Connective tissue

Rheumatology- Dr Thikra

diseases
- Common Rheumatologic Diseases slides- 2

- ARF and endocarditis slides - 104

Dr. Dhikra Nabil
- chromosomal abnormalities slides - 167
Connective tissue
diseases
Dr. Dhikra Nabil
 Connective tissues

Two proteins:
1. Collagen: tendons, e
ligaments, skin, cornea, cartilage, bone,
-

and blood vessels. -

2. Elastin: ligaments and skin

 Connective tissue diseases
• Rheumatoid Arthritis(RA)
• Scleroderma
• Granuolomatosis with polyangiitis
• Chrug- Strauss syndrome
• Systemic Lupus Erythematosus (SLE)
• Microscopic polyangiitis(MPA)
• Polymyositis/ dermatomyositis
• Mixed Connective Tissue Disease (MCTD)
• Undifferentiated connective tissue diseases
 Causes

• Genetics -
• Environmental ~
 Arthritis
2

• Swelling or effusion, or presence of ⑧

two of the
following:
• Limitation of range of motion
• Tenderness or pain of motion
• Increased heat in the joint

• A manifestation of several disorders

 Review of system in the differential diagnosis of
childhood joint pain and swelling

Dermatologic SLE Malar rash and hair

loss
Dermatomyositis Gottron's papules
Systemic JIA Evanescent pink
macular rash
HSP Lower extremity
purpuric lesions
Ophthalmologic Oligoarthritis or Asymptomatic
psoriatic JIA chronic anterior
uveitis
Enthesitis related Acute
arthritis symptomatic
uveitis (pain,
redness)
Kawasaki disease Conjunctival
injection without
discharge
Sjogren's Dry eyes with
syndrome keratitis
Oral SLE Painless oral
ulcers on palate
Behcet Disease Large extremely
painful oral ulcers
Respiratory CF or Recurrent pneumonia
immunodeficiency
Wegener's Destructive upper
granulomatosis tract lesions
SLE or systemic JIA Pleuritis
SLE or scleroderma Interstitial lung
disease
Churg-Strauss Eosinophilic
syndrome pneumonia
Cardiovascular ARF or endocarditis New heart murmur
SLE, systemic JIA, or Pericarditis
ARF
SLE or scleroderma Raynaud
phenomenon
Takayasu arteritis Absent pulses
Gastrointestinal IBD, SLE, or Weight loss or
vasculitis poor growth

IBD Diarrhea and

abdominal pain

Reactive arthritis Preceding

infectious
gastroenteritis

HSP Intermittent
colicky abdominal
pain

Genitourinary Gonococcal Pustular urethritis

arthritis or cervicitis

Reactive arthritis Non-gonococcal

urethritis

Behcet disease or Large painful

IBD genital ulcerations
Hematologic SLE or Hemolytic anemia
hemoglobinopathy
(eg, SCD)
SLE Pancytopenia
Bleeding disorders Hemarthrosis
Neurologic SLE Seizures and
psychosis
SLE or fibromyalgia Difficulty
concentrating
SLE, vasculitis, or Stroke
hypercoagulability
Vasculitis Asymmetric
polyneuropathy
Dermatomyositis and Proximal muscle
polymyositis weakness
 Classification of childhood arthritis

• American College of Rheumatology ( ACR)

• European League Against Rheumatism ( EULAR)
• International League of Associations for
Rheumatology ( ILAR)
 Rheumatic diseases

defined by the constellation of results of the physical

examination, autoimmune marker and other serologic
tests, tissue pathology, and imaging.
-JIA
-SLE
- JUVENILE DERMATOMYOSITIS
Juvenile Idiopathic
Arthritis (JIA)
Juvenile Idiopathic Arthritis (JIA)

• Is a common, rheumatic disease of children and

a major cause of chronic disability.
• It is characterized by a synovitis of the
peripheral joints manifesting in soft tissue
swelling and effusion.
 JIA classification
-
re
• Systemic onset JIA (SoJIA) need de
a
we
arthritis with fever and rash.

ge
• Oligoarthritis
< 5 joints in the first 6 months of illness.
• Polyarthritis
↳,
gyb"Y"
7

> 4 joints in the first 6 months of illness. · E -

i arr
I' ·

I
-
 "sdisigs- "85 gsin
ofanother schools daficate -A

↓
-
&
2
P
inflathe
mmation
of

A
at
site
insertion
for
do
a -
~
o

⑬
I
• Eighteen-month-old
-

girl with arthritis in her

right knee. Note the
flexion contracture of
I-
9
that knee. X ↓
s swalin ostwete
minimpaine
P ize
e
A general lit
a
-
is
-
Criteria for the Classification of Juvenile Rheumatoid Arthritis

Age at onset: <16 yr

Arthritis (swelling or effusion, or the presence of 2 or more of the following signs:

limitation of range of motion, tenderness or pain on motion, increased heat) in ≥1 joints

Duration of disease: ≥ 6 wk

Onset type defined by type of articular involvement in the 1st 6 mo after onset:

Polyarthritis: ≥5 inflamed joints

Oligoarthritis: ≤4 inflamed joints

Systemic disease: arthritis with a characteristic intermittent fever

Exclusion of other forms of juvenile arthritis

 ETIOLOGY.

• Unknown etiology
-

&
- -

• Autoimmune disease AND Genetic susceptabilty factors

=>
- -

-I

• Environmental (infection,trauma,and stress).

-

• --
Possible external triggers include viruses (parvovirus B19,
rubella, Epstein-Barr virus),
• Host hyperreactivity to specific self antigens (type II
collagen), and enhanced T-cell reactivity to bacterial or
mycobacterial heat shock proteins.
 EPIDEMIOLOGY.

• Describe in all races and geographical areas

• The incidence of JRA is ≈13.9/100,000
children/yr among white children ≤15 yr of age,
with a prevalence of ≈113/100,000 children.
• Female predominance 2:1
⑰

inflammmy incidence
in temale 1

-
-
 CLINICAL MANIFESTATIONS

Initial symptoms
• subtle or acute
-

• morning stiffness
• easy fatigability, particularly after school in the early afternoon
• joint pain

3
-

• joint swelling
-

• Joint stiffness
-

• limp
-

• Restriction of movement
-

• Eye symptoms
-

• Systemic manifestation .
-
 Free state
flexure
said
st
redness

L
S anterior
par ⑧

very
-
 Oligoarthritis (pauciarticular
gi,586915
disease)
55 6I!

&
5 5 i,
&
• Persistent vs. extended
- - -

• predominantly affects the joints of the lower main got e

extremities, such as the knees and ankles . I

-

• Isolated involvement of upper extremity large unityt

i 3
joints is not characteristic of this type of onset. waterre
- -

• Involvement
⑧ - of the hip is almost never a
presenting sign of JRA.
--I I-
Tr
-
ult
is
~I
s
I
· sis
⑧
 ieee
S

->
 Polyarthritis

• is generally characterized by involvement of

both large and small joints ?
-
of both upper
-

and lower extremities .

