetically and chemically heterogenous between and within types
OI Type 1 (most common):
Ocular: deep blue sclera due to transmission of color of underlying choroids
Oral: opalescent, hypoplastic dentin with yellowing, transparency, premature wear, caries,
breakage, late eruption; blue gray dentin with shortened tooth roots and constricted
coronoradicular junctions
Excessive bone fragility, multiple fractures of vertebrae and tubular bones of
varying age, few have congenital fracture
Easy bruising, short stature, kyphoscoliosis, joint hypermobility, femoral bowing, bone
angulation from repeated fracture, inguinal or umbilical hernia
Presenile conductive hearing loss in adolescence progressing to adulthood due to defective
ossicles
OI Type 2 (subtype A “OI Congenita”)
Extreme bone fragility with intrauterine or early infant death
Multiple fractures of ribs (“beaded”) with hypoplastic chest and crumbled long bone
Deep blue sclera
Severe osteopenia of skull with ballotable brain; wormian bones in the skull
Occurrence largely due to new mutation
7.C.4. Marfan Syndrome
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autosomal dominant disorder of connective tissues, affecting fibrillin 1 (a major component of
microfibrils found in the extracellular matrix).
Fibrillin 1 serves as scaffolding for the deposition of elastin and are considered integral components of
elastic fibers.
Fibrillin 1 is encoded by the FBN1 gene, maps to chromosome (15q21.1>> defective FNB 2 gene (5q3)
Results in decrease frbrillin quantity and quality which in turn leads to microfibrillar aggregate
scaffolding for tropoelastin deposition.
Mutations in the FBN1 gene are found in all patients with Marfan syndrome. However, molecular
diagnosis of Marfan syndrome is not feasible because over 100 distinct mutations affecting the FBN1
gene have been found.
Since heterozygotes have clinical symptoms, it follows that the mutant fibrillin 1 protein must act as a
dominant negative by preventing the assembly of normal microfibrils.
Broad spectrum of manifestations, underestimated prevalence “1/10,000-20,000”
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Approximately 75% of cases are familial, and the rest are sporadic, arising from new mutations in the
germ cells of parents.
70-85 percent familial with variable expressivity
Most gene defects are mis-sense and lead to a decrease in the number and strength of elastic fibers.
MORPHOLOGY:
 Skeletal abnormalities are the most obvious feature of Marfan syndrome.
o Patients have a slender, elongated habitus with abnormally long legs, arms, and fingers
(arachnodactyly); a high-arched palate; and hyperextensibility of joints. A variety of spinal
deformities, such as severe kyphoscoliosis, may appear.
o The chest is classically deformed, exhibiting either pectus excavatum (i.e., deeply depressed
sternum) or a pigeon-breast deformity.
o Oral/dental
 Narrow high arched palate which leads to crowding of teeth.
 Malocclusion due to retrognathia.
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The most characteristic ocular change is bilateral dislocation, or subluxation, of the lens owing to
weakness of its suspensory ligaments. It should be noted that the ciliary zonules that support the lens are
devoid of elastin and are made up exclusively of fibrillin.
o Lens subluxation or detatchment (ectopia lentis)
o 50-80 percent usually bilateral
o Relatively flat corneas, iris may transilluminate
o Axial length of globe increased which can lead to retinal detachment
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Most serious, however, is the involvement of the cardiovascular system.
o Fragmentation of the elastic fibers in the tunica media of the aorta predisposes to aneurysmal
dilation and aortic dissection.
o Loss of medial support causes dilation of the aortic valve ring, giving rise to aortic
incompetence.
o The cardiac valves, especially the mitral and, less commonly, the tricuspid valve, may be
excessively distensible and regurgitant (floppy valve syndrome), giving rise to congestive
cardiac failure.
o Death from aortic rupture may occur at any age and is the most common cause of death. Less
commonly, cardiac failure is the terminal event.
o Mitral valve prolapse, regurgitation.
o Aortic root dilation aortic regurgitation
o Cardiac dilation CHF and aortic dissection
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In addition to these features, Marfan patients have defects in:
o skin
o skeletal muscles
o lungs
o "Stretch marks" occur in areas of flexural stress
o muscle appears myopathic with loss of bulk and hypotonia
o damage to the connective tissue in lungs may manifest as spontaneous pneumothorax.
o 50 percent have a neuropsychological deficits (attention deficit).
Although the lesions described are typical of Marfan syndrome, they are not seen in all cases. There is
much variation in clinical expression, and some patients may exhibit predominantly cardiovascular
lesions with minimal skeletal and ocular changes.
o The variable expressivity is believed to be related to different allelic mutations in the fibrillin
gene. Because of such variations, it is not feasible to develop a simple screening test that can
detect all mutations that underlie Marfan syndrome.
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7.C.5. Huntington’s Disease
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is a hereditary, progressive, fatal disorder involving the "extrapyramidal" motor system, characterized by
involuntary movements (chorea) and dementia.
autosomal dominant trait with complete penetrance.
It usually does not become apparent until adulthood, often after affected individuals have had children,
although juvenile-onset cases also occur.
Early-onset cases, in particular, are more likely to be associated with inheritance of the mutation from
the father than from the mother.
The responsible gene (which encodes a protein called huntingtin) has been localized to the short arm of
chromosome 4.
The disease is caused by trinucleotide repeat mutations in the huntingtin gene which cause, in turn, the
synthesis of a form of the huntingtin protein containing an abnormal number of glutamine residues.
The normal huntingtin gene contains between 6 and 34 copies of the cytosine-adenine-guanine (CAG)
sequence. In HD, the number of triplet repeats is increased to 40 and 55 CAG copies.
o The larger the number of trinucleotide repeats, the earlier the onset of disease; juvenile-onset
HD carry greater than 70 CAG repeats.
o Affected individuals can be identified before the development of symptoms by the
demonstration of excessive CAG triplet repeats in the responsible gene.
The molecular pathogenesis of HD is not fully understood. Huntingtin is expressed in all somatic tissues,
and its expression is clearly essential to normal embryonic development. Nevertheless, the exact
function of huntigton remains unknown. Because HD is an autosomal dominant disorder, it follows that
the mutant huntingtin in some manner impairs the function of normal huntingtin produced by the normal
allele. Such mutations are referred to as "gain of function" mutations. Although the exact mechanism
whereby the mutant huntingtin causes brain injury remains unclear, it is likely that the presence of
abnormal huntingtin causes cell loss by some combination of activation of apoptotic pathways and
impairment of normal energy metabolism in susceptible neurons.
MORPHOLOGY
 The brain in HD is usually small, often weighing less than 1100 g.
 The most distinguishing feature of the disorder is striking atrophy of the caudate nucleus, putamen,
and, in more advanced cases, the globus pallidus, with the caudate often reduced to a thin band
adjacent to the lateral ventricles.
 Microscopically, this disease is characterized by a severe loss of neurons within the caudate and
putamen, accompanied by fibrillary gliosis in these areas. The smaller neurons in the corpus striatum,
particularly those projecting to the lateral segment of the globus pallidus, are preferentially affected, but
there is often some loss of larger neurons as well. Cortical neuronal loss is often present and correlates
with the degree of dementia.
 Clinical Features:
 The clinical onset of HD is usually in the fourth or fifth decade, although some cases present during
childhood.
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Like other trinucleotide repeat mutations, the CAG expansions affecting the huntingtin gene are
dynamic.
 During spermatogenesis, the number of CAG repeats can increase, and hence HD tends to present
earlier in successive generations, a phenomenon known as anticipation.
 The initial manifestations in most patients include involuntary, writhing movements known as
choreiform movements.
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Neuropsychiatric disturbances, including depression and cognitive impairment, typically develop after
the onset of motor abnormalities, but they may be the presenting manifestations.
 Symptoms progress inexorably, typically over a period of 15 to 20 years.
 Common causes of death include:suicide and intercurrent infections.
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7.C.6. Familial Hypercholesterolemia
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Familial Hypercholesterolemia (FH) is an inherited disorder that causes very high cholesterol levels and
greatly increases the chance of having a heart attack early in life.
Heart attacks usually occur in men when they are 40-55 years old and in women when they are 50-65
years old.
The most common autosomal dominant form of hypercholesterolemia is caused by mutation in the LDL
receptor gene (LDLR) on chromosome 19 in band 19p13.2.
Unfortunately, they can sometimes occur when people are in their mid-twenties.
The first case of FH was described over 100 years ago and the characteristics of FH passing from
generation to generation was understood in the late 1930's. Actual genetic proof was discovered in the
1960's and 1970's.
Causes:
 Cholesterol is removed from the blood by the liver using Low Density Lipoprotein (LDL) receptors.
Each person has two genes that are responsible for making the LDL receptors: one received from the
father and one received from the mother. In a person with FH, an abnormal gene was passed on from
one parent who has FH and a normal gene was passed on from the other parent. Therefore, half of the
LDL receptors are absent or do not work properly and the other half are normal. Because half of the
receptors do not remove the cholesterol normally, cholesterol levels increase in the blood. This results in
damage to blood vessels, blockage of arteries and heart attacks at an early age.
 If a person has FH, then each of his or her children will have a 50% chance of inheriting FH. You are
either born with FH or not. Most persons with the disease are neither recognized nor treated.
7.D. Understand the major clinical features and mechanism of disease for the following
autosomal recessive genetic diseases and explain the general features of autosomal
recessive disorders.
7D1. Tay-Sachs Disease: Automsomal recessive disease; lysosomal storage disorder (enzyme defect of
acid hydrolase activity which results in accumulation of partially degraded metabolite which cannot
be removed from cell lysosomes); affects mainly neurons (swelling and disfunction); clinical
features: onset age 3-6 months, death by age 2-5, mental retardation, retinal cherry red spot (optic
nerve swells and retinal cells become white/opacified), startle response to sound, seizures,
blindness, hypotonia, affects 1/30 Ashkenazi Jews; mechanism: enzyme defect in hexoaminidase
Aα subunit, which normally breaks down GM2 gangliosides that are found in cell membranes (you
don’t have the hexoaminidase and you can’t break down your gangliosides)
7D2. Gaucher’s Disease: Autosomal recessive disease; lysosomal storage disorder; affects mainly
macrophages; mechanism: enzyme defect in glucocerebrosidase, which normally breaks down
glucocerebrosides, so glucocerebrosides build up in macrophages and form Gaucher cells in liver,
spleen, and bone marrow; sometimes requires hepatosplenomegaly and bone marrow transplant;
clinical features: Type 1- chronic non-neuronopathic form, 99% all cases, absence of CNS
involvement and characterized by hepatosplenomegaly, compatible with life, gaucher cells in lymph
nodes, liver, spleen, and bone marrow; Type 2- highly lethal (affects children by 6 months), severe
