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Genetic and Pediatric DiseasesGenetic and Pediatric Diseases
PATHOLOGY
HSC 381/581
1
All diseases involve some changes in gene structure or
expression - Robbins Basic Pathology
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Genetic DiseasesGenetic Diseases
DefinitionDefinition::
y A pathological condition caused by an absent or defective gene
or by a chromosomal aberration is termed as a genetic disorder.
y Humans have 30,000 genes that can involve in changes to
their structure, causing diseases.
yy Hereditary disordersHereditary disorders diseases derived from parents
yy Familial disordersFamilial disorders diseases transmitted in gametes
through generations
yy Congenital disordersCongenital disorders diseases present at birth.
y Note:Some congenital diseases are not genetic and not all
genetic diseases are congenital
2
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The GeneThe Gene
3
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MutationsMutations
y Mutation implies permanent changes in the DNA;
y Mutations affecting germ cells transmitted to progeny;
mutations affecting somatic cells not transmitted but causes
cancers or malformations
Common types of gene mutations:
y Point mutations (missense mutations) substitution of a
single nucleotide base resulting in replacement of single amino
acid in protein molecule. e.g. sickle cell anemia
y Frameshift mutation insertion or deletion of one or two
base pairs; changes DNA reading frame e.g.Tay-Sachs disease
y Trinucleotide repeat mutations amplification of 3
sequential nucleotides e.g. Fragile X syndrome 4
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Categories of Genetic DisordersCategories of Genetic Disorders
Disorders occur due to:
1) Mutant genes of large effect
MendelianMendelian disordersdisorders e.g. storage diseases; from single genemutations.They are hereditary and familial.
2) Multifactorial inheritancedue to both genetic and environmental influences
e.g. hypertension, diabetes mellitus
3) Chromosomal aberrations
due to numeric or structural aberrations. e.g. Downssyndrome,Turners syndrome, Jacobsen syndrome
Single gene disorders with nonclassic inheritance
- Due to mutations in mitochondrial DNA, genomic imprinting, or
due to triplet repeat mutations. e.g. Angelman syndrome 6
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Father of GeneticsFather of Genetics
7
Gregor Johann Mendel (1822 1884)
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MendelianMendelian DisordersDisorders(Single(Single--Gene Defect)Gene Defect)
FollowsMendelian pattern ofinheritance. Three patterns:
1) Autosomal Dominant disorders
2) Autosomal Recessive disorders
3) X-linked disorders
AutosomalAutosomal DominantDominant:
Manifests in heterozygous states;mutation of one allele
At least one parent is affected,males/female; both can
transmit Enzyme proteins not affected but receptors and
structural proteins are involved; onset late sometimese.g. Marfans syndrome, Achondroplasia, Huntingtons disease
If an affected person marries an unaffected individual, every
child has 50% chance of inheriting the disorder 8
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AutosomalAutosomal RecessiveRecessive:
Largest group; both copies (alleles) are mutated;
a) Parents asymptomatic (trait); but children show diseaseb) Siblings have 1 in 4 chance of being affected (25% risk)
c) Possibility more in consanguineous marriage
d) Males and females equally affected; early onset
e) It involves enzyme proteins.e.g. Cystic Fibrosis, Wilsons disease, Sickle cell anemia
XX--linkedlinked:
Sex-linked disorders; all are X-linked ; no Ys yet most are recessive
transmitted by heterozygous females to their sons,
affected males do not transmit to sons but daughtersbecome carriers
e.g. Hemophilia, Duchenne muscular dystrophy 9
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SomeSome MendelianMendelian DisordersDisorders
y Adult polycystic kidney disease
y Familial hypercholestrolemia
y Hereditary hemorrhagic telangiectesia (Osler- Weber-
Rendu syndrome)y Hereditary spherocytosis
y Huntingtons disease
y Marfans syndrome
y Neurofibromatosis (von Recklinghausens disease)
y Tuberous sclerosis
y Von Hippel- Lindau disease
10
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Mutations of structural proteinsMutations of structural proteins
MarfanMarfan SyndromeSyndrome
Autosomal dominant disorder of connective tissue affecting
fibrillin,found in ECM, a glycoprotein secreted by
fibroblasts; prevalence 1 in 20,000; 75% familial