-

• As many as 20–40 joints may be affected in

the more severely involved child, although
inflammation of only ≥5 joints is required as
a criterion for classification of this type of
onset.
• Rheumatoid factor (+ve / –ve)
 • Rheumatoid nodules on the extensor surfaces of the
elbows and over the Achilles tendons, while unusual,
lower are associated with a more severe course
⑳ -awis
undersi
-ze• Micrognathia reflects chronic temporomandibular
~

&

joint disease.
Facet
• Cervical spine involvement of the apophyseal joints
-

occurs frequently with a risk of atlantoaxial

- -

subluxation and potential neurologic sequelae.

e
-
 O-
rg
microgram.
inte
on
malleolus
&
->

oper
 -e Zit,

--
daily
-16.
//

O -

,gis Some
// -
/ and
I, 9

Serositis refers to inflammation of the serous

- tissues of the body, the tissues lining the
lungs (pleura), heart (pericardium), and the
inner lining of the abdomen (peritoneum) and
organs within
11 • Child with pericardial

⑧
- -

effusion due to systemic

-

onset juvenile idiopathic

arthritis (JIA).
water • serositis (pericarditis)
--

bottle
sign
Systemic juvenile idiopathic arthritis
(JIA) rash
• Salmon-colored, erythomatous non pruritic macules
 DIAGNOSIS

• Based on a history compatible with

-
inflammatory joint disease and a physical
-

examination that confirms the presence

of arthritis
• No one pathognomonic finding
• The classic intermittent fever , the typical
rash and objective -
arthritis highly
suggestive of systemic-onset JRA.
 Laboratory abnormalities

• elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP),

• leukocytosis,
• thrombocytosis, t
•
I
anemia of chronic disease.
-
~
An -econgest
-
• anti-cyclic citrullinated peptide (CCP) antibody has very high specificity for
Enthesitis is inflammation
of the entheses, the sites rheumatoid arthritis may detected before RF (poor prognosis)

&
where tendons or

• Carriage of HLA27 antigen is associated with increased risk of developing

ligaments insert into the
bone

enthesitis –associated arthritis

-
antennis
• ANA is associated with increased risk of &
O iridocyclitis in pt with oligoarthritis

xi-nucle age I
• RF is positive only in 5% of pt when polyarticular disease occur after 8 yrs of

antibodies. te
Iridocyclitis is an acute inflammation of the iris
and ciliary body; this is the most common pattern
of uveitis, which is present in 85% of affected
-

patients. Typical clinical features of iridocyclitis

include eye redness, pain, blurred vision,
photophobia, and miosis
 Systemic onset Pauciarticular Polyarticular
JIA onset JIA onset JIA

Percent of JIA 10 to 15 50 30 to 40
patients
-
-
commonest
--

Sex F=M F>M F>M 2 peaks

Age any <17 years &
peak 2 to 3 peaks 2 to 5, 10
-

years, rare >10 to 14 years

-

Joints any large joints, but any, rare to start

--
->
rarely hips mainly
&
in in hip
- >

Fever, rash,
lymphadenopath
-
yes no
-
no
-

y,
hepatosplenome
galy
Uveitis rare 20 percent, esp less frequent
- * ANA + -
 Systemic Pauciarticular Polyarticular
onset JIA onset JIA onset JIA
Laboratory abnormalities mainly
-> in
systematic

- Leukocytosis marked no no
- Anemia marked no mild
- Elevated ESR marked mild mild
- ANA absent low titer low titer
common common in
younger
- Rheumatoid rare absent 10 to 20
factor percent in those
>10 years
Destructive >50 percent rare >50 percent
arthritis
Disease O
DMAR
commonly used rarely used commonly used
modifying drugs
 Differential diagnosis of jointO pain or
bij
presentation swelling in children
D
common
• Trauma
-

• Irritable hip and transient synovitis

- - -

• septic arthritis and osteomyelitis,

- I
-
fever

• Infection: bacterial ,viral ,Lyme disease

- - - -

• Hematologic: leukemia ,bleeding diatheses, and hemoglobinopathies

- - -
-
/
aepophilia
-

• Tumor: Musculoskeletal neoplasia (eg, osteosarcoma), lymphoma, and neuroblastoma

-
-

• Leg-Calve- Perthes disease

-

• Slipped capital femoral epiphysis

-

to
Diagnosis of JIA requires the exclusion of all the above diagnoses.

↳
-

ak itbilateral
?
S OR

unilateral
 Management

• Remissions and relapses

-

• No cure but treatable

-

• Relieve pain ,reduce inflammation ,preserve

- - -

joint function ,maintain normal growth and

-
-

development ~

-
 Management

• Screen for uveites by periodic slit-lamp

ophthalmologic examinations of all patients
• Require multidisciplinary team (MDT)
approach
• dietary evaluation and counseling to ensure
appropriate calcium, vitamin D, protein, caloric
intake;
• physical and occupational therapy.
• A social worker
*
I
Medical
-

S
management
-5
"Wit for pain
->
• Nonsteroidal anti-inflammatory drugs (NSAIDs) : Ibuprofen ,Naproxen
,Piroxicam
-
-

• Disease modifying anti rheumatic drugs (DMAR)

-

• Under supervision of rheumatologist

• -methotrexate the safest, most efficacious, and least toxic given once weekly
• azathioprine and cyclophosphamide, are reserved for the few children who do
-
not respond to less aggressive therapy.
e

• Joints steroid injections

-
- stred
-

• Corticosteroid : oral or IV methyleprednisolone

-
-

uycemic
↳spertension
• Toxicity :-
↳gorg
• Cushing syndrome, growth retardation, and osteopenia -

• TNF-α blockers :block the immune protein TNF etanercept infliximab

 Systemic Lupus
Erythematosus (SLE)
in children
 Rash
malar
=>

Rash
Butterfly internal
mainly
• Systemic lupus erythematosus (SLE) inO
children is
fundamentally the same disease as in adults with
similar etiology, pathogenesis, clinical manifestations,
and laboratory findings.
• However, the care of children and adolescents with
SLE is very different from that of adults because of
the impact of the disease and its therapy on physical
and psychological growth and development.
 Systemic lupus erythematosis

• A chronic inflammatoryX
-
multi-systemic autoimmune
-
- -
-

disease characterized by widespread inflammation of

Vasculitis blood vessel and connective tissue
-

/
- -

/
• The primary pathology is of persistent polyclonal B-
cell stimulation resulting in autoantibody production
-

with wide spread tissue antibody production ,with the

-

widespread tissue deposition of immune complex

-
• The pathogenesis of SLE remains largely unknown, but
several genetics, hormonal and environmental factors.
• Prevalence of SLE in children and adolescents (1-
6/100,000) .
• More among African-Americans, Asians, Hispanics,
Native Americans, and Pacific Islanders for both adult
and pediatric populations.
• SLE predominantly affects females
 Overview of the Pathogenesis of Systemic Lupus Erythematosus.

Tsokos GC. N Engl J Med 2011;365:2110-2121.

 American College of Rheumatology Criteria for the Diagnosis of Systemic Lupus
Yet II to diagnosed Erythematosus (SLE).

① -

& -
-
-

& -

E
*
superfacial mainly
- >
painless/painful
-

-
-

⑰ -

& - -
rane

& - pancytopenia.