CNS involvement, liver, and spleen; Type 3- juvenile variant, brain and viscera involved, course
intermediate between Type 1 & 2
7D3. Phenylketonuria (PKU): Autosomal recessive; lysosomal storage disorder; mechanism: lack of
phenylalanine hydroxylase, can’t break down phenylalanine to tyrosine, which is important for
protein synthesis, leading to hyperphenylalaninemia; clinical features: impairs brain development of
developing infants in few weeks, by 6 months severe mental retardation, seizures, decreased
pigmentation of hair and skin, eczema, musty odor in urine and sweat (because excreting
intermediate metabolites from incomplete phenylalanine metabolism)
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7D4. Cystic fibrosis: Autosomal recessive; clinical features: recurrent pulmonary infections, exocrine
pancreatic insufficiency (malabsorption, steatorrhea, malnutrition), hepatic cirrhosis, intestinal
obstruction, male infertility, death in adolescence/early adulthood; mechanism: CFTR gene
mutation on chromosome 7 causes defect in secretory process of all exocrine glands, and epithelial
lining of respiratory, GI, and reproductive tracts, get abnormally viscous mucus secretions that
block airways and ducts due to defective chloride channels; Sweat test for diagnosis detects elevated
Cl
7.D.5. Sickle Cell Anemia: The prototype and most prevalent hemoglobinopathy is caused by a mutation
in the gene encoding the B-globin chain that causes the formation of sickle Hb (HbS). HbS results
from a single amino acid substitution in the globin chain.
Approx. 8% of American blacks are heterozygous for HbS. In the US, it affects approx. 1 of every
600 African-Americans. It is the worldwide sickle cell anemia is the most common form of familial
hemolytic anemia.
On deoxygenation, HbS molecules undergo polymerization, a process sometimes called gelation or
crystallization. The change in the physical state of HbS distorts the RBC’s which assume an
elongated crescentic, or sickle, shape. Sickling of RBC’s is initially reversible by oxygenation;
however, membrane damage occurs with each episode of sickling, and eventually the cells
accumulate calcium, lose potassium and water, and become irreversibly sickled, despite adequate
oxygenation. The three most important factors influencing sickling of RBC’s are:
a. The presence of hemoglobins other than HbA.
b. The concentration of HbS in the cell.
c. The length of time that RBC’s are exposed to low oxygen tension.
Two major consequences stem from the sickling of RBC’s. First, repeated episodes of
deoxygenation cause membrane damage and dehydration of RBC’s which become rigid and
irreversibly sickled. These dysfunctional RBCs are removed by mononuclear phagocyte cells,
producing a chronic extravascular hemolytic anemia. Second the sickling of RBCs produces
widespread microvascular obstructions and resulting ischemic tissue damage.
Homozygous sickle cell disease usually becomes apparent after the sixth month of life, as HbF is
gradually replaced by HbS. From the time of onset, the process runs an unremitting course,
punctuated by sudden episodes of so-called crises, the most serious of these are the vaso-occlusive,
or pain crises. Pain crises can involved many sites but are most commonly localized to the bone
marrow. They occur without warning and the often progress to marrow infarction and necrosis. In
addition to these crises, patients with sickle cell disease are prone to infections. The clinical course
of patients with sickle cell anemia is highly variable. As a result of improvements in supportive
care, an increasing number of patients are surviving into adulthood and producing offspring.
The anatomic alterations stem from three aspects of the disease: (1) hemolysis, with resultant
anemia, (2) increased breakdown of Hb, with billirubin formation, (3) capillary stasis, leading to
tissue ischemia and infarction. In peripheral smears, irreversibly sickled RBCs are evident as
bizarre, elongated, spindled, or boat-shaped structures.
7.D.6. Wilson’s Disease: Wilson’s disease is an autosomal recessive disorder of copper metabolism is
marked by the accumulation of toxic levels of copper in many tissues and organs, principally the
liver, brain, and eye. Frequency of Wilson’s Disease is 1:200 however, the incidence of this
disease is approx. 1:30,000. In Wilson’s disease the initial steps of copper absorption and transport
to the liver are normal. However, absorbed copper fails to enter the circulation in the form of
ceruloplasmin and biliary excretion of copper is markedly diminished. The gene responsible for
Wilson disease is ATP7B, located on chromosome 13. This codes for and ATP-dependent metal ion
transporter that localizes to the Golgi region of hepatocytes. Defective function of this transporter
leads to failure to excrete copper into bile, the primary route for copper elimination from the body.
Copper then accumulated into the liver and causes toxic liver injury by promoting the formation of
free radicals, binding to sulfhydrayl groups of cellular proteins, and displacing other metals in
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hepatic metalloenzymes. The biochemical diagnosis of Wilson disease is based on a decrease in
serum ceruloplamin, increase in hepatic copper content, and increase in urinary excretion of copper.
Age of onset is variable, but the disorder rarely manifests before age 6 years. The most common
presentation is acute or chronic liver disease. Neuropsychiatric manifestations, including mild
behavioral changes, frank psychosis, or a Parkinson disease-like syndrome, are the initial features in
most of the remaining cases. Demonstration of Kayser-Fleischer rings or markedly elevated hepatic
copper levels in a patient with a low serum ceruloplamin level strongly favor the diagnosis.
The liver often bears the brunt of injury in Wilson disease, with hepatic changes ranging from
relatively minor to massive damage. Fatty change may be mild to moderate with occasional
hepatocyte focal necrosis. In the brain, toxic injury primarily affects the basal ganglia. Nearly all
patients with neurologic involvement develop eye lesions called Kayser-Fleischer rings.
7.D.7. Retinoblastoma: Retinoblastoma is the most common malignant eye tumor of childhood. This
condition is unusual in several aspects when compared with most other solid tumors. It occurs as a
congenital tumor, with incidence decreasing with age. Retinoblastomas occur in both familial and
sporadic patterns. They serve as a prototype of a diverse group of human cancers associated with
recessive, loss-of-function mutations at distince genetic loci harboring cancer suppressor genes.
The median age at presentation is 2 years, although the tumor may be present at birth. Presenting
findings include poor vision, strabismus, a whitish hue to the pupil, and pain and tenderness in the
eye. Most of the tumors are associated with germ-line mutations in the RB1 gene and are heritable,
with the remaining being sporadic and have somatic RB1 gene mutations. If left untreated, these
tumors are usually fatal.
Retinoblastoma is believed to arise from a cell of neuroepithelial origin, usually in the posterior
retina. The tumors tend to be nodular masses. Tumor cells may disseminate beyond the eye
through the optic nerve or subarachnoid space. Differentiated structures are found within many
retinoblastomas, the most characteristic of these being Flexner-Wintersteiner rosettes. These
structures consist of clusters of cuboidal or short columnar cells arranged around a central lumen.
The most common sites of distant metastases are the central nervous system, skull, distal bones, and
lymph nodes.
7.E. Understand the major clinical features and mechanism of disease for the following
X-linked recessive genetic diseases and explain the general features of X-linked
disorders.
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General features of X-linked recessive disorders
All sex linked disorders are X-inked (no Y-linked disease known)
Transmitted by heterozygous female carriers virtually only to sons (hemizygous)
Heterozygous females rarely express the full phenotypic change, owing to presence of paired normal
allele (because of inactivation of X chromosome it is remotely possible for the normal allele to be
inactivated)
An affected male does not transmit disorder to sons, but all daughters are carriers. (son of heterozygous
mom have one chance in two to receive mutant gene).
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7.E.1. Hemophilia A
**Most common hereditary disease associated with serious bleeding.
Mechanism of Disease:
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X-linked recessive – occurs in males or homozygous females, although excessive bleeding has
been described in heterozygous females
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Caused by reduced activity of factor VIII procoagulant.
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30% of cases are caused by new mutations and hence do not have a family history.
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Severe deficiency (<1% factor VIII activity) – usually only ones to develop clinical symptoms.
Mild (1%-5% activity) or Moderate (5%-75% activity) are usually asymptomatic, although posttraumatic bleeding may be excessive. These different levels of deficiency of factor VIII
procoagulant are related to type of mutation in gene.
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10% of patient levels of factor VIII appear normal by immunoassay, but coagulative activity by
bioassay is low. Normal bleeding time, normal platelet counts, and normal PTT, with prolonged
PTT that is corrected by mixing with normal plasma. If antibodies against factor VIII are
present in patient’s plasma then mixing fails to correct the PTT. Factor VIII assays are required
for diagnosis.
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Approx. 15% of most severely affected have antibodies to factor VIII.
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Treatment – infusion of factor VIII (now use recombinant factor instead of human plasma)
Major Clinical Features:
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Easy bruising/massive hemorrhage after trauma or surgery, also “spontaneous” hemorrhages
maybe frequent in areas subject to trauma (i.e. joints – hemathroses).
Petechiae are
characteristically absent.
7.E.2. Fragile X Syndrome
**2nd most common cause of mental retardation in males.
Mechanism of Disease:
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X-linked recessive disease, tri-nucleotide repeat disease - amplification of specific set of 3
nucleotides within the gene disrupts its functions, noncoding region repeats – causes loss of
function
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CGG (Xq27.3) tri-nucleotide repeats. Gene FMR1 that maps Xq27.3. Average CGG repeats in
FMR1 gene in the normal populations is 29, where as affected individuals have 230-4000
repeats. These are believed to arise from an intermediate stage of 52-230 repeats found in
carrier male and females and are called permutations. Amplification occurs in females – carrier
males don’t actually make it worse (because permutations can be converted to full mutations
only in oogenesis, not spermatogenesis)
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The product of FMR1 gene is FMR protein (FMRP) is widely expressed in normal tissues, but
higher in brain and testis. The FMRP is thought to be an RNA binding protein that regulates
protein translation. Loss of FMRP dysregulates the production of critical target proteins
involved in normal neuronal functions.
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Exhibits dosage effect and anticipation with increasing severity and earlier age of onset in
successive generations. 20-50% carrier males are normal (transmitting male). The “carrier
males” can transmit the disease to grandsons thru their phenotypical normal daughter. Risk of
carrier female having retarded child depends on her phenotype:
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Normal Carrier Mother – 76% males affected, 33% females affected
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Retarded Carrier Mother – 100% males affected, 50% females affected
Major Clinical Features:
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Long face with large mandible, large protruding everted ears with soft cartilages, thickened
nasal bridge, pale blue eyes and large testicles (macro-orchidism – the only physical
abnormality detected in at least 90% of post pubertal males). 80% of males have IQ (30-55).
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30% of females are borderline to mildly retarded. Other symptoms of hyperkinetic and
emotional liability. These phenotypes are not always present or may be quite subtle.
7.E.3. Agammaglobulinemia
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Also referred to as Bruton Disease
Characterized by the failure of pre-B cells to differentiate into B cells
As a result, there is an absence of gamma globulin in the blood
In Bruton’s, B cell maturation stops after the initial heavy-chain gene rearrangement because of
mutations in a tyrosine kinase involved in pre-B cell signal transduction (called Bruton Tyrosine
Kinase (BTK))
Because it maps to the X chromosome, it is seen primarily in males. Sporadic cases have been
described in females.
This disease is characterized by:
 Absent or decreased B cell numbers
 Depressed serum levels of all immunoglobulin classes
 Pre-B cells in the bone marrow are in normal numbers
 Underdeveloped germinal centers in peripheral lymph nodes
 Absence of plasma cells throughout body
 Normal T-cell mediated response
Disease unapparent until 6 months of age when maternal immunoglobulin are depleted
Recurrent bacterial infections common
Also susceptible to certain viral infections, especially those caused by enteroviruses
Replacement therapy can be done with IV immunoglobin
For unknown reasons, autoimmune disease occurs in up to 20% of these patients.
7.E.4. Duchenne Muscular Dystrophy
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DMD is an X-linked hereditary disease caused by the absence of the structural protein
dystrophin.
1/3500 live male births affected
Dystrophin gene is the short arm of chromosome X (Xp21); also one of the largest genes in the
human genome (spans 2400 kb)
Large size makes the gene vulnerable to deletions/mutations
Dystrophin is expressed in many tissues (all muscle types, brain, peripheral nerves, etc.)
Adds to structure and functional integrity of the myocyte
Absences or mutations yield impaired contraction and other derangements of skeletal and
cardiac muscles
Most affected patients male. Female cases are rare.
Cardinal manifestation is muscle weakness (especially in proximal muscles)
Generalized clumsiness, weakness in pelvic and shoulder girdles.
Muscle enlargement may be seen early on, especially in calf muscles
Muscle atrophy follows
Signs and symptoms may begin by 5 years of age.
Most patients wheelchair-bound by their teens.
Most die in their 20s, usually from respiratory failure or pneumonia
Cardiac abnormalities may also be associated
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7.F. Explain what is meant by a “multifactorial genetic disorder” and be able to
recognize examples of common conditions that are included in this classification. (page
227, PowerPoint from Faye-Petersen)
Multifactorial traits are defined as one governed by the additive effect of two or more genes of small
effect but conditioned by environmental, nongenetic influences. Multifactorial (also called polygenic)
inheritance is involved in many physiological human characteristics--for example, hair color, height,
weight and blood pressure. The phenotypic attributes governed by multifactorial genetics follow a
normal Gaussian distribution. These disorders only become manifest when a certain number of effector
genes and conditioning environmental influences are involved, therefore displaying a threshold effect.
This explains why the parents of a child with a multifactorial genetic disorder may be normal. Once
threshold is exceeded, the severity of the disease depends on the number and influence of the
pathological genes (directly proportional). The risk of expressing a multifactorial disorder is conditioned
by the number of mutant genes inherited. The risk is greater in siblings of parents who have severe
expression of the disorder. The rate of recurrence is 2-7% for all first-degree relatives. If the parents
have one affected child, there is a 2-7% chance that the next child will be affected as well. If there are
two affected siblings, the recurrence rate jumps to 9% for the third child. Identical twins are much more
likely to be affected than non-identical twins. This form of inheritance is believed to underlie the
following diseases (the ones mentioned in Dr. Faye-Petersen's lecture are starred.*):
 diabetes mellitus*
 hypertension*
 gout*
 schizophrenia
 bipolar disorder
 certain forms of congenital disease
 some skeletal abnormalities
 cleft lip/cleft palate*
 congenital heart disease*
 coronary heart disease*
 pyloric stenosis*
7.G. Describe the major clinical manifestations and diagnostic features of the following
conditions:
7.G.1. Down Syndrome (Trisomy 21).
Check out figure 7-18 on page 231 for
7.G.2. Edward Syndrome (Trisomy 18)
a picture that does a good job to
distinguishing between these three
7.G.3. Patau Syndrome (Trisomy 13)
trisomies.
7.G.4. Turner Syndrome
Clinical Manifestations: Large low-set ears, short 4th metacarpals, small mandible, primary
hypogonadism in phenotypic females, growth retardation, swelling of the nape of the neck due to
distended lymphatic channels, low posterior hairline, cubitus valgus (an increase in carrying angle
of arms), shieldlike chest with widely spaced nipples, high-arch palate, lymphedema of hands and
feet, variety of congenital malformations (horseshoe kidney, bicuspid aortic valve, coarctation of
aorta.). There is also abnormal development of secondary sex characteristics, genitalia remain
infantile, breast development is minimal, and little pubic hair appears. Also, there is transformation
of the ovaries into streaks of fibrous stroma.
Diagnostic Features: In 57% of patients, the entire X chromosome is missing. This results in 45X
karyotypes. Diagnosis is made at birth or early childhood. 43 % of the patients are either mosaics
Page 11 of 37
with one line being 45X, or they have structural abnormalities of X chromosomes. The most
common deletion is of small arm, resulting in formation of isochromosomes of long arm,
46Xi(X)(q10). The net effect is to produce partial monosomy of X chromosome. Those who have
mosaics or deletion variants may have an almost normal appearance and may present only with
primary amenorrhea.
7.G.5. Klinefelter Syndrome
Klinefelter is defined as male hypogonadism that develops when there are at least 2 X chromosomes
and 1 chromosome.
Clinical Manifestations: Tall and long limbs, hypogonadism in some patients, but in most patients
they have a distinctive body habitus with an increase in length between the soles and pubic bone,
which creates appearance of elongated body. There are also other manifestations such as:
eunuchoid body habitus, reduced facial, body and pubic hair, and gynecomastia. The testes are
reduced in size, and the patients are sterile, due to impaired spermatogenesis. Histologically, there
is hyalinization of tubules, prominent leydig cells. Klinefelter may be associated with mental
retardation, but the degree is mild. Reduction of intelligence is correlated with the number of X
chromosomes.
Diagnostic Features: Most patients have 47XXY. The extra X may be from the mother or father.
15% of patients show mosaic patterns including 46XX/47XXY, 47XXY/48XXXY and other
variations. 46 XY line is usually associated with milder clinical condition.
7.G.6. Triploidy
Clinical Manifestations: Large head and thin body with hypertrophic thighs, ambiguous genitalia,
death in less than 6 months of age. Other manifestations include meningomyelocele, sharp features,
low-set ears, mid-facial cleft, syndactyly of the third and fourth fingers, single palmar crease,
pulmonary and adrenal hypoplasia, renal cystic dysplasia, and umbilical hernia.
Diagnostic Features: 69XXY or 69XXX in most patients (mosaics or mixoploidy). There is a high
spontaneous abortion rate, and the placenta is usually abnormal with partial moles.
7.H. Explain the concept of genetic imprinting and how it applies to:
7.H.1. Angelman Syndrome
7.H.2. Prader-Willi Syndrome
All humans inherit two copies of each gene, carried on homologous maternal and paternal chromosome.
However, in several genes, functional differences exist between the paternal and the maternal genes.
Genomic imprinting: an epigenetic process whereby certain genes are differentially inactivated during
paternal and maternal gametogenesis. Occurs in the ovum or sperm and is then transmitted to all somatic
cells derived from the zygote.
Maternal imprinting: transcriptional silencing (inacativation) of the maternal allele
Paternal imprinting: transcriptional silencing (inacativation) of the paternal allele
Prader-Willi syndrome: patients are born with a deletion of the PATERNALLY derived chromosome
15 (q12 region). Characterized by:
mental retardation (IQ 20-80)
narrow bifrontal diameter
almond shaped palpebral fissures
blonde hair
fair skin
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-
short stature
hypotonial
obesity
small hands and feet
hypogonadism
Angelman syndrome: patients are born with a deletion of the MATERNALLY derived chromosome 15
(q12 region). aka Happy Puppet syndrome (b/c of laughter and ataxia)
Characterized by:
mental retardation
post-natal growth deficiency
ataxic gait (inability to coordinate the movements of muscles)
jerky arm movements
seizures
inappropriate laughter, absent speech
large mouth with tongue protrusion
Molecular basis of Prader-Willi:
a set of genes on maternal chromosome 15q12 is
imprinted and as a result, silenced. So the only
functional alleles are provided by the paternal
chromosome. When these are lost as a result of a
deletion (in the paternal chromosome), the patient
develops Prader-Willi syndrome.
Uniparental Disomy (Isodisomy): inheritance of
both chromosomes of a pair from one parent .
Angelman & Prader-Willi syndrome could both be
expected as a result of uniparental disomy. PWS:
both normal chromosome 15s are derived from the
mother.
AS: both normal chromosome 15s are derived from
the father.
7.I. Explain terms “penetrance” and “expressivity” (page 215).
Autosomal Dominant Disorders
- at least 1 parent of an index case is usually infected, can be male or female and both can
transmit condition
- if unaffected and affected person child has a 50% chance of getting it
A)
Some people can get the disorder from new mutations in egg or sperm. Parents nor siblings are
infected or at risk for infection.
B)
Some individuals can inherit a mutant gene but are phenotypically normal. This is referred to as
“reduced penetrance” factor that affect penetrance are not clearly understood.
C)
In contrast to penetrance, if a trait is seen in all individuals carrying the mutant gene but is
expressed differently among individuals- this is called variable expressivity. Ex: neurofibromitosis
Type 1- range from brown spots on the skin to multiple tumors or skeletal deformities.
Page 13 of 37
7.J. Explain the following terms: malformation, deformation, disruption (page 238)
Malformation:
 primary errors of morphogenesis
 intrinsically abnormal developmental process and skeletal
 usually multifactorial rather than a single deformities gene or chromosomal defect
 present in several patterns
 ex: congenital Heart Diseasesingle body systems may be involved whereas in other cases, multiple
malformation involving many organs and tissues coexist.
Disruption:
 secondary destruction of an organ or body region that was previously normal in
development
 unlike malformations, disruptions arise from an extrinsic disturbances arise from an extrinsic disturbance
in morphogenesis
 can be environmental
 not heritable and not assoc. with recurrence of subsequent pregnancies.
Deformations:
 Like disruptions, extrinsic disturbance of development.
 Common-affect ~ 2% of newborn infants to various degrees.
 Pathogenesis of deformations is localized or generalized compression of the growing fetus by abnormal
biochemical forces leading to structural abnormalities
 Ex. Uterine constraint: baby grows fast b/t 35-38 weeks gestation- growth of the fetus is greater than
growth of uterus and amniotic fluid decreases.
7.K. Understand major causes of congenital malformations. (Table 7-9, page 240)