Deficiency of fibrillin can production of cytokineTGF-
(transforming growth factor)
Clinical manifestations are seen mainly in:
*Skeleton long legs, arms, fingers (arachnodactyly); high
arched palate, kyphoscoliosis, pectu
s excavatum
or pigeonchest deformity, hyperextensible joints
*Eyes subluxation of lens
*CardiovascularAneurysms, aortic dissection, aortic
incompetence,mitral valve prolapse, congestive cardiac
failure; death can occur due to aortic rupture 11
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12
Marfan Syndrome
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EhlersEhlers-- DanlosDanlos SyndromesSyndromes (EDSs)(EDSs)
y Single gene disorder but can show all 3 Mendelian patterns
y Characterized by defects in collagen synthesis or structure;
six variants of the disease are presented
y Skin, ligaments and joints affectedClinical Features:
y Extraordinarily stretchable and fragile skin
vulnerable to trauma
Produce gaping wounds, show poor wound healing
y Hypermobile joints
y Internal complications like rupture of colon or large
arteries, diaphragmatic hernias, rupture of cornea and
retinal detachments due to collagen deficiency 13
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14
Ehlers-Danlos Syndromes
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Mutations of receptor proteinsMutations of receptor proteins
FamilialHypercholesterolemiaFamilialHypercholesterolemia
y Most common mendelian disorder; 1 in 500
y Autosomal dominant disorder;mutations in genes for LDL
receptor
y Results in impairment of intracellular LDL transport andcatabolism; in addition, there is excessive synthesis of LDL;
this leads to hypercholesterolemia; best treated by statins
y Hypercholesterolemia leads to premature atherosclerosis
and xanthomasy Heterozygotes are symptomless until adulthood; only show
elevated serum cholesterol,es risk for atherosclerosis,CAD
y H
om
ozygotes greater risk, die by age 15 du
e to MI
15
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Mutations of enzyme proteinsMutations of enzyme proteins
PhenylketonuriaPhenylketonuria (PKU)(PKU)
y Common in Caucasians and esp. Scandinavians
y Autosomal recessive disorder
y Show inability to convert phenylalanine to tyrosine due to
lack of phenylalanine hydroxylasey Clinical features
severe mental retardation
inability to walk or talk, suffer from seizures
hypopigmentation of hair and skin (musty odor); eczemay Avoided by restriction of phenylalanine in diet during early
life
y Clinically normal pregnant females with unrestricted dietgive birth to mentally retarded children (maternal PKU);also increases risk of spontaneous abortion 16
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PhenylketonuriaPhenylketonuria
17
Avoid high
protein
foods, such
as milk, dairy
products,
meat, fish,chicken,
eggs, beans,
and nuts
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GalactosemiaGalactosemia
y Autosomal recessive; affects 1 in 30,000
y Show inability to convert galactose to glucose due to lack
of a transferase enzyme
y Clinical features:Mainly affects liver, brain, eye
y Infancy
Develop vomiting, diarrhea from birth; fail to thrive;
jaundice and hepatomegaly (fatty liver) after 1 week;
later aminoaciduria, chances of E.coli sepsis
y Older children/adults (without appropriate therapy)
cataract, speech defects, neurological deficits, cirrhosis
liver, ovarian failure
y Clinical and morphological changes prevented by early
avoidance of galactose in diet for first 2 years of life 18
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LysosomeLysosome Storage DiseasesStorage Diseases
y Due to lack of lysosomal enzymes
y Resultant accumulation of substances like, sphingolipids
and mucopolysaccharides within lysosomes as a result of
ingestion by phagocytosis
y Autosomal recessive; 40 lysosomal storage diseases
present, each lacking specific lysosomal enzymes
y Affects infants and young children
y Show hepatosplenomegaly, cellular dysfunctions (due tomacrophage activation, cytokines release), CNS neuronal
damage
19
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TayTay--Sachs DiseaseSachs Disease (gangliosidosis)(gangliosidosis)
y Inability to metabolize GM2 gangliosides due to deficiencyof hexosaminidase A, a lysosomal enzyme
y Common among Ashkenazi Jews
y Causes accumulations in brain cells; affected cells appear
swollen & foamy, with whorled lysosomes; also seen inspinal cord, peripheral nerves
y Infants appear normal at birth with motor weakness
beginning at 3-6 months of age
mental retardation,
blindness,
neurological dysfunction;
death follows within 2-3 yrs.