⑯
⑪ ⑭g
Tsokos GC. N Engl J Med 2011;365:2110-2121.
 ----
-
d

bs
i

sy
 Signs and symptoms

• The disease can affect a wide range of organ systems

the 00
• Generalized symptoms such as fever , weight loss ,
at
on
and &
malaise are common
• Other common signs and symptoms include fever
,anorexia ,Raynauds phenomenon , vasculitis ,
chorea, neuropathy, depression, and cognitive
changes
 wit
markch

·
 Laboratory findings

• Complete blood counts

• Leukopenia ,anemia ,thrombocytopenia
• 15% coombs test- positive
• ESR frequently elevated
• CRP with active SLE is normal but elevated may be
due to infectious causes especially bacterial infection
• Urine analysis for proteinuria and hematuria
 Laboratory findings
• Complements :- C3& C4 are frequently reduced due to increased
consumption

nierig•• ANA is positive in 95-100% of patients usually at titer 1:320 or above

Anti double -strand DNA sensitive and specific , raised particularly in
lupus nephritis
• Anti-smith antibody are specific for lupus and are related to CNS
involvement, positive in only 30% ,lack sensitivity as diagnostic test
• Antiphospholipid antibodies found in approximately 50-60% of
pediatric SLE patients , increase risk of thrombosis
• Anticardiolipin antibodies are detected in up to 50% of children with
lupus ,associated with episode of arterial and venous thrombosis
 Autoantibodies Found in Systemic
Lupus Erythematosus Antibody
Manifestation
• Coombs antibodies : Hemolytic anemia
• Antiphospholipid antibodies :Antiphospholipid antibody
syndrome : Lupus anticoagulant ,Coagulopathy
• Antithyroid antibodies : Hypothyroidism
• Antiribosomal
- P antibody : Lupus cerebritis
 Treatment

x e
• Mild SLE:
• NSAID
• Hydroxychloroquine
• Moderate SLE
• High-dose glucocorticoids
• Mycophenolate mofetil
• Sever SLE
• Cyclophosphamide
• Prednisone
Neonatal lupus
-
syndrom
*
X
w

mother
Dissol
52z
• Results from the passive transfer of maternal
immunoglobulin G autoantibodies to the fetus.
• The vast majority of are associated with maternal
anti-Ro and anti-La antibodies
 Clinical manifestations of neonatal
lupus
• Characteristic annular or macular rash typically affecting
the face (especially the periorbital area), trunk, and scalp
Typically appears within the 1st 6 wk of life after exposure to
ultraviolet light and lasts 3-4 mo.
• Infants may also have cytopenias and hepatitis,
• Congenital heart block is the most feared complication.
-
->
do
heat
->
eso
block
weat
• Conduction system abnormalities range from -> for

prolongation of the PR interval to complete heart block, peeke

with development of progressive cardiomyopathy
 Course and prognosis

• Cutaneous and hematological manifestations are

reversible condicht
• Congenital heart block is permanent with nee
wet
for
2
Danalxex

moxer
ex
20 Libe rh

• Hepatic fibrosis is occasional &

liner
in 4

-3
Eit
• Some risk of SLE in teenage or adult year e
I
③
mt
 Management:

• Symptomatic for transient manifestations

• Heart block may need pace maker
Juvenile dermatomyositis
(JDM)and Polymyositis
• Non –suppurative myositis with characteristic skin
rash and vasculitis
• Girls more than boys
• Peak incidence 4-10 yrs of age
• juvenile polymyositis involves direct T-cell invasion
of muscle fibers similar to that seen in adult
polymyositis ,accounts 3-6% of cases.
 CLASSIFICATION AND
DIAGNOSTIC CRITERIA
• Classic rash plus 3 of the following:
1. Weakness
2. Muscle enzyme elevation
3. Electromyographic changes
4. Muscle biopsy
 CLASSIFICATION AND
DIAGNOSTIC CRITERIA
• Characteristic cutaneous changes :-
• heliotrope dermatitis (reddish-purple rash on the upper
eyelids with periorbital edema) and
• Gottron's papules (erythematous, papulosquamous
eruption over the dorsal surfaces of the knuckles)
• Symmetrical weakness of the proximal muscles
Clinical images of typical juvenile
dermatomyositis

• A) Heliotrope
discoloration of the
eyelids, and malar or
facial erythema and
• (B) scaly, red rash on
the knuckles with
Gottron's papules.
• Elevation of the serum level of one of the muscle enzymes
• Creatine kinase (CK)
• Lactate dehydrogenase (LDH)
• AST
• Aldolase
• ANA positive in some
• Electromyography: useful to distinguish myopathic from
neuropathic causes of muscle weakness (myopathy vs.
denervation)
 Muscle biopsy

• Is indicated in cases of myositis without the

pathognomonic rash.
• Muscle biopsy displaying fiber necrosis and
inflammation, small vessel occlusive vasculitis
 Magnetic resonance imaging

• MRI scan of quadriceps muscle can be used in

equivocal cases to confirm the presence of
inflammatory myositis
 Treatment

• Suppression of inflammatory response and prevention of

the loss of muscle function and joint range of motion
• Assessment of the ventilatory effort and swallowing
• Corticosteroids prednisone or pulse methylprednisolone
• Methotrexate
• In severe cases cyclosporine or cyclophosphamide
• For skin manifestation :Hydroxychloroquine and
intravenous immunoglobulin
 Prognosis

• Variable
• Usually good with adequate treatment
• Recurrent rate 10-20%
• Small percent develop extensive muscle wasting
,severe contracture and wide spread calcinosis
• Dermatomyositis in children is not associated with
increase risk of cancer as in adult
Familial Mediterranean Fever
FMF
 FMF

• Autosomal recessive.
• Brief acute self-limited episodes of fever and
polyserositis.
• Have irregular intervals.
• Associated with the development of amyloidosis.
 Etiology

• Responsible gene: on short arm of chr. 16p13.3( MEFV)

• More than 70 mutations, the most common ones:
• M694V (20-67% of cases, full penetrance, if homozygous;
-[ more sever and higher risk of amyloidosis))
• V726A (7-35%, milder disease, less amyloidosis)
• M694I
• M680I
• E148Q( low penetrance, very mild)
 Epidemilogy

• Primarily among ethnic groups of Mediterranean

origin (Sephardic Jews, Turks ,Armenians, Arabs)
• The carrier frequency is estimated to be 1 in 5
persons
• Onset : 65% before 5 years, 90% before 20 years,
may present as early as 6 months of age
 Pathogenesis

• The exact pathogenesis of acute episodes is unknown.

• FMF mutations lead to a gain-of-function and IL-1B-
dependent inflammation, with a gene dosage effect.
• These results explains why:
• many heterozygous carriers of FMF mutations have
biochemical evidence of inflammation
• As many as 30% of symptomatic FMF patients have only one
demonstrable mutation
• IL-1 inhibitors have a therapeutic effect in FMF
 Clinical manifestations

• fever plus 1 or more:

• Pleuritic chest pain, sterile peritonitis ;sever abdominal
pain), arthritis , rash.
• Pleural pain20%: typically unilateral
• Abdominal pain 90%: generalized or localized to one quadrant
• Arthritis or arthralgia 85% : in large joints, large neutrophil-
rich effusion, nonerosive, nondestructive
• Erysipeloid erythematous rash overlies the ankles and dorsum
of foot
 Other clinical findings(Rare)
• Scrotal pain; inflammation of tunica vaginalis testis( acute
scrotum)
• Pericaditis
• Febrile myalgia
• Exercise-induced myalgia (common in children)
• Association with other forms of vasculitis( ex. HSP 5%
of pediatric cases)
• Splenomegaly
• Neurological involvement
 FMF episodes

• May be triggered by menses, stress, infections,

surgery
• Acute episodes last 1-4 days
• Between flares: symptom-free with persistent
elevation of inflammatory markers
• Attack frequency :from weekly to 1-2 flares/year
 Diagnosis