Malformations represent primary errors of morphogenesis, meaning there is an intrinsically
abnormal developmental process.
Known causes of human malformations grouped into 2 categories: genetic and environmental.
However, almost half have no known cause.
Genetic include:
All chromosomal syndromes (10-15% of malformed live births), such as Down’s and other
trisomies, Turner’s, and Klinefelter’s. These are not familial, but arise during gametogenesis.
Mendelian Inheritance (2-10%) which are single gene mutations such as holoprosencephaly
(forebrain and midface defects), Sonic Hedgehog homologue, and PAX6 gene mutations
(congenital absence of iris present – aniridia).
Multifactorial Inheritance (20-23%) implies the interaction of environmental factors with 2 or
more genes of small effect. It is the most common cause of genetic congenital malformations.
Include cleft lip or palate, and neural tube defects.
Environmental influences (viral infections, drugs, maternal exposure to radiation, etc.) include:
Maternal/placental infections (2-3%) such as Cytomegalovirus, Rubella, Toxoplasmosis, Syphilis,
and HIV. [Maternal Rubella is an environmental teratogen where gestational age at fetal exposure
is critical. Causes heart defects, cataracts, deafness, and mental retardation.]
Drugs and chemicals (1%) are teratogenic. These could include thalidomide, folic antagonists,
androgenic hormones, alcohol, anticonvolusants, warfarin, 13-cis-reinoic acid, and nicotine.
Page 14 of 37
Maternal diseases (6-8%) such as diabetes (6-10% of diabetic moms have malformed babies),
phenylketonuria, and endocrinopathies.
Irradiation (1%)
Unknown cause (40-60%) .
7.L. Understand the pathogenesis of respiratory distress syndrome in the newborn.
(pages 242-244)
Respiratory distress has many possible causes in the newborn:
 excessive sedation of mother
 fetal head injury during delivery
 aspiration of blood or amniotic fluid
 intrauterine hypoxia because umbilical cord coils around neck
 Respiratory Distress Syndrome (RDS) is the most common cause.** This is also referred to
as hyaline membrane disease because there are formation of membranes in the peripheral air
spaces of affected infants. There are 60,000 RDS cases reported each year and 5,000 deaths per
year.
Pathogenesis of RDS
 Primarily a disease of premature infants
 Affects 15-20% of babies born between 32-36 weeks
 Prevalence increases to 60% for infants delivered before 28 weeks
 Influenced by maternal diabetes, C-sections before onset of labor, and twin gestation
 The main defect is inability of immature lungs to make sufficient surfactant. (Remember from
physiology that surfactant is made by Type II pneumocytes. When a healthy newborn breathes
it’s first breath, surfactant rapidly coats alveoli surfaces, reduces surface tension, and decreases
the pressure needed to keep alveoli from collapsing. When a lung is deficient in surfactant,
open alveoli have a tendency to collapse and it takes a much greater effort to open alveoli with
each breath.)
 The infant tires from breathing
 Generalized atelectasis (total or partial collapse of the lung) sets in
 Hypoxia results in a sequence of events (see figure 7-28 on page 243) that results in epithelial
and endothelial damage
 Eventually hyaline membranes are formed from fibrin and necrotic cells
 Surfactant synthesis is regulated by hormones—corticosteriods stimulate formation of
surfactant lipids and associated apoprotiens.
 Increased intrauterine distress and fetal growth restriction increase corticosteroids and decrease
the risk of developing RDS
 Thyroxine acts synergistically with corticosteroids
 Insulin antagonizes this effect (uncontrolled diabetes in pregnant women yields compensatory
high insulin in the fetus and can suppress surfactant synthesis). Therefore there’s an increased
risk of RDS in babies born to diabetic mothers.
 Labor increases surfactant synthesis, so C-sections before onset of labor may increase RDS
risk.
Clinical Features of RDS
 Infants with RDS usually appear normal at birth
 Within minutes to hours they get a grunting respiration that worsens
 Unless they receive therapy to control it, they will die.
 RDS is the major cause of death in the neonatal period.
 Treatment supports ventilation until the baby can breathe on its own
 Therapy involves aerosolized natural or recombinant surfactant
Page 15 of 37