20
Lysosome Storage Diseases
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NiemannNiemann--Pick Disease:Pick Disease:Types A & BTypes A & B
Caused by deficiency of sphingomyelinase enzyme,
accumulation of sphingomyelin in phagocytes and nerve
cells
Affected organs are spleen, liver, bone marrow, lymph nodes
and lungs; leads to visceromegaly, neurological dysfunction
and death by 3 years of age
Type B has organomegaly but no neuronal damage
Type C: (NPC) More common than A or B, defect in
cholesterol transport; resulting in accumulations of
cholesterol and gangliosides
Affected children have ataxia, gaze palsy, dystonia, dysarthria,
and psychomotor regression 21
Lysosome Storage Diseases
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GaucherGaucher DiseaseDisease
y Accumulation of glucosylceramide in
phagocytes due to lack of enzyme
glucosylceramidase
y Phagocytes transform to Gaucher cells in liver, spleen,bone marrow, and lymph nodes
y Hepatosplenomegaly, bone erosion result
Type 1 no neurological involvement, have long life;
common in Ashkenazi JewsType II,Type IIIneurological involvement dominant,Type
II severe (short life span),Type III is milder
Treatment Enzyme replacement by infusing purified
enzym
e, drugs, gene therapy 22
Lysosome Storage Diseases
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GaucherGaucher DiseaseDisease
23
A typical Gauchercell (a lipid
laden macrophage) in the
bone marrow.
The 14-year old girl in this
photo has Gaucher
Disease (GD).
Lysosome Storage Diseases
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MucopolysaccharidosesMucopolysaccharidoses
Due to defective degradation and accumulation of
mucopolysaccharides within lysosomes in liver, spleen,
heart, blood vessels, brain, cornea, joints.
[Mucopolysaccharides (dermatan sulphate, chondroitin
sulphate) form part of ECM]
Patients have course facial features, corneal clouding, joint
stiffness and mental retardation
Type Ior Hurlers syndrome severe, death in childhood
(6-10 yrs) due to cardiovascular complications
Type IIor Hunter syndrome milder course, X-linked;
absence of corneal clouding
24
Lysosome Storage Diseases
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MucopolysacccharidosesMucopolysacccharidosesType 1Type 1
25
Photograph showing coarse facies, corneal clouding and large mouth.
Lysosome Storage Diseases
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Glycogen Storage DiseasesGlycogen Storage Diseases
Accumu
lation of glycogen due to deficiency of enzy
me in glycogensynthesis or degradation
1. Hepatic type
- Results in hepatomegaly and hypoglycemia e.g. vonGierkedisease,most important, due to glucose-6-phosphatase
deficiency,2. Myopathic type
Muscle weakness, cramps,myoglobinuria, failure to induceed lactic acid after exercise (Type V McArdle disease)
3. Type II
Pompe disease (variant - is a form of lysosomal storagedisease), deposition of glycogen in every organ,cardiomegaly prominent
Type IV
Brancher glycogenosis (in liver, heart and muscles)
26
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von Gierke disease Pompe diseasevon Gierke disease Pompe disease
27
This is the heart of a 9
month old child who died
of congestivefailure. The
ventricularwalls are
eno
rmously thick
en
ed.
Liverwith a pale, bulging surface,
filled with glycogen in von Gierke's
disease due to lack of glucose-6-
phosphataseenzyme
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Cytogenetic DisordersCytogenetic Disorders
One in 200 newborn infants show some alterations in numberor structure of chromosomes
Numeric Abnormalities
y May affect autosomes or sex chromosomes.
y The normal chromosomal count is 46, that is 2n=46; 23 (n-haploid number) from each parent (22 autosomes and 1 sexchromosome).
y Euploid exact multiple of haploid number (2n)
y Polypoid increasing multiples, i.e. 3n or 4n; results in
spontaneous abortiony Aneuploid not an exact multiple of n
y Gametes then have an extra chromosome (n+1) or one less(n-1); Fertilization of such gametes by normal gametes result
in 2n+1 (Trisomy) or 2n-1(monosomy) 28
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Structural AbnormalitiesStructural Abnormalities
These result fro
mchro
moso
mal breakage followed by loss orrearrangement ofmaterial.The different loss/ rearrangements
are:
yy TranslocationTranslocation
yy IsochromosomesIsochromosomes
yy
DeletionDeletionyy InversionsInversions
yy Ring chromosomesRing chromosomes
Chromosomes:
Described as having short arm (p=petit) and long arm (q)
Each arm then divided into numbered regions (1,2,3.) fromthe centromere outward
Each region has bands that are numerically arranged
Thus 2q34 = chro
moso
me 2, long ar
m, region 3, band 4 29
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TranslocationTranslocation
y Is the exchange of
chromosomal segmentsbetween non-homologous
chromosomes.