• Clinical manifestations plus genetic testing

• Clinically:
Duration, recurrence, documentation of fever,
characteristic serositis, synovitis, erysipeloid rash,
responsiveness to daily colchicine prophylaxis, absence of
other causative factor.
• Genetic testing is diagnostic
 Treatment

• Attacks can be prevented by prophylaxis daily oral

colchicine
• 20-30 % shows improvement( decrease number and
severity of attacks)
• 5-10% no response
• Biological treatment: like IL-1 inhibitor Anakinra is
good for cases not responding to colchicine
 Colchicine
• Reduce the frequency of acute attack
• Decrease development of amyloidosis
• May produce partial regression in amyloidosis
• Untreated amyloidosis will end in renal failure within 3-5 years
• GI side effects reduce the compliance
• Toxic effect: Acute myopathy, BM hypoplasia
• Safe during pregnancy to mother and fetus, and during lactation
• No effect on male or female fertility
 Complications and prognosis
• Renal amyloidosis: 30-50% of children, 75% of adult
• Manifestation of serum amyloidosis A (SAA):
Proteinuria, nephrotic syndrome, renal failure.
Transplantation may be required
• Mortality from FMF usually results from the
complications of renal failure and amyloidosis:
Infections, thromboembolism, uremia.
• Others: joint contracture, abdominal adhesion,
impairments in social development.
 Amyloidosis

• Serum AA : acute phase reactant: deposit most commonly

in : kidney, GI, lungs, spleen,, testes, thyroid. Adrenals.
• Rarely cardiac amyloidosis may develop
• Macroglossia and neuropathy NOT seen in amyloidosis
of FMF
• Diagnosis confirmed by rectal or renal biopsy
• Might proceed overt FMF attacks, due subclinical
manifestations
 Amyloidosis

• Risk factors:
• Homozygousity of M694V
• Polymorphism of serum AA gene
• Non compliance with colchicine
• Male gender
• Positive FHX of AA amyloid
• Country of origin
Kawasaki disease
 Kawasaki disease (KD)

• Acute febrile illness of childhood

• Leading cause of acquired heart disease in children in
the developed countries
• Vasculitis, coronary arteries
 Etiology

• Unknown
• Epidemiologic and clinical features support the
infection origin with a genetic role in the
pathogenesis
 Epidemiology

• 80% less than 5 years( median age 2-3 years)

• More among patient of Asian and pacific islander
background.
 Pathology
• Vasculitis of medium-sized arteries
• Edema of endothelial and smooth muscle cells , with intense
inflammatory infiltration of the vascular wall initially with PMN
cells then by macrophages, lymphocytes( CD8+T cell), plasma cells.
• IgA plasma cells prominent in inflammatory infiltrate
• In sever vessels, all layers are affected with destruction of internal
elastic lamina.
• Weakness of vessel wall lead to the aneurysm
• Thrombi may be formed and lead to blood flow obstruction
• Arterial stenosis and occlusion occurs due to progressive vascular
wall fibrosis
 Clinical manifestation

S -

-
• Other associated symptoms might occur 10 days prior to
the diagnosis
• Respiratory 30% or GI 65% symptoms
• Irritability; reflect aseptic meningitis
• Mild hepatitis
• Hydrops gallbladder
• Urethritis, meatitis with sterile pyurea
• Arthritis, arthralgia
 Cardiovascular involvement
• Cardiac involvement is the most important manifestation
• Tachycardia out of proportion to fever, with diminished
left ventricular systolic function which rarely might lead to
shock
• Pericarditis with pericardial effusion can occur
• Mitral regurge in 25% at presentation
• Coronary artery aneurysm in 25% of untreated patient
within 2-3 weeks
• Aneurysm in other arteries (axillary, popliteal, iliac…)
 Phases of Kawasaki disease

• In the absence of treatment:

• Acute febrile phase(1-2 wks):
Fever plus acute signs of the illness
• Subacute phase(for 2 weeks):
Desquamation, thrombocytosis, coronary aneurysms
Highest risk of sudden death if aneurysms developed
• Convalescent phase( 6-8 wks):
Begins when all clinical signs of KD disappeared
Continues until ESR is normal
 Echocardiogram

• At diagnosis then after 2-3 weeks of illness

• If normal, repeat 6-8 weeks after onset of illness
• If abnormal echo or recurrent symptoms, more
frequent echo needed
• If no coronary abnormality, repeat echo and do lipid
profile in 1 year, then cardiologic follow up every 5
years
 Diagnosis

• Classic KD: fever for at least 4 days and at least 4

of 5 of the other principle characteristics of the
illness
• Atypical or incomplete KD: persistent fever but
with fewer than 4 of the characteristics
• Incomplete cases high in infants and have higher risk
to develop coronary artery abnormalities
Treatment

-IE
 Complications

• Coronary artery aneurisms

• Acute thrombosis
• Reyes syndrome : patient should receive annual
influenza vaccine
• Delay in life-attenuated vaccines for 11 months, due
IVIG interfere with immune response
 Prognosis
• Majority of cases return to normal health
• Acute KD recurs in 1-3%
• 50% of coronary artery aneurysm regress to normal by 1-2 years,
but thickness of myointimal wall and function might be affected.
• Giant aneurysms: unlikely to resolve, lead to thrombosis and
stenosis
• Might need coronary artery bypass grafting or heart transplantation
• Occurrence of atherosclerotic heart diseases in adulthood is
unclear
THANK YOU
 CARDIAC INFECTIONS:
ARF AND ENDOCARDITIS
MARWAN SHALABI, MD
ASSISTANT PROFESSOR IN PEDIATRIC INFECTIOUS DISEASES.
- Etiolgy. OUTLINES
- Epidemiology
- Pathophysiology
- Jones criteria
- Diagnosis
- Treatment
- Complications
- Prevention
- Prognosis
ETIOLOGY Astreptococcus)
streptocomspays(Group
->
• Proceeded by GAS pharyngitis.
biotic -ene

• ABT
- -
to treat GAS pharyngitis prevents rheumatic fever.
• ABT prophylaxis prevents-ARF recurrence

-
-- -
-
• serotypes of GAS (M types 1, 3, 5, 6, 18, 29) are more frequently isolated
-

Se
/
 throat
- Habitates ->
Human
Skin

EPIDEMIOLOGY Mode oftransmission--Air

droplets
Directcontac
->

• Why more frequent in developing countries:

-

-
-

• Host factors:
• genetic susceptibility
-

• Lack of appropriate medical care.

-

• Poverty and crowding.