Greater birth weight and gestational age give a better outlook for the infant
Of the infants who survive RDS, a minority will have long term sequelae. This includes
pulmonary lung disease (bronchopulmonary dysplasia) resulting from primary anoxic injury, as
well as from high concentrations of oxygen and positive pressure ventilation required during
treatment for the disease.
Prevention is the key to reducing morbidity and mortality from RDS. This includes prevention
of premature delivery until the baby’s lung is capable of adequate surfactant synthesis.
Measuring the concentration of surfactant phospholipids in the amniotic fluid (via
amniocentesis) can give an estimation of fetal pulmonary maturity. If early delivery is
unavoidable, corticosteroids may be delivered to the mother. This decreases the risk for RDS
by increasing surfactant synthesis.
7.M. Understand the pathogenesis of necrotizing enterocolitis in the newborn. (pages
244-245)
Necrotizing enterocolitis (NEC):
 Predominately a complication of premature infants
 Associated with a high perinatal morbidity and mortality
Cause NEC:
 Controversial; in all likelihood is multifactorial
Predisposing Factors:
 Intestinal ischemia- may result from either generalized hypoperfusion or selective reduction of
blood flow to the intestines o order to divert oxygen to vital organs such as the brain
 Bacterial colonization of the gut- aggravate mucosal injury in the immature bowel
 Administration of formula feeds- aggravate mucosal injury in the immature bowel
 NEC typically involves the terminal ileum, cecum, and right colon.
 Part of the small or large intestine may be involved
 Involved segment is distended, friable, and congested
 Can also be frankly gangrenous
 Intestinal perforation with accompanying peritonitis may be seen
Features Associated:
 Microscopically, mucosal or transmural coagulative necrosis, ulceration, bacterial colonization, and
submucosal gas bubbles
 Reparative changes, such as granulation tissue and fibrosis, may be seen shortly after the acute
episode
The Clinical Course of NEC:
 Fairly typical, with the onset of bloody stools, abdominal distention, and development of circulatory
collapse
 Abdominal radiographs often demonstrate gas within the intestinal wall (pneumatosis intestinalis)
Management of NEC:
 When detected early on, NEC can often be managed conservatively
 Many cases require operative intervention and resection of the necrotic segments of the bowel
 NEC is associated with high perinatal mortality
 Infants who survive often develop post-NEC strictures from fibrosis caused by the healing process
Page 16 of 37
7.N. Understand proposed mechanism and major risk factors associated with SIDS.
(page 245)
SIDS is the “sudden death of an infant less than 1 year of age whose death remains unexplained after the
performance of a complete autopsy, examination of the scene of death, and a review of the case history.”
The “proposed mechanism” that the study guide asks us to understand is not even understood by the
experts, so I’ll do my best. Basically, in SIDS, children die in their sleep for no apparent reason (thus the
difficulty in trying to explain it). The diagnosis of SIDS must only follow the ruling out of all other
possibilities. Some microscopic changes have been seen in the brain, thymus, and lungs of some
children; however, these are in no way conclusive evidence due to their sporadic appearance. The basic
theories revolve around multiple organ system dysfunction. Some experts believe it involves the
metabolism of fatty acids, while others point to neural delays, respiratory dysfunction, or microbial
infection. Basically, a plethora of theories exist, none of which seem to hold much water.
Basic risk factors include:
Maternal
Youth (< 20 yrs old)
Unmarried
Short intergestational intervals
Low socioeconomic status
Smoking
Drug Abuse
African-American
Infant
Prematurity
Low birth weight
Male
Part of a multiple birth
Not first sibling
SIDS in sibling(s)
7.0. Explain what is meant by “hydrops fetalis” and provide examples of how this
condition may occur, including specifically, ABO incompatibility and Rh incompatibility
(pages 245-248
Hydrops fetalis is the term used for generalized edema of the fetus that can frequently be lethal. Major
causes of hydrops fetalis include: chromosomal abnormalities (Turner’s syndrome and trisomies (21, 13,
18)), cardiovascular (cardiac anomalies and arrhythmias), twin pregnancy (twin-twin transfusion
syndrome), non immune fetal anemia (homozygous alpha thalassemia and parvovirus B19), and immune
fetal anemia (Rh and ABO hemolysis).
Rh hemolysis is preventable with the administration of anti-D (major antigen of the Rh-system that
causes Rh incompatibility) globulin making fetomaternal ABO incompatibility the most common cause
of immune hemolytic disease of the newborn. Fetal RBC may reach the maternal circulation during the
last trimester of pregnancy or during childbirth itself thus the mother may become sensitized to the
foreign antigen and develop antibodies that can freely traverse the placenta to the fetus and cause RBC
destruction. ABO hemolytic dz occurs almost exclusively in infants of group A or B who are born to
group O mothers.
Several factors influence the immune response to Rh positive fetal RBC that reach the maternal
circulation:
1.
2.
Concurrent ABO incompatibility protects the mother against Rh immunization because the
fetal RBC are promptly coated by isohemagglutinins and removed from the maternal
circulation.
The antibody response depends on the dose of immunizing antigen. Hemolytic dz can only
occur when the mother has had significant transplacental bleed (>1 mL of Rh-positive
RBC)
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3.
IgG, but not IgM crosses the placenta. The initial exposure to Rh antigen evokes the
formation of IgM antibodies thus Rh dz is very uncommon with the first pregnancy, but
subsequent exposure during the second or third pregnancy leads to a brisk IgG response.
7.P. Describe the most common tumors that occur in children. (pages 251-256)
7P.1. Leukemia- leukemia, cancers of the white blood cells, is not described in the book but is in the slides
noted as the most common malignant neoplasm of infancy and childhood. It causes more deaths in
children less than 15 yrs. of age than all other types combined. It comprises 50% of all childhood
neoplasia. There is a great risk of developing leukemia with Down’s Syndrome. The prognosis is
improving, especially with ALL, or Acute Lymphocytic Leukemia.
7P.2. Neuroblastoma- (THERE WILL BE A TEST QUESTION ON NEUROBLASTOMA! ) One of the
most common extracranial childhood solid tumors. It accounts for about 15% of all childhood cancer
deaths. 80-90% are found in children less than 5 yrs. with many being in the first year of life. The
median age is 3 months. The tumors may arise in the adrenal gland in the medulla where
catecholamines occur (not the cortex as stated in the lecture on Thursday) or anywhere in the
sympathetic nervous system. Most occur sporadically, but a few are familial with autosomal dominant
transmission. On examination, they are gray-white, soft, and friable. The easiest way to determine
leukemia from other neoplasms is with a urine assay for catecholamines. Well-differentiated lesions
may contain many more large cells resembling neurons. These neoplasms merit the designation
ganglioneuroma. Staging of neuroblastomas is very important in determining prognosis. Special note
should be taken of stage IV-S because these patients have an excellent outlook despite the spread of the
disease. Patient presents usually with a protuberant abdomen owing to an abdominal mass, fever, and
weight loss. Children less than one year have a more favorable outlook. Deletion of the short arm of
chromosome 1 and amplification of the N-myc oncogene, both point to a poor prognosis. The tumors
sometimes spontaneously regress.
7P.3. Retinoblastoma- the most common intraocular tumor of childhood. It also can undergo spontaneous
regression. Often a congenital tumor, and the incidence decreases with age, with most cases being
diagnoses between 16 months and 2 years. It arises in the retina and lining of the globe.
Morphologically, these cells are small, round, and have large hyperchromatic nuclei and scant
cytoplasm. The most common characteristic being rosettes, or clusters of cuboidal or short columnar
cells around a central lumen. The nuclei are displaced away from the lumen. The tumors are
occasionally bilateral and can occur from a deletion of the long arm of chromosome 13. Presenting
features include poor vision, strabismus, a whitish hue to the pupil, and tenderness to the eye. Untreated
the tumors are usually fatal. Retinoblastoma increases the risk of developing other soft tissue tumors.
7P.4. Nephroblastoma (Wilm’s Tumor)- This is the most common renal tumor of childhood. It is usually
diagnosed between ages 6 months and 2 years. Patients at risk are those with WAGR syndrome,
characterized by aniridia, genital abnormalities, and mental retardation. These conditions are associated
with the loss of the short arm of chromosome 11. Children with Denys-Drash syndrome and Beck-withWiedmann syndrome are also at risk. It tends to present as a large, solitary well-circumscribed mass.
The tumor is soft and tan and gray (good picture in text). Differentiation is usually in the form of
abortive tubules or glomeruli. Patients complaints are usually referable to the tumor’s enormous size.
Commonly there is a palpable abdominal mass, which may extend down to the pelvis. The outlook is
generally very good. Metastases often disappear after treatments begin, usually consisting of radiation,
nephrectomy, and chemotherapy.
Page 18 of 37
7.Q. Explain the term “Apgar Score”.
5 parameters are measured at 1 and 5 minutes after birth. The 5 parameters are:
Activity (muscle tone)
Pulse,
Grimace (response to noxious stimuli),
Appearance (color),
Respiration.
The baby is rated 0-2 (with 2 being best) for each of these 5 parameters, the scores are totaled, and a perfect
score is 10. The “Apgar score” correlates with perinatal outcome.
7.R. Understand the major causes of death in infants, children 1-4 years of age, and in
older children. (Waites outline)
Infants (under 1 year old
-perinatal conditions
-congenital anomalies
-Sudden infant death (SIDS)
-Infection
5-9 years old
-injuries
-neoplasia
-homicide
-congenital anomalies
-heart dz
10-14 years old
-injuries
-homicide
-suicide
-congenital anomalies
-neoplasia
1-4 years old
-injuries
-congenital anomalies
-neoplasia
-homicide
-heart dz