y Denoted by t
y E.g. Downs syndrome,
t (14q:21q)
IsochromosomeA transverse rather than a
longitudinal division occurs.One arm is lost and the
remaining one duplicates
Results in new chromosome
with two short arms or two
long arms 30
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DeletionDeletion
y Is most often absence of a
portion of a chromosome,
although it can be loss of an
entire chromosome.
y Denoted by - (minus)
y p- short arm
y q- long arm
y E.g. cri du chat 46XY, 5p-
InversionIs reunion of a chromosome at
two points, in which the
internal fragment is reinserted
in an inverted position. 31
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SexChromosomesSexChromosomes
y Extreme karyotype deviations in sex chromosomes are
compatible with life
y This is believed to be due to the Lyonization (inactivation)
of X chromosome and scant genetic information carried
by the Y chromosomes.
y All but one X chromosome is inactivated and so a 48,
XXXX female has only one active X chromosome
y The inactive X, forms a discrete body within the nucleus
called a Barr body (Sex chromatin)
y Normal females (XX) will have one Barr body
y Normal males (XY) or (XO) individuals will have no Barr
bodies.
32
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In summaryIn summary
Chromosomal disorders occur:
y Due to absence (deletion,monosomy), excess
(trisomy),or abnormal arrangements (translocations)
of chromosomes
y Loss effects more severe defects than gain
y Sex chromosome abnormalities are better tolerated than
autosome abnormalities
y Sex chromosome disorders are subtle and sometimes are
not detected at birth e.g. infertility
y Usually chromosomal disorders are the result ofde novo
changes.Hence if parents are normal, risk of recurrence in
siblings is low; exception Down syndrome
33
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Disorders ofDisorders of autosomesautosomes
TrisomyTrisomy 21 (Down Syndrome)21 (Down Syndrome)
y Causes- Meiotic non-disjunction of chromosome 21, results in
extra chromosome count (47; 2n+1)
y Mostly, parents are normal; Incidence increases with maternal age
y In a few (familial form), translocation occurs from chromosome 21
to chromosome 22 or 14 (no extra)
y Is marked by:
Severe mental retardation
Large forehead, broad nasal bridge, wide-spaces eyes, epicanthal
folds, large protruding tongue Brushfields spots (white spots on the iris)
Short, broad hands with curvature of the fifth finger
Simian crease, a single palmar crease
Unu
su
ally wide space between 1st and 2nd toes 34
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Downs SyndromeDowns Syndrome
35
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36
HandHand - features
short and b
roadhands,
Clinodactyly
(curving), with a
singleflexion
crease (20%) of
littlefinger, andhyperextensible
finger joints.
FootFoot - space
between great toe
(big) and se
condtoe is increased.
HipHip - acquired hip
dislocation (6%).
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ComplicationsComplications
y Congenital heart disease (40%), VSD
y Acute leukemia (20x) ALL
y Increased susceptibility to infection
y Median age at death 47 years; usually due tocardiac or infectious causes
y Patients surviving to middle age, proceed to
Alzheimers disease
y Many develop frank dementia
37
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y There is an abnormal transverse crease across the palm of eachhand seen here.Together with the single flexion crease on the 5thdigit, this is quite typical for trisomy 21 (e.g.,47,XX,+21).
38
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Edwards syndromeEdwards syndrome
y Results from nondisjunction resulting in trisomy 18
y Mental retardation, prominent occiput,
microganthia, low set ears, short neck, rocker-
bottom feet, flexion deformities of the fingers and
congenital heart disease.
39
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PatausPataus syndrome (syndrome (trisomytrisomy 13)13)
y Is manifested by mental retardation,
microcephaly,micropthalmia, brain
abnormalities, cleft lip and palate, polydactyly,
rocker-bottom feet, umbilical hernia, renal
defects and congenital heart disease.