-

• Pathogen factors i -

A OM serotype
• Certain GAS are rheumatogenic serotypes (types 1, 3, 5, 6, and 18)
L
-

• Most common form of acquired heart disease The # most common cause

(3240 viral
·

->
j;ssayist
ciss/

pharyngitis
-

of
->

this having
is the
age of
active
I 72yer+S
• peaks : 5-15 yr of ageis why lymphatic
-
(the tissue

infection)get
age
to

• Once happened increased risk of ↳ recurrence

-
-
-m
 of
issu
pock G-Ho
&* Lymphoid T

rowthof
9 y age

0 ⑧
PATHOGENESIS

• Cytotoxicity theory:
• GAS toxin leads to ARF and rheumatic heart disease.
-

• Immunologic theory
• Latency.
e n

- - -
- -
• Cross antigenicity of several GAS and tissues (e.g., heart valve, sarcomere, brain, joint)
b
in our tissue

Si
-
 -

-
-

-
-
-
- - -
---

↳
- -

- -

-
nee

GAS infection

·testin
- -
-

pharyngitis
-
fonsolitis
~

S
⑲

E Gritis I
glomerulonep
w
-

E
Trainthe -
permrt -

-
 important
-> very --

JONES CRITERIA
-

MAJOR MINOR EVIDENCE OF GAS

MANIFESTATIONS MANIFESTATIONS INFECTION
1.Carditis 1.Arthralgia Spain)
-
-
-
1.Positive throat culture
-

2. Polyarthritis 2.Fever 2.or rapid strep. test

3. Erythema marginatum⑧
- - -

-
3.High ESR or CRP
-
3.or ASO titer
-

4.Subcutaneous nodules
-
4.Prolonged P-R
↳Ist
-

heartblock
degree
5.Chorea B
-
-
meane

• Guidelines for the Diagnosis of Initial or Recurrent Attack of Rheumatic Fever (Jones Criteria, Updated 2015)
• 2 major or 1 major and 2 minor criteria PLUS evidence of preceding GAS infection needed to diagnose ARF
• recurrent ARF: presence of 3 minor criteria PLUS evidence of preceding GAS infection.
 JONES CRITERIA

• Initial attack:
• 2 major manifestations, plus evidence of recent GAS infection.
• Or 1 major and 2 minor manifestations, plus evidence of recent GAS infection.
-
later •
-

-
S
Chorea alone, plus evidence of recent GAS infection.
month nee

• D
2
Recurrent attack: 2 major, or 1 major and 2 minor, or 3 minor manifestations , plus
-
-

evidence of recent GAS infection -

O
-

• Carditis is now defined as clinical and/or subclinical (echocardiographic valvulitis)

-

• Arthritis: monoarthritis or polyarthralgia ↳

- -
by E
O *

- -

like chore
 CLINICAL MANIFESTATION- ONSET & DURATION
D

rg
↳ !
 MIGRATORY POLYARTHRITIS

• In 75% of ARF.
• larger joints (knees, ankles, wrists, and elbows
O• Migratory

·ss:**
car S

orev, ↳es
out • Arthritis is the earliest manifestation -

yj •
is 3
s

i I An -
Last weeks if untreated. A B

↑
/

~-
S
C

-
•
-

Response to salicylates is characteristic

• Not deforming
• inverse relationship between the severity of arthritis and severity of cardiac involvement
we are
 CARDITIS

Greiber
• 50-60% of all ARF
O
• subclinical carditis accepted in revised jones criteria 2015.
• subclinical carditis defined: without a murmur but with echocardiographic evidence of valvulitis
• clinical carditis (with a valvulitis murmur)
• Pancarditis: but mainly Endocarditis (valvulitis) v
• MR or MR+AR mitrgach
• insufficiency is characteristic
• mitral and/or aortic valvular stenosis usually appears in
- years
• tachycardia and cardiac murmur
• Most serious ARF complication, May require valve replacement, if recurrent
-
 SYDENHAM CHOREA

• 10-15% of ARF.
/
• could be Isolated, frequentlyO subtle
• Emotional lability, incoordination, poor school performance, uncontrollable movements, and
facial grimacing, all exacerbated by stress and disappearing with sleep,- are characteristic.
%see
-
• Later than arthritis or carditis (ASO may disappear when chorea presents)
- ~

• Occurs in 10-15% of pts with acute RF

- Occasionally unilateral
-

-lasts 3 m to 2-3 yrs , no permeant damage

!S
->

--- I

-,545
·
-

/
 SUBCUTANEOUS NODULES

• rare (≤1%
• firm nodules
• along the extensor surfaces of tendons near bony prominences
• Corollates with significant rheumatic heart disease.
 ERYTHEMA MARGINATUM

• On trunk and extremities, but not on the face

• accentuated by warming the skin
 MINOR CRITERIA

• Arhtralgia: (only if arthritis is not used as a major criterion) - *

• Fever, more than 38.0° /x3,9 gich

s

achra-y
• elevated acute phase reactants
arixxic
Ess criterich
S
S
minor
• prolonged P-R interval on ECG (unless carditis is a major criterion)
 X

• First-degree heart block with prolonged PR interval (interval between

arrows), which may be present as a minor criterion for acute rheumatic
fever.
 RECENT GAS INFECTION

• Must have.
• ARF devlpes 2-4 wk post GAS pharyngitis.
• 1/3 have no Hx of pharyngitis.
• 80-85% have high ASO.
• 95-100% have an elevation if 3 different antibodies (antistreptolysin
--
O, anti–DNase
B, antihyaluronidase) hyalinrece
- > -
↓
&s

• Clinical findings of acute rheumatic fever generally coincide with peak

-
Nucleuse
-marize

- antistreptococcal antibody responses. E or

↳ de
at
O
cur X
ve

during dire
same
 DDX OF ARF
ARTHRITIS CARDITIS CHOREA
Juvenile idiopathic arthritis Viral myocarditis Huntington chorea
X

Reactive arthritis (e.g., Shigella, Salmonella, Viral pericarditis Wilson disease

Yersinia)
Serum sickness Infective endocarditis SLE
Sickle cell disease Kawasaki disease Cerebral palsy
Malignancy Congenital heart disease Tic disorder
SLE Mitral valve prolapse Hyperactivity
Lyme disease (Borrelia burgdorferi) Innocent murmurs
Pyogenic arthritis
Post strep RA
 D
I treatment
-

• bed rest (esp if caditis present).

ne

wall
• ABT: - penicilin (which
is

•&PCV V K 10 days. it's

I
linjx because
• Or Amoxcillin oral for⑧
-
10 days
-
• Or Benzathenine Penicillin G X 1 intramuscular inj
Long acting.

• If PCN allergic: erythromycin, azithromycin or clindamycin

-
-
-> S15-
-
Killing
- -
- -

penicillin i
Jess
-
·
 ANTIINFLAMMATORY THERAPY
initially notuse

• Early treatment may mask the disease.

so

paracetamol
-

• Use Acetaminophen early if still unsure if DX.

-
-A

• Salicylates.: (High dose aspirin) then

low few
dose for a week.

michbede • 50-70 mg/kg/day QID PO X 3-5 days

0
• Then 50 mg/kg/day in 4 QID PO X 3 wk
xe
gesist
I

• Then half that 2-4 wk

• Corticosteroids. If Carditis present.
-

• prednisone is 2 mg/kg/day QID X 2-3 wk

• followed by half the dose for 2-3 wk
• then by 5 mg/24 hr every 2-3 days.
• Repeat if ARF rebounded
-

• Carditis Rx: Steroid, Digoxcin, fluid and salt restriction, diuretics, and oxygen
---- -
-
 -prescription
~ mebric melt
SYDENHAM CHOREA RX Great

• Late: usually anti-inflammatory not needed.

• Sedatives:
• phenobarbital, drug of choice
• Alternate choices: haloperidol or chlorpromazine
• Plus minus corticosteroids.
 COMPLICATIONS

• “Acute Rheumatic Fever licks the joints and bites the heart” (Laseque 1884)
PROGNOSIS

• 50-70% of carditis recover.