Diseases of infancy pose the highest risk of mortality. During this phase, the neonatal period (first 4
weeks of life) is the most hazardous time.
Between the ages of 1 and 15 years, injuries resulting from accidents are the leading cause of death.
7.S. Explain the following terms:
encephalocele
meningocele
meningomyelocele
omphalocele
gastroschisis
(1st defn = Stedman’s; 2nd = text):
CRANIAL NEURAL TUBE DEFECTS (less severe than anencephaly):

Encephalocele - A congenital gap/defect in the skull that usually results in a protrusion of
brain material (meninges and brain parenchyma). Also called bifid cranium, cephalocele,
craniocele. Most common in the occipital region (but can occur anywhere).
Page 19 of 37

Meningocele - Protrusion of the meninges of the brain or spinal cord through a defect in the
skull or spinal column forming a cyst filled with cerebrospinal fluid (protrusion of brain
material and CSF in herniated tissue)
POSTERIOR VERTEBRAL DEFECTS:
 Meningomyelocele or myelomeningoceles - Protrusion of the spinal membranes/meninges
and spinal cord through a defect in the (posterior) vertebral column. Observe cystlike
outpouching (spina bifida cystica) above buttocks. May be exposed or covered by skin.
Associations: hydrocephalus and Arnold-Chiari malformation. Manifestations: infections (since
CNS exposed to environment, lower extremity paralysis, disturbances of bladder/bowel control.
Due to failure of closure of caudal neural tube.
DEVELOPMENTAL ANOMALIES:
 Omphalocele - Congenital herniation of viscera into the base of the umbilical cord
(periumbilical abdominal wall). Leaves behind a membranous sac, into which the intestines
herniated.
(not in book):
 Gastroschisis - A congenital fissure in the abdominal wall usually accompanied by protrusion of
the viscera
7.T. Describe the pathogenesis and clinical manifestations of congenital infections caused
by Cytomegalovirus and Rubella.
Congenital Cytomegalovirus:




The "C" in TORCH
Most common cause of infection in births, 1/100 pregnancies
No harm to baby if mother is already infected with CMV before conception and has protective
immunoglobins, danger comes when the mother is infected during pregnancy
Clinical manifestations include Thrombocytopenia, Hepatosplenomegaly, mental retardation,
microcephaly, blindness, deafness
Congenital Rubella:


Very rare due to vaccination
Rubella Triad: Ventricular septal defects, Deafness, Cataracts
7.U. Explain the relationship between oligohydramnios and Potter’s Syndrome
Oligohydramnios is defined as inadequate amniotic fluid, and may be caused by maternal, placental or
fetal abnormalities. This may include:
 Chronic leakage of amniotic fluid leading to rupture of the amnion
 Uteroplacental insufficiency due to maternal hypertension or severe toxemia
 Renal agenesis in the fetus
This occurs in renal agenesis in Potter’s Syndrome where children are born without kidneys. The
amniotic fluid provides support for the baby, so the absence of amniotic fluid means the baby gets
compressed by the uterus and other structures, causing organs not to develop. The baby will present
with:
Page 20 of 37
 Flattened facial features
 Deformed hands and feet
 Low-set ears
This condition is incompatible with life and the baby soon dies after birth.
Pulmonary hypoplasia also occurs during oligohydramnios. The lungs are very small in the chest cavity
due to the lack of amniotic fluid during gestation.
7.V. Understand major features of fetal alcohol syndrome.





Alcohol, perhaps the most widely used agent today, is an important environmental teratogen.
Affected infants show pre- and post-natal growth retardation
Facial anomalies (microencephaly, short palpebral fissures, maxillary hypoplasia)
Psychomotor disturbances
These all together are labeled Fetal Alcohol Syndrome
Chapter 8 Environmental Diseases and Forensic Pathology
The material on Forensic Pathology is derived from Dr. Davis’ outline and objectives.
There are no specific learning objectives other than material included on the outline for
that lecture.
8.A.
Understand the lab case studies and recognize the pathologic lesions associated
with each condition.
Please review on your own.
8.B.
Explain the term “pneumoconiosis” and describe examples of diseases that fall into
this classification. (pages 268-274)
8.A.1. asbestosis
8.A.2. silicosis
Pneumoconiosis:
Inflammation commonly leading to fibrosis of the lungs
caused by the inhalation of dust incident to various
occupations; characterized by pain in the chest, cough
with little or no expectoration, dyspnea, reduced
thoracic excursion, sometimes cyanosis, and fatigue
after slight exertion; degree of disability depends on
the types of particles inhaled, as well as the level
of exposure to them. Syn: pneumonoconiosis,
anthracotic tuberculosis, pneumonokoniosis
Asbestosis:
Pneumoconiosis due to inhalation of asbestos fibers
suspended in the ambient air; sometimes complicated by
Page 21 of 37
pleural mesothelioma or bronchogenic carcinoma;
ferruginous bodies are the histologic hallmark of
exposure to asbestos.
Silicosis:
A form of pneumoconiosis resulting from occupational
exposure to and inhalation of silica dust over a
period of years; characterized by a slowly progressive
fibrosis of the lungs, which may result in impairment
of lung function; silicosis predisposes to pulmonary
tuberculosis. Syn: silicatosis, pneumosilicosis,
stone-mason's disease
8.C.
Understand the effects of tobacco smoke on lung function and the numerous
adverse effects of smoking. (pages 274-275, Table 8-7, Figure 8-7)
Effects on Lung Function
1.
Agents in smoke can irritate tracheobronchial mucosa which can cause inflammation and
increased mucous production (bronchitis).
2.
Cigarette smoke brings leukocytes to the lung with increased local elastase production and
injury to lung tissue. This leads to emphysema.
3.
Components of cigarette smoke (especially tars) produce carcinogens and cancer promoters.
4.
Other effects are impaired O2 transport and use, toxicity to cilia, and irritation.
Adverse Effects
1.
Most common effects are emphysema, chronic bronchitis, and lung cancer
2.
Can also cause atherosclerosis, myocardial infarction, oral cavity cancer, cancer of the larynx,
esophageal cancer, peptic ulcers, pancreatic cancer, bladder cancer
3.
In pregnant women, smoking causes increased chances of spontaneous abortions, preterm births,
and small babies.
8.D.
Explain the pathogenesis, epidemiology, and clinical manifestations of lead
poisoning. (pages 278-280, Figure 8-8)
Lead levels accumulate over weeks and months until they reach toxic levels. Adults and children
present with lead toxicity differently. Adults have colicky abdominal pain, fatigue, and headache. In
infants and children, it might not be suspected until it erupts into an encephalopathic crisis. It is difficult
to avoid exposure to lead because there are a lot of sources of lead.
Epidemiology (Sources of lead)
Occupational: spray painting
foundry work
mining/extracting lead
battery burning
Non-occupational: water supply
pain dust/flakes
house dust
urban soil
newsprint
automobile exhaust
Environmental lead is mainly absorbed through the GI tract or lungs. Major sources of lead are urban
air, soil, water, and food. Volatized lead is almost all absorbed in the lungs. However, ingested lead is
only partially (a fraction) absorbed. Urban adults daily average intake of lead is 100 to 150 μg which
comes from water and food and only 10% is absorbed. Kids have a lower daily intake and absorb 50%.
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Highest risk of toxicity in kids occurs with the ingestion of lead paint chips (in old homes) and soil
contamination where up to 200 μg/day may occur.
Most of the absorbed lead is taken up by bone and developing teeth (80-85%), some via blood (5-10%)
and the rest is distributed through soft tissues. In growing kids, excess lead interferes with the normal
remodeling of calcified cartilage and primary bone trabeculae in the epiphyses leading to increased bone
density seen as “lead lines” on the radiographs. Lead lines may also be seen in gums where you can see
hyperpigmentation of the gum tissue adjacent to the teeth. Kidneys can excrete urine and can possibly
produce kidney damage.
Pathogenesis: Lead has a high affinity for sulfhydryl groups and interferes with enzymes involved in
heme synthesis—aminolevulinic acid dehydratase and delta ferrochelatase; thus iron incorporation into
heme is hindered or blocked, leading to hypochromic anemia. Lead also competes with Ca and is stored
in bones. It interferes with nerve transmission and brain development in infants. It interferes with Na/K
ion pumps thus leading to decreased RBC survival and hemolytic anemia.
Clinical manifestations:
Adult: headache, memory loss, demyelination of peripheral nerves
Child: encephalopathy, mental deterioration, radiodense deposits in epiphyses
General: lead line in gingival, anemia, red cell basophilic stippling, chronic tubulointerstitial disease,
and abdominal pain
How do you diagnose it? Neurologic changes in children and unexplained anemia with basophilic
stippling in red cells. Elevated blood lead and free erythrocyte protoporphyrin levels (above 50 μg/dl) or
zink protoporphyrin levels are required for definitive diagnosis.
8.E.
Explain the pathogenesis of carbon monoxide poisoning. (page 280)
Carbon Monoxide (CO) is a non-irritating, colorless, tasteless and odorless gas produced by the
imperfect oxidation of carbonaceous materials. Sources include car engines, industrial processes using
fossil fuels, home heating with oil (not natural gas) and cigarette smoke. The low levels in atmosphere
from these sources can contribute to impaired respiratory function but are not life threatening. However
large doses of CO are toxic. Hemoglogin as a 200% greater affinity for CO than for O 2 . Hemoglobin
carrying CO can’t carry O2 so tissues asphyxiate. Systemic hypoxia is when hemoglobin is 20-30%
saturated by CO and unconsciousness and death can occur with 60-70% CO saturation. CO poisoning
can be acute or chronic. Acute CO poisoning occurs with large somewhat brief dose and produces
cherry red coloration of skin and mucous membrane in individuals with light skin. The brain can be
edematous with punctuate hemorrhages and hypoxia induced neuronal changes if the individual survives
longer after exposure. Individuals experiencing shorter exposure can completely recover with only some
retaining vision, hearing, memory and speech impairment. Chronic CO poisoning occurs when
individuals are consistently exposed to low levels. Because carboxyhemoglobin is very stable once
formed it can build up in the tissues with persistent exposure and result in slow developing hypoxia and
ischemic changes in the basal ganglia and lenticular nuclei of the CNS. If exposure ceases these
individuals can also recover but with permanent neurologic sequelae.
8.F.
Explain how ethanol is toxic to tissues and how this accounts for damage to
multiple organ systems. (pages 280-282)
After consumption ETOH is absorbed and distributed to tissues and fluids in the body based on
proportion of blood flow. Most alcohol is transformed to acetylaldehyde by alcohol dehydrogenase in the
cytosol of cells. Transformation also occurs via cytochrome P450 in blood adn catalase in the liver. From
Page 23 of 37
these reactions NADH and acetic acid are formed. The NADH opposses gluconeogenesis and inhibits
fatty acid synthesis which can directly lead to cirrhosis of the liver. Gastric ulcerations can also occur
from alcoholism. Free radical injury and immune rxns agaist hepatic neoantigens formed by
acetylaldehyde are other ways alcohol can lead to destruction of tissue.
Liver-cirrhosis
GI- ulcers and bleeding
CNS - cerebral atrophy, cerebellar degeneration, and peripheral neuropathies
CV-myocardium damage, coronary heart disease
Pancrease- pancreatitis
8.G.
Describe and explain the sequelae of cocaine, heroin, and marijuana abuse. (pages
282-284.
Cocaine
 The most serious physical effects of cocaine relate to its acute action on the cardiovascular system,
where it behaves as a sympathomietic. It facilitates neurotransmission both in CNS, where it blocks reuptake of dopamine, and at adrenergic nerve endings, where it blocks re-uptake of epinephrine and
norepinephrine while stimulating the presynaptic release of norepinephrine. The net effect is
accumulation of these 2 neurotransmitters in synapses, resulting in excess stimulation, manifested by
tachycardia and hypertension. Cocaine also induces myocardial ischemia, the basis for which is multifactorial. It causes coronary artery vasoconstriction, produces thrombus formation by facilitating platelet
aggregation, and induces premature artherosclerosis in long term users. Cocaine induced coronary
vasospasms is potentiated by cigarette smoking. Cocaine induces increased myocardial oxygen demand
and decreases coronary blood flow, thus setting the stage for myocardial ischemia that can lead to
myocardial infarction. Arrhythmias generated by enhanced sympathetic activity as well as by disrupting
normal ion transport into myocardium.
Manifestations of Acute Cocaine Toxicity:
 Sympathetic nervous system stimulation, dilated pupils, vasoconstriction, increase in arterial
blood press, tachycardia.
 Lethal arrhythmias and myocardial infarction
 Cerebral infarction and intracranial hemorrhage
 Rhabdomyolysis, sometimes accompanied by renal failure
 Pregnant women – dec. blood flow to placenta, fetal hypoxia and spontaneous abortion. In
chronic users fetal neurological development may be impaired.
Chronic Cocaine Use
 Perforation of nasal septum in cocaine snorters
 Decreased lung diffusing capacity in those who inhale smoke form
 Rarely development of dilated cardiomyopathy
 Cocaine has been shown to be teratogenic in mice.
Heroin
 The problems resulting from heroin use occur as a result of:
 Pharmacologic action of agent
 Reaction to cutting agent or contaminant
 Hypersensitivity rxns to drug or its adulterant (quinine itself has neurologic, renal, and auditory toxicity)
 Diseases contracted incident to the use of the needle
Page 24 of 37
Sequelae of heroin include:
 Sudden death related to overdose because purity of the drug is unknown. Mechanisms of death
include: profound respiratory depression, arrhythmia, and cardiac arrest and severe pulmonary
edema.
 Pulmonary complications include: moderate to severe edema, septic embolism, lung abscess,
opportunistic infections, and foreign body granulomas from talc and other adulterants.
 Infectious complications are common. 4 sites most commonly affected: skin, heart valve, liver,
and lungs. Viral hepatitis is most common infection among addicted persons and is acquired by
the sharing of dirty needles.
 Cutaneous lesions are the most tell-tale sign of heroin addiction. Acute changes include:
abscesses, cellulitis, and ulcerations owing to subcutaneous injections. Scarring at injection
sites, hyper pigmentation over commonly used veins, and thrombosed veins are the usual
sequelae of repeated IV inoculations.
 Kidney disease is relatively common. The 2 most common forms: amyloidosis and focal
glomerulosclerosis. Both induce heavy proteinuria and the nephrotic syndrome. Amyloidosis is
secondary to chronic skin infection.
Marijuana
 Pot distorts sensory perception and impairs motor coordination – this clears in4-5 hours. With continued
use these changes may progress to cognitive and psychomotor impairment such as inability to judge
time, speed, and distance
 Lungs are affected by chronic pot smoking; laryngitis, pharyngitis, bronchitis, cough, and hoarseness,
and asthma like symptoms have all been described along with mild but significant airway obstruction.
Increases risk for lung cancer.
 Marijuana increases heart rate and sometimes blood pressure and in a person with fixed coronary artery
narrowing may cause angina.
 Marijuana may induce chromosomal damage in somatic and germ cells.
8.H.
Define the terms abrasion, contusion, laceration, incised wound, puncture wound.
(page 285)