40
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Cri du chat (cry of a cat)Cri du chat (cry of a cat)
((LeLe JeunesJeunes syndrome)syndrome)
y Is caused by deletion of the short arm of
chromosome 5 (5p-)
y Sever mental retardation,microcephalyand unusual catlike cry.
y LBW, round face, hypertelorism, low set
ears and epicanthal folds.
42
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Abnormalities of sex chromosomesAbnormalities of sex chromosomes
Klinefelters syndrome
y Male hypogonadism, with 2 X and 1 or more Y
chromosomes e.g. 47, XXY
y Single Barr body on buccal smeary Advanced maternal age or irradiation of either parents
may be contributing factors
y Features:Atrophic testis, tall stature, an eunuchoid
appearance with gynecom
astia,m
ental retardation (m
ild)y Decreased testosterone production and increased
pituitary gonadotropins.
y Have associated disorders like cancers (breast) or
autoimmune diseases (SLE)43
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Turners syndrome (Turners syndrome (45,X45,X))
y Hypogonadism in females; Is most common cause ofprimary amenorrhea.
y No Barr body
y Not complicated by mental retardation
y Ovaries are replaced by fibrous streaks
y Decreased estrogen production and increased pituitary
gonadotropins
y Infantile genitalia and poor breast development
y Short stature, webbed neck, shield like chest with widelyspaced nipples, high-arched palate, and a wide carrying angle
of the arms (cubitus valgus).
y Bicuspid aortic valve, coarctation of aorta, horse-shoe kidney
y Lymphadema of extremities, cystic hygroma 44
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KlinefeltersKlinefelters Syndrome Turners SyndromeSyndrome Turners Syndrome
45
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Single gene disorders withSingle gene disorders with nonclassicnonclassic
inheritanceinheritance
TripletTriplet--Repeat MutationsRepeat Mutations
Fragile X syndromeFragile X syndrome
y Is an important cause of familial mental retardation second
in frequency only to Down syndrome.
y Defect on long arm of chromosome X repeatingsequences of 3 nucleotides
y Usually affects males (but 20% ofmales are only carriers;
can develop neurodegenerative syndrome); females are
usually carriers (b
ut 50% have
mental retardation, 30%ovarian failure)
y Mental retardation, long face, large mandible, and large
everted ears, bilateral macro-orchidism
y Results frommutation of FMR1 gene46
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47
Fragile X syndrome
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Genomic ImprintingGenomic Imprinting
Usually homologous genes from both parents are functionally
identicalFunctional differences are seen sometimes, arising from epigenetic
process and this is called genomic imprinting.
Some genes are silenced/inactivated during this process
Imprinting first occurs in ovum and sperm and then transmitted to
all somatic cells; best seen in:
Prader-Willi Syndrome:
y Mental retardation, short stature, hypotonia, obesity, small handsand feet, hypogonadism.
y Deletion of band q12 in long arm of chromosome 15 from thefather.
Angelman Syndrome:
y Deletion of same chromosomal region frommother. Ataxia,seizures, inappropriate laughter in addition to mental retardation.Happy puppet Syndrome. 48
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Pediatric DiseasesPediatric Diseases
49
Infancy: Covers first year of life highest risk of mortality
Neonatal period: Covers first 4 weeks of life - most dangerous andsusceptible period
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TermsTerms
Conge
nital anomalies: Structural defects present atbirth; Extrinsic or Intrinsic
Malformations intrinsic abnormal development;
usually multifactorial e.g. cleft lip, cleft palate,
polydactyly
Disruptions due to extrinsic disturbance in
development, not heritable, no recurrence risks e.g.
Amniotic bands, Thalidomide baby, diabetic
embryopathy
Deformations extrinsic disturbance, usually abnormalbiomechanical forces e.g. uterine constraints like
small uterus, multiple fetuses, abnormal presentations
Sequence multiple anomalies from secondary effects
of a single local aberration e.g. Potter sequence
50
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Disruptions SequenceDisruptions Sequence
Thalidomide BabyThalidomide Baby Potter sequencePotter sequence
51
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DisruptionsDisruptions -- Amniotic band syndromeAmniotic band syndrome
52
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Polydactyly SyndactylyPolydactyly Syndactyly
53
Malformations
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MalformationsMalformations -- Cleft lip and palateCleft lip and palate
54
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Causes of Pediatric DiseasesCauses of Pediatric Diseases
Genetic: Chrom
osom
al anom
alies e.g. Downs,Tu
rners,Klinefelters syndromes
Environmental: Influences like e.g. Rubella embryopathy, fetal
alcohol syndrome, diabetic embryopathy, drugs -thalidomide,
anticonvulsants, warfarin
Multifactorial: Interaction of environmental influences with two
or more genes e.g. cleft lip and palate, neural tube defects
Timing of prenatal insult has profound impact.