• Worsoning carditis may occur in subsequent attacks. *
• ARF recurrence 50% risk with each GAS pharyngitis
• ARF Recurrence is highest in the 1st 5 yr
• 20% of patients who present with “pure” chorea who are not given secondary
prophylaxis develop rheumatic heart disease within 20 yr.
 git
7i
:" ~ixul
·

PREVENTION 3) harf S

xreutDeniciti O da
or
P

O
illness
• primary prevention:
•
↑
DX and treat GAS pharyngitis X 10 days before ARF appears.
/

Essen
Effective if PCN given in first 9 days of pharyngitis
• host

See
secondary prevention:

1.
, •
•
Maitance ABT since recurrence likely.
Benzathine PCN G IM X 1 Q 4 weeks
v
exible
•
confirm
Or PCV V K PO v
• Or Sulfa -
• Macrolide if PCN allergic
~
 DURATION OF PROPHYLAXIS BY AHA *
** group
age
*
axis.
Duration of

(15)
-

according to

CATEGORY DURATION
*

age.

jei s;? &

Rheumatic
sites,
debt
fever without carditis
s9sei
21
5d! i
C
5 yr or until 21 yr of age,
- -> j(
05sIs
S
siS
S
SSo
-
-
-
es
=so
E 27039
-
it
3,
e
carditis s-os1-15 ogsly
17, whichever is longer
-
-
&

10
-

s
i
- =

-
I

!I is Rheumatic fever with carditis but 10 yr or until 21 yr of age,

& I
-
a

j
- -
-

without residual heart disease (no whichever is longer

- -

---- -
- 28 is s
valvular disease)
-
Jes
-, -(

Rheumatic fever with carditis and D 10 yr or until 40 yr of age, Jobi

- - - -
&
residual
-
heart disease (persistent whichever is longer; sometimes
- -
-

valvular disease) -

-
 -
-
of
source heat
Bacteric -
⑪
Damaged
-

v
↑

⑪
 WHO DEVELOPS PEDIATRIC ENDOCARDITIS?

• Marked decline in Rheumatic HD

~
• 80-90% occur in congenital HD
verticular
L
• (VSD, PDA, TOF, aortic valve abnormalities; operated patients with S-P shunts, prosthetic
-

-
material) patent
--

septal
Tetralogy of Fallot (TOF) is
a combination of four
ductus

toffett
congenital (present at
defet -

Not&
arteriosus. birth) heart defects that

• ASD
affect infants and children.

se

• Central venous catheters, pacemakers, IV drug users

- -

•-10% in normal hearts

• Highest risk: Aortic valve prosthesis or systemic-pulmonary shunt
-
-
 ETIOLOGY

• STREPTOCOCCI (~ 45%)
• Viridans 35%
• Enterococci ~ 5%
• S. pneumoniae, beta streptococci (GBS) - ~ 7%
• STAPHYLOCOCCI: especially post-op, foreign body-associated or in normal
>

hearts (~ 40%)
-

• S. aureus ~ 30% -
• Coagulase-negative staph ~ 10% -
X
 ETIOLOGY
-
↑

• HACEK group: ~ 5%:

-
-----

• Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis,

Eikenella corrodens, Kingella kingae
• fastidious Gram-negative coccobacilli

• Others ~ 5-7%
• Fungi, especially Candida ~ 2-5%
• Gram-negative enterics ~ 3%
• Culture-negative ~ 5%
 INFECTIVE ENDOCARDITIS
PATHOGENESIS
value is
(eg,

- Thrombus, jsshigh pressur

• Areas of turbulent flow (jet effect, eddies)
-
infectiv
-
-
I:s -
predisposed t

• Stenosis (valves, coarct) S

xisis" S
s
large t
lurbrats
• Small
0
->
if VSD verticee
~ /
-
5, • Endothelial disruption results (also occurs with indwelling line) -
niqe
-
/
• Sterile fibrin-platelet thrombus develops on the disrupted surface
• Entrapment of bacteria from “stray bacteremia” initiates focus of infection; platelets
and fibrin deposit to form vegetation. Receptors are involved-(MSCRAMM’s). recep Bauterie
To
....

-
--
-

G
-
on

S lat det o
P Latelt
⑭ Fibrin acteri Lagel
-
B
y
/
-notSibrit-
/
 s
INFECTIVE ENDOCARDITIS
PATHOGENESIS
X
ASYMPTOMATIC ↳
BACTEREMIA OCCURS IN:

S.
-

Si -

;
-⑨
I
S
- -
-

/
- - -
-
1

- - -

From Everett ED, Hirschmann JU. Transient bacteremia and endocarditis prophylaxis: a review. Medicine (Baltimore) 1977;56:61–77.
© 1977, The Williams & Wilkins Company, Baltimore.
 INFECTIVE ENDOCARDITIS
CLINICAL SYNDROMES
• Acute Presentation
• High fever, toxicity, ± CHF
-

24
• S. aureus most common; β strep, S. pneumoniae
• Early post-op; normal heart; indwelling lines
• Subacute Presentation (more common)
t
so • Insidious, non-toxic, malaise, immune phenomena
• Viridans strep most common pathogen 25
• Also fungal, HACEK agents, coagulase-negative staph
• Extracardiac manifestations are less common than in adults (splenomegaly, hematuria,
immune phenomena)
 Qi,
C/P
presentati
• Causes of the clinical picture and complications:
• Embolization V
• Heart damage ~
• Circulating immune complexes -
 C/P

Diamet
 INFECTIVE ENDOCARDITIS
EVALUATION a
-
si 4o

I
·

See ."I
-

/
/

/
-
• 3 or more blood cultures (separate venipunctures) over 6-24 hours before
- ne

therapy:
• Continuous bacteremia is the rule in endocarditis
• Trans-thoracic Echo (~ 80% sensitive, higher than in adults)
 INFECTIVE ENDOCARDITIS
EVALUATION

• Role of Trans-esophageal Echo (TEE) in kids is evolving:

• Better imaging of aortic root structures
• Superior in individuals with thick chest walls, obesity
• Superior with prosthetic valves
• Superior for vegetations, abscesses
 SELECTED LABORATORY FINDINGS OF
BACTERIAL ENDOCARDITIS IN CHILDREN

-i
 INFECTIVE ENDOCARDITIS
DIAGNOSTIC CRITERIA

• Duke Criteria:
*
iss",
Det
&

• Definite IE: Pathologic evidence, or 2 majors, or 1 major and 3 minors,

-
- -

or 5 minors ''
eh
-9
• Possible IE: 1 major and 1 or 2 minors, or 3-4 minors alone moncl*
s
X E

• Rejected: Firm alternate diagnosis; or-

&

-
-
-
I -
-
-
resolution of illness or absence
-

diamosis of evidence of IE at surgery or autopsy after ≤ 4 days of antibiotics

- -
>-
re

...
j. k

Einst
- >

d
Vegetation gies"
-

I
--
-
-
d utopsy
 INFECTIVE ENDOCARDITIS
REVISED DUKE CRITERIA (2000)
• MAJOR CRITERIA
-
5.0, 15
D • Positive blood cultures
i
*

-
ive
sisisgiabs
• Typical IE organism from ≥ 2 cultures or
-

• Persistently positive cultures (≥ 2 BC at least 12 hr apart or all of 3 or majority of ≥ 4 BC at least

-

↳
-

en
Y
1 hr apart)
- & 12 2.1, s, culture
t: 9; e
(1

4(6 24)
sti
I

•
-

Single positive for C. burnetii or-

IgG > 1:800
-

3 culture
-
-

--
↳>
⑳ • Evidence of endocardial involvement
liter
-

• Positive
- echocardiogram or
• New valvar Dr
-
regurgitation
INFECTIVE ENDOCARDITIS
REVISED DUKE CRITERIA (CONT.)