Abrasion—a wound produced by scraping or rubbing, resulting in removal of the superficial layer. Skin
abrasions may remove only the epidermal layer.

Contusion—(aka bruise) is a wound usually produced by a blunt object and is characterized by damage
to blood vessels and extravasation of blood into tissues

Laceration—a tear or disruptive stretching of tissue caused by the application of force by a blunt object.
In contrast to an incision, most lacerations have intact bridging blood vessels and jagged, irregular edges.

Incised wound—one inflicted by a sharp instrument. The bridging blood vessels are severed.

Puncture wound—caused by a long narrow instrument and is termed penetrating when the instrument
pierces the tissue and perforating when it traverses a tissue to also create an exit wound. Gunshot
wounds are special forms of puncture wounds that demonstrate distinctive features important to the
forensic pathologist. For example, wound from a bullet fired at close range leaves powder burns,
whereas one fired from more than 4 or 5 feet away does not.
Page 25 of 37
8.I.
Explain the differences between 1st, 2nd, 3rd and 4th degree burns. (page 286)
The clinical significance of burns depends on the following factors:
 depth of burn
 percentage of body surface involved
 possible presence of internal injuries from inhalation of hot and toxic fumes
 promptness and efficacy of therapy, especially fluid and electrolyte management and prevention
or control of wound infections
Full thickness burns - 3rd and 4th degree burns:
 involve total destruction of epidermis and dermis
 loss of dermal appendages that would have provided cells for epithelial regeneration
Partial thickness burns – 1st and 2nd degree burns:
 at least the deeper portions of the dermal appendages are spared
 1st degree – epithelial involvement only
 2nd degree – both epidermis and superficial dermis involved
8.J.
Explain the clinical manifestations of the various degrees of hyperthermia (e.g.
heat cramps, heat exhaustion, heat stroke). (page 286)
Heat cramps-results from loss of electrolytes from sweating, has normal body temperatures
Heat exhaustion- most common hyperthermia symptom. Onset is sudden with collapse caused by
failure of the cardiovascular system to compensate for hypovolemia from water depletion.
Heat Stroke- body temperatures reach 106 or higher from high ambient temperatures, and has a
mortality rate of 50%. Elderly, young atheletes, and people with CV disease are prime candidates for
heat stroke. Mechanism is peripheral vasodilation with peripheral pooling of blood and decreased
circulating blood.
8.K.
Describe the effects of hypothermia on the body. (pages 286-287).
Prolonged exposure to low ambient temperature leads to hypothermia. When the body temperature is
lowered to 90ºF loss of consciousness occurs, followed by bradycardia and atrial fibrillation at lower
core temperatures.
Chilling or freezing of cells and tissues causes injury in two ways.
1. Direct effects are mediated by physical dislocations within cells and high salt concentrations
due to the crystallization of the intra- and extracellular water.
2. Indirect effects are exerted by circulatory changes. Slow to develop chilling may induce
vasoconstriction and increased permeability, leading to edematous changes. Atrophy and
fibrosis may follow.
Rapid drop in temperature that is persistent will cause
vasoconstriction and increased viscosity of the blood in the local area and can cause
ischemic injury and degenerative changes in peripheral nerves. In this situation, only after
the temperature begins to return to normal does the vascular injury and other effects
become apparent.
Page 26 of 37
8.L.
Explain the damaging effects of the various types of ionizing radiation at the
cellular and tissue levels and understand factors that influence radiation
absorption. Pay close attention to histologic manifestations as shown in lab case
study. (pages 287-290, Figure 8-15)
Ionizing radiation occurs in two forms:
1. electromagnetic waves ( x-rays and gamma rays)
2. high energy neutrons and charged particles ( alpha and beta particles and protons)
All ionizing radiation effect cells by displacing electrons from molecules and atoms. This can alter cells
transiently or permanently. The most important target is DNA. Ionizing radiation can either
cause direct damage to DNA or more often, indirect damage by the formation of free radicals.
Other cell molecules that are tartest of ionizing radiation include lipids in the cell membranes
and proteins that function as critical enzymes. Biological effects may be present within minutes
or not apparent for decades.
Terms used to express radiation dose:
 Roentgen (R) is a unit of x- or gamma radiation that ionizes a specific volume of air. Measures
exposure.
 Radiation absorbed dose (rad) and grays ( Gy) are units that express the energy absorbed by
target tissue from x- or gamma rays. A rad or a centigray (cGy) is the dose that results in the
absorption of 100 erg of energy per gram of tissue.
 Rem is the dose that produces the biological effect equivalent to 1 rad.
 Curie (Ci) defines the disintegrations per second of a disintegrating radioisotope.
 Linear energy transfer (LET) can directly quantify energy transferred per unit of tissue and can
predict the biologic effects. LET is very high for alpha particles, less for beta particles and even
less for x- and gamma rays. So alpha and beta particles penetrate short distances and interact
with many molecules thus inducing heavy damage in a superficial restricted area. Gamma and
x-rays penetrated deeply but interact with few molecules so the energy is dissipated over a
longer, deeper course producing less damage per unit of tissue.
Factors that influence radiation absorptions:
1. Primary target of ionizing radiation is DNA so rapidly dividing cells are more vulnerable to injury
than intermitotic cells. Bone marrow, lymphoid tissue, and the mucosa of the GI tract are
extremely vulnerable due to their high rate of cell turnover. Brain and myocardium are
nondividing cells so they do not demonstrate radiation effects except at high doses that impair
DNA transcription.
2. Effects of radiation are complex because tissues are made up of many cell types.
3. Rate of delivery of radiation can modify the biologic effects. Radiation effects are cumulative but
dividing the doses may allow cells to repair some of the damage before the next treatment.
Normal cells are capable of more rapid repair and recovery that tumor cells.
4. Radiant energy can interact with molecular oxygen to induce free radicals, such as superoxide. This
increases the cellular injury.
5. The size of the field exposed to radiation has a great impact. High doses of radiation to small,
shielded areas can be sustained, while smaller doses delivered to larger fields can be lethal.
6. Radiation can alter gene expression. It can increase expression of protooncogens, cytokines such has
TNG, or TP53.
Page 27 of 37
Effects on Organ Systems:
 The hematopoietic and lymphoid systems are extremely susceptible to radiant injury.
Lymphopenia can appear within hours, with shrinkage of lymph nodes and spleen. It directly
destroys lymphocytes in both the circulation and in tissues.
 Platelets are effected similarly to lymphocytes causing thrombocytopenia. Hematopoietc
cells in the bone marrow are very sensitive to radiation. Even though erythrocytes are
resistant, anemia occurs because the precursor cells in the bone marrow are affected.
 Radiation can cause malignant transformation. Any cell that is capable of division has the
potential to become cancerous. The level of radiation required to increase the risk of cancer
is hard to determine. Relatively high doses are associated with increased risk of developing
neoplasms. Prolonged doses to low dose radiation can impose a risk as well.
Refer to figure 8-15 page 290
3 often fatal acute radiation syndromes associated with various levels of total-body irradiation:
Syndrome
Dose (rad)
Manifestations
Hematopoietic
200-500
nausea, vomiting, lymphopenia,
thrombocytopenia, neutropenia,
anemia
Gastrointestinal
500-1000
diarrhea, hemorrhage, with low
doses, death within days
with high doses
Cerebral
>5000
listlessness, convulsions, coma,
death within hours
Be sure to look at the two lab case studies, Lung Radiation Fibrosis and Ileum Radiation Changes, to see
the histological manifestations.
8.M.
Learn the primary dietary sources and mechanism of actions of vitamins A,B1,
B2, B3, B6, B12, C, D, E, K, iodine, iron, and fluoride. Be able to list
manifestations of deficiencies of these substances. (pages 293-303, Tables 8-14, 815)
Vitamin Deficiencies
There are a total of 13 vitamins. Four (A, D, E, and K) are fat soluble, and the rest are water-soluble
vitamins. They are poorly absorbed in gastrointestinal disorder of fat malabsorption. Certain vitamins
are endogenously, such as Vit D from steroids, vit K and biotin by intestinal microflora, and niacin from
tryptophan. A dietary supply of all vitamins is essential for health without this endogenous synthesis.
Vitamin A
Fat-soluble vitamin that is obtained by dietary source of animal-derived (liver, fish, eggs, milk, butter)
and leafy green veges (carrots, squash, and spinach.. large amounts of carotenoids). Carotenoids are
provitamins that are metabolized to active Vitamin A in vivo, the most important is B-carotene. Retinol
is the most important form of Vitamin A as a transport form and storage form. It can be oxidized to
retinal, a form of visual pigment, and retinoic acid (affects growth regulation and differentiation).
Page 28 of 37
Retinoic acid is a small fraction in the blood for epithelial differentiation and growth but not for vision.
The digestion and absorption of carotenes and retinoids require bile, pancreatic enzymes, and antioxidant
activity in the food. Retinol is transported to the liver for storage and esterfication. More than 90% of the
body’s Vitamin A reserves are stored in the liver.
Functions:
1.
Maintain normal vision
Visual process involves 4 forms of vit. A: rhodopsin in rods (most light sensitive pigment… likes the
dark) and 3 iodopsins in cone cells (for color in bright light)
2.
Potentiating the differentiation of specialized epithelial cell..mucus-secreting cells
With a deficiency, the epithelium undergoes squamous metaplasia and differentiation to a keratinized
epithelium. Due to the retionic acid regulating the gene expression and the number of cell receptors.
Also, Promyelocyteic leukemia (PML) is due to a truncated retinoic acid receptor alpha gene (RARA)
blocking the myeloid cell differentiation.
3.
Enhancing immunity to infections, particularly in children and measles
It can stimulate the immune system through a metabolite called 14-hydroxyretinol. During an infection,
the formation of RBP (retinal binding protein) is reduced which causes a depression of circulation retinal
levels.
Deficiency State
Vitamin A defiency is world-wide either from undernutrition or malabsorption of fats. The earliest form
of deficiency is impaired vision (aka…NIGHT BLINDNESS). Other ocular changes include: dry eye
(xerophtahalmia), dryness of the conjuctiva (scerosis conjunctivae) These are due to the mucus-secreting
epithelium being replaced by keratinized epithelium. This can lead to Bitot spot (build up of keratin
debris). Eventually, the cornea will erode (keratomalacia) and total blindness.
The upper respiratory passage and urinary tract is replaced by keratinizing squamous cells ( squamous
metaplasia). This can cause seconday pulmonary infections and renal and urinary bladder stones.
Another consequence is immune deficiency which can lead to measles, pneumonia, and infectious
diarrhea. Megadoses of vitamin A offers no protection from lung cancer. (FYI…. there was an episode
on tv about night blindness in east asia and a doctor put drops of vit a on the people tongues and the
people experienced almost immediate recover in their vision..)
Vitamin D
The fat-soluble vitamin D is the maintenance of normal plasma levels of calcium and phosphorus. It is to
prevent bone diseases such as rickets in kid and osteomalacia in adults. Vit. D maintains the correct
concentration of ionized calcium for neural excitation and relaxation of muscles. Insufficient amounts
leads to continuous muscle excitation which leads to hypocalcemic tetany.
Metabolism (page 296)
The major source of endogenous synthesis is in the skin by conversion of 7-degydrocholesterol by UV
light. 90% of vit. D is by endogenous syn. and some from dietary source like deep-sea fish, plants, and
grains.
Normal Metabolism:
Absorption of Vit. D –- throught the blood to the liver-- converted to 25-OH-D by 25 hydorxylas in the
liver--25-OH-D to 1,25 dihydroxyvitamin D(1,25 (OH)2-D) by alpha1-hydroxylase in the kidney (this
is the most active form of Vit. D) ---1,25 (OH)2-D is regulated in the kidney by 3 mechanism:
1.
feedback loop to inhibiting alpha1-hydroxylase
2.
due to hypocalcemia, parathyroid hormone (PTH) is increased to increase 1,25 (OH)2-D
3.
hypophosphatemia increases its formation through alpha1-hydroxylase
Page 29 of 37
Functions:
1,25(OH)2-D is best regarded as a steroid hormone. This active form of vitamin D stimulates intestinal
absorption of calcium and phosphorus, collaborates with PTH in mobilization of calcium from bone, and
stimulates the PTH-dependent reabsorpiton of calcium in the distal renal tubules. The main function of
vitamin D is to maintain calcum and phosphorus at supersaturated levels in the plasma. However,
vitamin D can activate osteoblasts for bone mineralization.
Defiency States
Rickets and osteomalacia are skeletal disorders. It can result from deficient diets and limited sun
exposure. A deficiency in Vitamin D tends to cause hypocalcemia. When this occurs the PTH is
increased. The serum level of calcium is restored to near normal, but phpophosphatemis persists, and so
mineralization of bone is impaired.
In rickets: overgrowth of epiphyseal cartilage due to inadequate calcification and failure of cartilage
cells to grow, distorted masses of cartilage (mainly in the bone marrow), deposition of osteiod matrix,
disruption of cartilage replacement by osteiod matrix, abnormal growth of capillaries and fibroblast,
deformed of the skeleton, rigidity of developing bones.
In adults: lack of vitamin D deranges the normal bone remodeling that occurs throughout life.
Inadequate minerilization of osteoblast produces excess of persistant osteoid. Although the contours of
the bone are not affected, the bones are weak and vulnerable to gross fractures.
Prolonged sun exposure doesn’t cause excess of vitamin D, but orally administered forms have potential.
Excess can cause metastatic calcification of soft tissues. Large amounts can be a toxic, potent
rodenticide.
Vitamin C ( Abcorbic acid)
Ascorbic acid cannot be synthesized endogenously. It is water-soluble. It depends entirely on the diet (
milk, fruits, veges, liver, fish). A deficiency leads to the development of scurvy. It is not a global
problem. It can be seen in people that live alone, alcoholics, elderly, dialysis patients, or baby formula
w/o vit. C supplement.
The function of vitamin C is to provide hydroxylation of procollagen. Inadequate amounts lead to poor
helical formation which results in poorly secreting fibroblast. Collagen will lack tensile strength and be
more vulnerable to enzymatic degeneration. Besides the role in collagen synthesis, it has an antioxidant
property. It can act indirectly to regenerate the antioxidant form of Vit E. Vit E and Vit C act as
synergist. They may retard arhtersclerosis by reducing the oxidation of LDL.
Megadoses of vitamin C will protect from the common cold. Large excess excreted in the urine can
sometimes cause uricosuria and have increased absorption of iron (potential to iron overload).