First 3 weeks after fertilization death and abortion or
recovery without damage
Between 3 -9 weeks susceptible to teratogenesis
Peak sensitivity between 4th and 5thweeks.
After 9 weeks susceptible to growth retardation and injury to
formed organs 55
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PerinatalPerinatal InfectionsInfections
Transcervical :Ascending infections from vagina; acquired
in utero or during birth e.g. bacterial and viral infections.
Fetus acquires infection by inhaling infected amniotic fluid
into lungs. e.g. pneumonia, sepsis,meningitis
Transplacental:Hematologic, by crossing the placenta,
occurs during gestation or at the time of delivery. e.g.
parasitic, viral infections, hepatitis B,HIV
TORCH Infections:Toxoplasma(T); Herpes (H);
Rubella (R); Others (O)
CMV (C);56
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PrematurityPrematurity
y Gestational age less than 37 weeks
y Infants weigh less than normal (
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Respiratory Distress Syndrome (RDS)Respiratory Distress Syndrome (RDS)
y Contributory factors of respiratory distress
x excessive sedation ofmother
x fetal head injury, aspiration
x cord around the neck
x diabetic mother
x cesarean section before onset of labor
x twin gestation
x hyaline membrane disease (RDS)
y RDS is usually a disease of premature infants
y Occurs in 60% of infants born preterm (
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Role of SurfactantRole of Surfactant
59
=Surface active agent in water=Surface active agent in water
Secreted by some alveolarepithelialSecreted by some alveolarepithelial
cells (typeIIcells (typeII pneumocytespneumocytes))
Similarto soapSimilarto soap
Lowers surface tensionLowers surface tension
Made of phospholipids,Made of phospholipids,proteins, and ionsproteins, and ions
PhospholipidPhospholipid
dipalmitoylphosphatidylcholinedipalmitoylphosphatidylcholine
It reduces the surface tension, thus decreasing the pressure to
keep the alveoli open. Lack of it leads to atelectasis.
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NecrotizingNecrotizing EnterocolitisEnterocolitis
y Occurs in premature infants (birth weight
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NecrotizingNecrotizing EnterocolitisEnterocolitis
61
The plain abdominal filmshows air in the portal
vein, air in the bowel
walls, and a large
pneumoperitoneum
[subdiaphragmatic freeair, perihepatic free air,
double wall sign (blue
arrows), triangle sign
(green arrows), andfalciform ligament (red
arrow)].
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Sudden Infant Death Syndrome (SIDS)Sudden Infant Death Syndrome (SIDS)
y
Death under 1 year of age with unexplained cause;usually between 2-4 months of age
y Usually occurs in sleep, hence called crib death or cot
death
y
Delayed developm
ent of arousal and cardiorespiratorycontrol, the best hypothesis; hence low response to
stimuli like hypercarbia, hypoxia, thermal stress
Potential environmental causes prone sleeping
position, soft bedding
Morphology: Petechiae on thymus, pleura and epicardium
62
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FetalFetal HydropsHydrops
Refers to accumulation of edema fluid in fetusImmune Hydrops:
y Antibody-induced hemolytic disease in newborn due to
ABO or Rh (D) incompatibilty between mother and fetus.
y Due to seepage of fetus RBCs into maternal circulationduring last trimester causing antibodies to develop in
mother.These antibodies can traverse placenta initiating
hemolysis in fetus . Rh hemolytic disease is uncommon in
first pregnancy.