• MINOR CRITERIA
Durdrug
abuser

• Predisposing heart disease or IVDA

-

• Fever 38° C
-

• Vascular phenomena (Janeway lesions, emboli, conjunctival hemorrhages, mycotic

-

- - -

aneurysms, strokes)
-

• Immunologic phenomena (nephritis, Osler nodes, Roth spots, rheumatoid factor)

-
- -
- - -

• Positive blood cultures not meeting-

-

major criterion
-
959 8-=
 -

- -

-
- -

-
>
---

& ---

e
 ation
->
/
 of
due
VASCULAR PHENOMENA
-
to

infected
shedding
I

thromb
• Janeway lesions
-

• Emboli
-

• Conjunctival hemorrhages
e

• Mycotic aneurysms
-

• Strokes
-
 flat L
-
↳
JANEWAY LESIONS paies 8

painless small erythematous or hemorrhagic lesions on the palms and soles

-
-
-

- -
-
IMMUNOLOGIC PHENOMENA

• Nephritis
• Osler nodes
• Roth spots
• Rheumatoid factor
• Splinter hemorrhages
 -
Roth Spots

• "white-centered" hemorrhages
• not specific for endocarditis
 OSLER NODES
fa
Osler nodes :tender, pea-sized intradermal
nodules in the pads of the fingers and toes
SPLINTER HEMORRHAGES

linear lesions beneath the nails.

• may present vasculitis produced by circulating antigen-antibody complexes..
 INFECTIVE ENDOCARDITIS
TREATMENT I

• PROLONGED norParmentybeand 5, wec

en
t**
/
S

as
X
et • PARENTERAL
• BACTERICIDAL ANTIBIOTICS
s
"
↓ I I
gl-

combine
"

res
in
is
4
 RX IN NATIVE VALVE IE

I
~ ~

w
2

~
 RX IN NATIVE VALVE IE

#
 RX IN POSTHETIC VALVE IE

A
 INFECTIVE ENDOCARDITIS

• HACEK Agents
•
TREATMENT II

Ceftriaxone 4 weeks, or Ampicillin and Gentamicin 4 weeks

X
“CULTURE - NEGATIVE”
ENDOCARDITIS INCLUDES

·
Sts.
-

Ii!
S

. xibi
• Partially treated endocarditis -
a
sssdiagnos
Sin
• Nutritionally deficient streptococci
·

• Fungal endocarditis
• Q fever (rare) Chlamydia
• Bartonella quintana
•
+
Rx: 4-6 weeks of amp-sulbactam or vancomycin and gentamicin, possibly with cipro.
Ceftriaxone and gentamicin ± doxycycline if Bartonella suspected
-
2.
↳ /
5,
·
 HIGH RISK FOR COMPLICATIONS
• Prosthetic valve IE
• Left-sided IE -
• Staphylococcus aureus IE -
• Fungal IE ~
• Previous episode of IE
• Prolonged symptoms (≥3 months) ~
Cyanotic defects are defects in which blood pumped to the body

• Cyanotic CHD contains less-than-normal amounts of oxygen, resulting in a

condition called cyanosis. It causes a blue discoloration of the skin.
Infants with cyanosis are often called "blue babies."

• Systemic-pulmonary shunts v
• Poor clinical response to antibiotics ~
PREVENTION OF IE

• Maintain good oral hygiene

• Antibiotic prophylaxis now recommended only for dental procedures in those with:
• Prosthetic valve
• History of previous IE
• Congenital heart disease
·bI
• Unrepaired cyanotic CHD v
• Repaired CHD in 1st 6 months after repair - procedure
• Repaired CHD with residual defect ~
in
• Heart transplant with valve dysfunction
so,

Wilson: Circulation 2007; 115

ENDOCARDITIS PROPHYLAXIS REGIMENS FOR A
single dose,
DENTAL PROCEDURE
I hi
->
procedure before
-

dose
single
&
befor
procedure

#
E
>

,i
IV
-
-

Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association.
Circulation 2007;116:1736–54.
 Genetics
Chromosomal Abnormalities
 -
Background
• Human cells contain a multiple of 23 chromosomes
(n = 23).
• Haploid cell (n) has 23 chromosomes (typically in
the ovum or sperm).
• Diploid cell has a normal diploid number of 46 (2n)
chromosomes
• Abnormal cells that do not contain a multiple of
haploid number of chromosomes are termed
aneuploid cells.
• Aneuploidy is the most common and clinically
significant type of human chromosome
abnormality, occurring in at least 3-4% of all
clinically recognized pregnancies.
 -

• The most common numerical abnormalities in

live born children include:
– Trisomy 21 (Down syndrome), trisomy 18
(Edwards syndrome), trisomy 13 (Patau syndrome)
– Sex chromosomal aneuploidies: Turner syndrome
d
(usually 45,X), Klinefelter syndrome (47,XXY),
47,XXX, and 47,XYY.
+O
• Chromosomal disorders: Chromosome
deletions, duplications, and inversions that
affect whole chromosomes, or large portions
of a chromosome.
 Chromosomal Disorders
• The most common cause of aneuploidy is
nondisjunction, the failure of chromosomes
to disjoin normally during meiosis I or II or
during mitosis.
• After meiotic nondisjunction, the resulting
gamete either lacks a chromosome or has 2
copies instead of 1 normal copy, resulting in a
monosomic or trisomic zygote, respectively.
• Translocations: common type of chromosomal
anomaly, in which a piece of one chromosome
breaks off and becomes attached to a
different, nonhomologous chromosome.
• Mosaicism: when only a portion of cells carry
the chromosomal defect and rest of cells are
normal.
• Chromosomal disorders are typically identified
by chromosomal analysis (karyotyping)
• Genomic disorders are a group of diseases
caused by rearrangements of the genome
including deletions (loss of a copy of DNA),
duplications (addition of a new copy of DNA), and
inversions (altered organization of DNA).
• DiGeorge syndrome {deletions of genes located
on chromosome 22q11}
• Genomic disorders are often identified by
fluorescent in situ hybridization (FISH) or by
array comparative genome hybridization (aCGH)
technologies
 MENDELIAN INHERITANCE

• Human genome: 46 chromosomes (22 pair of

autosomes and one pair of sex chromosome)
• There are 3 classic forms of genetic
inheritance:
• Autosomal dominant
• Autosomal recessive
dominen
• X-linked -

↑recesse
Symbols in family pedigree
 Autosomal Dominant Inheritance
• Determined by the presence of one abnormal
gene on one of the autosomes (chromosomes
1 to 22)
• Change in 1 of the paired genes has an effect
on the phenotype; (physical manifestations,
behavioral characteristics ), or differences
detectable only through laboratory tests, even
though the other copy of the gene is
functioning correctly.
 Autosomal Dominant Inheritance

• Males and females are equally affected.

• 50% chance of transmission from parent to
offspring jeszy
->

• Vertical transmission, all generations.

• Parent to child transmission is a characteristic
of autosomal dominant inheritance
•-Male to male transmission essentially
confirms autosomal dominant inheritance
and exclude X linked disorder. female -st female
- -
 -

so
&

networ:
get
p
Autosomal Dominant Inheritance
di
are Eng
9
Sor
i
 Autosomal Dominant Inheritance

• Many patients with an autosomal dominant

disorder have no history of affected family
member :
– new mutation occurred in the DNA of the egg or
sperm that formed that individual.
– Incomplete penetrance, meaning that not all
individuals who carry the mutation have phenotypic
manifestations (skipped generation, in which an
unaffected individual links two affected persons)
– variable expression ,individuals with the same
autosomal dominant mutation can manifest the
disorder to different degrees.
 Autosomal Recessive Inheritance

• Involves mutations in both copies of a gene.