Scurvy is a growing child is more dramatic than adults. Hemorrhages is the most striking feature.
Defects in the collagen synthesis cause inadequate support of the walls in capillaries and venules.
Purpura and ecchymoses may be seen in the skin. Bleeding of the joints(gums, skin, joint, or periosteum)
, inadequate synthesis of osteoid, impaired wound healing can also occur in scurvy. Anemia is a common
result from bleeding and from a secondary decrease in iron absorption.
Vitamin B12 (Cobalamin) deficiency anemia: Pernicious anemia (pg. 413)
Inadequate levels of B12 result in megaloblastic macrocytic anemia, and also it can cause demyelination
disorder involving the peripheral nerves (most importantly the spinal cord). Pernicious anemia is a result
from inadequate gastric production or defective function of intrinsic factor (IF) necessary to absorb B12.
Malabsorption is the most common cause. A dietary deficiency of cobalamin is limited to strict
vegetarians. B12 is abundant in all animal foods, including eggs and dairy products. It is stored in the
liver and reabsorbed by the bile. The deranged synthesis of IF is caused by autoimmune reaction against
parietal cells producing gastic mucosal atrophy (Gastric autoimmunity). B12 intertwines with folate
metabolism. Both folate and B12 can give rise to megaloblastic anemia. Defiency of B12 can improve
with administration of folate ( not vice-versa.. add B12 with folate= no improvement).
Page 30 of 37
Clinical Features
Pallor, easy fatigability, dyspnea, congestive heart failure, mild jaundice, Neurological changes like
numbness, tingling, burning in the feet or hands, unsteady gait, loss of position sense.
Vitamins B1, B2, B3, B6, E, K, iodine, iron, and fluoride are only described in the big chart on pages
301-303.
8.N. Explain the terms marasmus, kwashiorkor, bulimia, and anorexia nervosa. (pages
291-293)
Marasmus- is a form of Protein-Energy Malnutrition (PEM). A child whose levels fall to less than 60%
of normal weight for sex, height, and age is considered to have marasmus. A marasmic child suffers
growth retardation and loss of muscle. The loss of muscle mass results from catabolism and depletion
of the somatic protein compartment (represented by skeletal muscle). This seems to be an adaptational
response that serves to provide the body with amino acids as a source of energy. The child’s
extremities become extremely small, making the head appear too large for the body.
Kwashiorkor- occurs when protein deprivation is relatively greater than the reduction in total calories.
This is the most common form of PEM seen is African children who have been weaned off of milk too
early and subsequently fed an exclusively carbohydrate diet. Its prevalence is also high in Southeast
Asia, and may occur in persons with chronic diarrhea. Kwashiorkor is more severe than marasmus
because it is involves protein deprivation (visceral protein compartment), and the resultant
hypoalbuminemia gives rise to generalized or dependent edema (swollen stomach, or puffiness of the
face, arms or legs). Children with kwashiorkor may be of normal weight (because of water
retention/edema) and tend to have enlarged, fatty livers.
Anorexia Nervosa- is a self-induced starvation, resulting in marked weight loss. The clinical effects are
similar to severe PEM /marasmus with additional affects to the endocrine system. Amenorrhea,
resulting from decreased secretion of GnRH, LH, and FSH, is so common that is a diagnostic feature
in this disease. Other common findings include cold intolerance, constipation, dry, scaly skin,
increased body hair, and decreased bone density. A major complication is an increased susceptibility
to cardiac arrhythmia and sudden death.
Bulimia- In Bulumia, binge eating is the norm. Huge amounts of food, mainly carbohydrates are
ingested, and followed by induced vomiting. Amenorrhea occurs in less that 50% of them. The major
medical complications of continual induced vomiting include: electrolyte imbalances, which
predispose patients to cardiac arrhythmias, pulmonary aspiration of gastric contents, brittle tooth
enamel, and esophageal and stomach cardiac rupture.
Page 31 of 37
Chapter 17. Diabetes Mellitus (pages 641-654)
17.A. Understand the classification, incidence, and public health burden of Type 1 and
Type 2 diabetes mellitus and the basis for this classification. (page 641and page 2,
McDonald’s outline)
Diabetes mellitus represents a heterogeneous group of disorders that have hyperglycemia as a common
feature. Traditionally has been classified into 2 major categories: Primary, the most common form,
arising from a defect in insulin production and/or action; and secondary, arising from any disease
causing extensive destruction of pancreatic islets, such as pancreatitis, tumors, certain drugs, iron
overload (hemochromatosis), surgical removal of pancreatic substance, or acquired or genetic
endocrinopathies in which insulin action is antagonized. The 2 major variants of diabetes (types 1 and 2)
differ in their patterns of inheritance, insulin responses, and origins. There is also gestational diabetes
which occurs during pregnancy. Postpartum carbohydrate metabolism usually returns to normal,
however, the woman has an increased risk of developing diabetes later in life.
Diabetes affects 17.7 million people in the USA (by 2030 estimated 30.3 million). Globally approx. 170
million affected (by 2030 estimated 334 million). Type 1 accounts for 10% of all cases of diabetes, while
type 2 accounts for 90%. It’s the 3 rd leading cause of death, leading cause of new blindness, 80% of
major amputations occur in diabetics, 50% of pts with IDDM die of chronic renal failure, and 75% of
NIDDM die of complications of atherosclerosis. The estimated cost of diabetes is $105 billion (~10% of
all medical costs). The risk is 2-5 times higher for African Americans, Native Americans, and Hispanics
compared to non-Hispanic Caucasians.
17.B. Compare and contrast features of Type 1 and Type 2 diabetes mellitus (page 2,
McDonald’s outline, Table 17-3, page 642)
Onset
Onset Severity
Body Weight
GeneticsParents/siblings
Monozygotic twins
HLA associations
Islet Cell antibodies
Islet lesions
Early
Late
Beta Cell Mass
Blood insulin
Treatment/management
Type 1
Type 2
less than 20
acute; severe
normal
after 30 years old
gradual, subtle
obese
less than 20%
50%
yes
yes
greater than 60%
90%
no
no
inflammation
atrophy and fibrosis
reduced
reduced
insulin and diet
none
fibrosis, amyloid
normal , slightly reduced
elevated/normal/sl reduc
diet & exercisehypo-glycemic
drugsinsulin
Thirty second version: Type I Diabetes usually occurs before adulthood due to an immune response that
destroys the Beta cells in the pancreas so that they cannot produce insulin. This immune response
contributes to the fibrosis and atrophy of the Beta cells. No insulin, no ability to take up glucose. There
is some genetic component, but it is not at strong as in Type II. Type I diabetes also has the potential for
ketoacidosis and usually has an abrupt onset.
Page 32 of 37
Type II Diabetes usually occurs later in adulthood and is typically (80%) seen in obese persons. The
beta cells have the ability to produce insulin but cannot keep up with the amount of glucose in the blood.
Eventually insulin receptors on the target organs (fat, liver, skeletal muscle) are reduced, further
contributing to the problem. There is an exceptionally strong genetic component in this disease.
Remittance occurs with diet and exercise. More severe cases may require hypoglycemic drugs and even
more severe cases insulin. These diabetics usually have a gradual onset and are not at such a strong risk
as Type I for ketoacidosis.
17.C. Understand pathogenesis of Type 1 versus Type 2 diabetes mellitus (pages 642652, Figures 17-7, 17-9, and summary on page 3 McDonald’s outline)
Type 1 pathogenesis:
Genetic Predispostion:
1. HLA-linked genes and other genetic foci
↓
Environmental Insult
1. Viral infection:
Molecular mimicry
AND/OR
Damage to beta cells
↓
2. Immune response against normal beta cells
AND/OR
Immune response against altered beta cells
↓
Autoimmune attack
Beta-cell destruction
↓
Type 1 Diabetes
(Above) Possible pathways of beta-cell destruction leading to type 1 (insulin-dependent) diabetes mellitus. An
environmental insult, possibly viral infection, is thought to provoke autoimmune attack on beta cells in
genetically susceptible individuals. Environmental insults may involve molecular mimicry, in which a viral
antigen evokes autoimmune attack against a cross-reactive beta-cell antigen, or may cause direct damage to beta
cells and thus evoke an immune response against altered bet-cell antigens.
Genetic predisposition: Type 1A diabetes mellitus occurs most frequently in persons of Northern European
descent.
Type 1 (IDDM) – Ketosis -prone
1. B-cell destruction primary
2. Absolute insulin deficiency
3. The cause is unknown:
* Autoimmune component
* insulitis
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*Anti-islet antibodies (e.g. GAD, IA-2, insulin) – possible new diagnostic tool
*genetic component – certain HLA antigens common – especially near DR locus search for gene (6 th
chromosome)
* Viral – associated with mumps and Coxsackie B viruses
*Toxins – animals
* Others – Cow’s milk (1992)
Type 2 Pathogenesis: (see flow chart on pg. 645 for more clarification – I am not good at drawing pics on the
computer – pg. 645, Fig. 17-9)
Genetic Predisposistion:
1. Multiple genetic defects
2.a Primary beta-cell defect (Deranged insulin secretion)
2.b Peripheral tissue insulin resistance (inadequate glucose utilization)
3. Hyperglycemia
4. Beta-cell exhaustion
5. Type 2 diabetes
Genetic predisposition and environmental influences converge to cause hyperglycemia and overt
diabetes. The primacy of deranged beta-cell insulin secretion and peripheral insulin resistance is not
established; in patients with clinical disease, both defects can be demonstrated.
Type 2 (NIDDM) – Non-ketosis – prone
1.
Probably several entities resulting in similar syndrome – heterogeneous
2.
genetic – strong – 60% have parent or sibling with NIDDM
a. no locus identified
3.
Obesity – very important association – 80% at diagnosis
4.
Features
a. Impaired pattern of insulin release – early often have excess absolue insulin
b. Target tissue (Skeletal muscle, liver, fat tissue) resistance – defect in receptors and intracellular
signal transduction
c. “Metabolic syndrome” – cluster of CVD risk factors:
i. Glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, visceral obesity,
hypercoagulability, and microalbuminuria (challenged as a true syndrome)
17.D. Understand and explain clinical and laboratory features of Type 1 versus Type 2
diabetes mellitus. (page 652-653 and summary on page 3 of McDonald’s outline)
Type 1: AKA insulin-dependent diabetes mellitus
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Only accounts for 10-20% of all cases of primary diabetes
Onset is usually under age 20 and is usually abrupt (due to uncontrolled hyperglycemia)
These people are of normal weight
Decreased blood insulin
Anti-islet cell antibodies (GAD, IA-2, insulin)
Ketoacidosis common
Dominated by polyuria, polydipsia (increased thirst), & ketoacidosis
B-cell destruction primary
Absolute insulin deficiency
Insulin shots needed
Will have DM for their entire life
Cause is unknown
o Autoimmune component
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o
o
o
 Insulitis
Genetic component
 Certain HLA antigens are common
Viral – assc w/Mumps & Coxsackie B virus
Toxins – animals
Type 2: AKA non-insulin-dependent diabetes mellitus
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Accounts for 80-90% of patients
Onset is usually after age 30
Obesity – 80% at diagnosis
Normal or increased blood insulin
No anti-islet cell antibodies
Ketoacidosis is RARE
Strong genetic correlation – 60% have parent or sibling with it
Impaired pattern of insulin release – early often have excess absolute insulin
Target tissue resistance – defect in receptors and intracellular signal transduction
Glucose intolerance, hypertension, visceral obesity, microalbuminuria
Polyuria, weakness, infections
Somewhat preventable
Controlled via diet and exercise
17.E. Explain the criteria for diagnosis of diabetes mellitus (page 3 McDonald’s outline)
TYPE I
~abrupt onset, due to uncontrolled hyperglycemia (excess of glucose in blood)
SYMPTOMS
- GLUCOSURIA: excess glucose in urine
- POLYURIA: excess urine output, leads to dehydration and electrolyte loss.
- LOSS of CALORIES: leads to hunger
- WEIGHT LOSS
- MOBILIZATION OF FAT STORES and PROTEIN
- ACIDOSIS: breakdown of proteins leads to ketone production
- KETOACIDIC COMA: can lead to death
Symptoms lead to dehydration, so a patient will complain of excessive thirst. Also loss of
electrolytes so the patient may also complain of fatigue.
TYPE II
~much slower onset than type I.
SYMPTOMS
- GRADUAL WEIGHT LOSS
- POLYURIA
- WEAKNESS
- INFECTIONS (gangrene)
- DO NOT DEVELOP KETOACIDOSIS
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17.F. Explain pathogenesis of complications of diabetes mellitus for heart and blood
vessels, kidneys, eyes, and nervous system shown in Figures 17-11 and 17-17 (pages 648654 and page 4 McDonald’s outline)
[Insulin as commonly administered does not prevent complications, however, intensive insulin
therapy appears to delay onset and decrease severity of complications (especially retinopathy)]
Heart and blood vessels = Vascular Disease
1.
Macrovascular – accelerated atherosclerosis, early cerebral and myocardial
infarcts, lesions identical to non-diabetics
2.
Microvascular - poor wound healing, foot ulcers and gangrene
Kidneys = 20-40% develop renal failure, can also develop Diabetic glomerulosclerosis
Eyes =
1.
2.
3.
4.
Lesions of small vessels
Retinopathy
Blindness
Laser surgery
Nervous System = Generally not life-threatening; Can be peripheral, or can be autonomic (gut,
erectile impotency, bladder dysfunction)
Pathogenesis – the available experimental and clinical evidence suggests most complications of
DM result from metabolic derangements, mainly hyperglycemia
~can cause AGEs (irreversible advanced glycosilation end products)
~ can cause disturbances in the polyol pathway

glucose + NADPH + H+
sorbitol
dehydrogenase

sorbitol + NAD

results in intracellular osmotic gradient
sorbitol + NADP+
fructose + NADH + H+
~Activation of protein kinase C.
~Increased flux through the hexosamine pathway.
Coexistent HTN present with DM can contribute to atherosclerosis
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17.G. Explain who should be screened for diabetes, when, why, and how. (McDonald’s
PowerPoint)
Testing for diabetes should be considered in...
1.
Individuals 45 and older (every three years if normal).
2.
On younger individual (and with greater frequency) if they:
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Are obese (≥ 120% desirable body weight)
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Have a first-degree relative with diabetes
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Are members of a high risk ethnic population (African-American, Native American)
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Have delivered a baby weighing > 9 lbs or have been diagnosed with GDM
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Are hypertensive (≥ 140/90)
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Have an HDL cholesterol level ≤ 35 mg/dl and/or a triglyceride level ≥ 250 mg/dl
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On previous testing, had IGT or IFG
The OGTT or FPG test may be used to diagnose diabetes; however, in clinical settings the FPG test is
greatly preferred because of ease of administration, convenience, acceptability to patients, and lower
cost.
Good luck 
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