Patho 2.1 - Genetic and Pediatric Diseases

8/3/2019 Patho 2.1 - Genetic and Pediatric Diseases

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Genetic and Pediatric DiseasesGenetic and Pediatric Diseases

PATHOLOGY

HSC 381/581

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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

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The GeneThe Gene

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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

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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

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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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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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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

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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

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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

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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.

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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



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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



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GaucherGaucher DiseaseDisease

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A typical Gauchercell (a lipid

laden macrophage) in the

bone marrow.

The 14-year old girl in this

photo has Gaucher

Disease (GD).



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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

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MucopolysacccharidosesMucopolysacccharidosesType 1Type 1

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Photograph showing coarse facies, corneal clouding and large mouth.



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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)

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von Gierke disease Pompe diseasevon Gierke disease Pompe disease

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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.

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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

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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

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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

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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).

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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.

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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.

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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.

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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

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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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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

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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

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Disruptions SequenceDisruptions Sequence

Thalidomide BabyThalidomide Baby Potter sequencePotter sequence

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DisruptionsDisruptions -- Amniotic band syndromeAmniotic band syndrome

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Polydactyly SyndactylyPolydactyly Syndactyly

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Malformations


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MalformationsMalformations -- Cleft lip and palateCleft lip and palate

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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

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=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

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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

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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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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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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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Patho 2.1 - Genetic and Pediatric Diseases