y Results in progressive anemia, cardiac failure, edema;The
severe anemia (Erythroblastosis fetalis) is treated by
exchange transfusion
y Prevented by anti-D globulin shots to mothers63
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Nonimmune Hydrops
Associated with cardiovascular defects, chromosomal
anomalies and fetal anemia resulting in intrauterinecardiac failure and hydrops. e.g inTurners syndrome,
mucopolysaccarridosis type VII, Parvovirus infection,-
thalassemia, cystic hygroma
________________________________________Diagnosis by testing Rh antibody titers in mother (rising
titer diagnostic)
Positive Coombs test in fetal cord blood
Management: Antenatal exchange transfusion, anti-Dglobulins to mother can prevent immune hydrops in
subsequent pregnancies; postnatal phototherapy for
associated jaundice
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Immune hydrops
Erythroblastosis Fetalis
Fetal Hydrops
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Cystic FibrosisCystic Fibrosis
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Most common lethal genetic disease of Caucasians;uncommon among Asians and African Americans;
autosomal recessive
Widespread epithelial disorder affecting fluid
transport in exocrine glands, in GI, respiratory andreproductive tracts
Results in increased viscosity of mucous and
increased sodium and chloride concentrations in
sweat and tears. Leads to recurrent lung infections and pancreatic
insufficiency
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Cystic FibrosisCystic Fibrosis
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Clinical manifestations:
Chronic pulmonary disease
Pancreatic insufficiency Meconium ileus
Liver involvement steatosis, cirrhosis
In males azoospermia, infertilty with bilateral
absence of vas deferens
Clinical symptoms:
y Malabsorption symptoms large, foul stools,
abdominal distension, persistent diarrhea, poor weightgain, avitaminosis A,D,K
y Cardiorespiratory chronic cough, persistent lung
infections, COPD, Cor pulmonale
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PediatricTumorsPediatricTumors
BenignTumors:HemangiomasHemangiomas most common, in the skin (face, scalp)
e.g. port-wine stains
May spontaneously regress or enlarge;merely of cosmetic
significanceLymphangiomasLymphangiomas characterized by cystic or cavernous
spaces containing pale fluid, surrounded by lymphoid
aggregates; occur on skin or deeper regions of neck,
axilla,mediastinum, and retroperitoneum
SacrococcygealSacrococcygeal teratomasteratomas:Most common germ cell
tumor; benign but 12% turn malignant
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PortPort--wine stainswine stains SacrococcygealSacrococcygeal teratomateratoma
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MalignantTumorsMalignantTumors
Neuroblastoma:Tumors of the sympathetic ganglia andadrenal medulla.
They demonstrate spontaneous regression and
spontaneous/or therapy-induced maturation
Prognosis depends on staging of tumor (4S beingexcellent) and age (children below 1 year of age better
outlook)
Present with fever, weight loss, protuberant abdomen
(ascitis), hepatomegaly, bone pain.
Can metastasize to liver, lungs, and bone marrow, skin
(blueberry muffin baby)
Secrete catecholamines; its metabolites (VMA,HVA) are
used for screening71
Bl b ffi b bBl b ffi b b
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Blueberry muffin babyBlueberry muffin baby
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Neuroblastoma. This tumor is composed of
small cells embedded in a finely fibrillar
matrix (neuropil). AHomer-Wright pseudo-
rosette (tumor cells arranged concentrically
around a central core of neuropil) is seen in
the upperright corner.
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RetinoblastomaRetinoblastoma
y Most common malignant eye tumor of childhood,
congenital,multifocal, bilateral
y Undergoes spontaneous regression
y Occur as familial and sporadic patterns
y Familial retinoblastoma have increased risk for
developing osteosarcoma
y Maymetastasize to CNS, skull, bones, and lymph nodes
y Patients have poor vision, strabismus, whitish blue pupil
(cats eye reflex), eye pain
y Treatment: Enucleation, chemo & radiotherapy
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RetinoblastomaRetinoblastoma
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RetinoblastomaRetinoblastoma
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cats eyereflex
Retinoblastoma.A, Note poorly
cohesive tumor in retina
abutting optic nerve. B, Higher
powerview showing Flexner-
Wintersteinerrosettes (arrows)
and numerous mitotic figures
Wil Wil TT
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WilmsWilmsTumorTumor
y Known as nephroblastoma, occurs in children between2 and 5 years
y Three congenital malformations are associated with riskof developing Wilms tumor
a) WAGR Syndrom
e (33% chance)b) Denys-Drash Syndrome (DDS) (~90% chance)
c) Beckwith Wiedemann Syndrome (BWS)
y Presents as large, solitary, well-circumscribed mass
Symptoms:Abdominal pain, fever, hematuria or intestinalobstruction
Prognosis: Excellent with surgery and chemo
Diffuse anaplasia, with extra-renal spread has bad prognosis
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WilmsTumorWilmsTumor