• Examples of autosomal recessive diseases are
cystic fibrosis and sickle cell disease.
• Characteristics of autosomal recessive traits
include horizontal transmission, the observation
of multiple affected members of a kindred in the
same generation, but no affected family
members in other generations;
• recurrence risk of 25% for parents with a previous
affected child
• males and females being equally affected
 Autosomal Recessive

&
cause
e
it Chance
⑧
xe orcarrial
sot
Autosomal Recessive Inheritance
carrier

Y L

4
I

- E
18
20
·

9.carrie
y
 most
ge"
- in
o bo
au
~
 X-Linked Inheritance
• Males are more commonly and more severely
affected than females.
• Female carriers are generally unaffected, or if
affected, they are affected more mildly than
males.

&
• Male-to-male transmission excludes X-linkage
(seen with autosomal dominant and rare
disorders of Y-linked inheritance)
 X-linked inheritance
• Female carriers have a
25% risk for having an
affected son, 25% risk
for a carrier daughter,
and 50% chance of
having child that does
⑧ not inherit the mutated

face
↑ no X-linked gene.
e
Land
 X-linked inheritance
• Affected males will have
only carrier daughters
(all) and have no chance
of having an affected
son because they will
pass the Y chromosome
to their sons.

carra
Gerde
100 gatte we
I
or so
X-Linked Recessive Inheritance

*
"
&.
3, i
si
t
 bau
->
zey

synde
L- 'I Dish
oral -
-

oxe
 Mitochondrial Inheritance

• Mitochondrial Inheritance
• An individual’s mitochondrial genome is entirely
derived from the mother because sperm contain
few mitochondria, which are typically shed upon
fertilization
• A woman with a mitochondrial genetic disorder
I
can have affected offspring of either sex, but an
affected father cannot pass on the disease to his
offspring
• e.g mitochondrial myopathy
 Clinical cytogenetics
• Clinical cytogenetics is the study of
chromosomes: their structure, function,
inheritance, and abnormalities.
• chromosome abnormalities are very common
• Occur in approximately 1-2% of live births, 5% of
stillbirths, and ~50% of early fetal losses in the 1st
trimester of pregnancy.
• Chromosome abnormalities are more common
among persons with mental retardation and
have a significant role in the development of
some neoplasms.
Risks of Chromosomal anomalies
– advanced maternal age
– multiple abnormalities on fetal ultrasound (prenatal testing)
– multiple congenital anomalies
– unexplained growth retardation in the fetus or postnatal
growth and development problems
– mental retardation
– ambiguous genitalia
– primary amenorrhea or infertility, recurrent miscarriages
(≥3) or prior history of stillbirths and neonatal deaths
– 1st-degree relative with a known or suspected structural
chromosome abnormality
– clinical findings consistent with certain chromosomal
anomaly
– Certain malignancies, and chromosome breakage syndromes
(e.g Fanconi anemia).
 Chromosomal disorders
• Trisomy is characterized by the presence of 3
chromosomes, instead of the normal 2, of any
particular chromosome.
• The occurrence of trisomy 21 and other trisomies
increases with advanced maternal age >35yr
• Most individuals with trisomy exhibit a consistent
and specific phenotype depending on the
chromosome involved:
– trisomy 21 (Down syndrome)
– trisomy 18 (Edwards syndrome)
– trisomy 13 (Patau syndrome)
Trisomy 21 (Down Syndrome)
 Down Syndrome
• Trisomy 21 is the most common genetic cause
of moderate mental retardation.
• The incidence of Down syndrome in live births
is approximately 1 in 733
• The life expectancy for children with Down
syndrome is reduced (approximately 50-55 yr.)
Down Syndrome -

or l
I

d
-
-
in
&
·xies,

int
standers
-5
-

->
~
a
~

In
↳
 Down Syndrome
• Neuropsychatric : (autism, disruptive behaviour,
depression, alzheimer disease)
• Musculoskeletal : (atlantoaxial instability, hip
dysplasia, Slipped capital femoral epiphyses,
joints dislocations

⑨
• Endocrine : (Congenital or acquired
hypothyroidism, DM, infertility, hyperthyroidism)
• Hematology: Transient lymphoproliferative
syndrome, acute lymphocytic leukemia, acute
myelogenous leukemia
• GI: Celiac disease, obesity increm
mich
-
 Down Syndrome
• Affected individuals are more prone to congenital
heart defects (40-50%) , commonest
atrioventricular septal defects
• Developmental delay is universal
• Cognitive impairment does not uniformly affect
all areas of development.
• Social development is relatively spared
• Most males with Down syndrome are sterile, but
some females have been able to reproduce, with
a 50% chance of having trisomy 21 pregnancies
 Down Syndrome
• Down syndrome patients are at risk for
leukemia (leukemias accounted for 60% of all
cancers in people with Down syndrome)
 Down Syndrome
• All women should be offered screening for
Down syndrome in their 2nd trimester by
quad screen : 4 maternal serum tests (free β-
human chorionic gonadotropin (β-hCG),
unconjugated estriol, inhibin, and α-
fetoprotein).
• Screening during the 1st trimester by fetal
U/S of nuchal translucency thickness
Edward’s Syndrome
Trisomy 18 (Edward Syndrome)
Patau Syndrome
Patau Syndrome
trisomy 13
 Turner syndrome
• Turner syndrome = 45X
• Maternal age is not a predisposing factor
• Turner syndrome occurs in approximately
1/5,000 female live births.
• In 75% of patients, the lost sex chromosome is
of paternal origin
• Most patients tend to be of normal
0
intelligence, but mental retardation is seen in
Pe6%
Karyotype for female with Turner syndrome—45XO
Turner Syndrome
reek
->
+ O
↳

&
 Turner Syndrome
• Phenotypic females with 45,X/46,XY
mosaicism have a 15-30% risk of developing
gonadoblastoma.
①
• The AAP has recommended the use of FISH
analysis to look for Y-chromosome mosaicism
in all 45,X patients. If Y chromosome material
is identified, laparoscopic gonadectomy is
recommended
 Noonan Syndrome -miner
⑳
W

male
• Noonan syndrome :autosomal dominant
-
disorder affect both sexes
• Features common to Turner syndrome include
short stature, low posterior hairline, shield
chest, congenital heart disease, and a short or
webbed neck
• Noonan syndrome has different pattern of
congenital heart disease typically involving
right-sided lesions.
- -

-
pulmwalloniambi
ng
Belvall
montSterois
-
 Klinefelter Syndrome
• Klinefelter syndrome pts are phenotypically male
• It is the most common cause of hypogonadism and
infertility in males and the most common sex
chromosome aneuploidy in humans
• 80% of Klinefelter syndrome have a male karyotype
with an extra X chromosome “47,XXY”
taf
• Remaining 20% have multiple sex chromosome-14. / X

r
aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), ·

mosaicism (46,XY/47,XXY). ↑
• Each additional X chromosome reduces the IQ by 10-
15 points. The main effect is seen in language skills
and social domains.
 Klinefelter Syndrome
• phenotypically normal male
• Puberty occurs at the normal age, but the testes
remain small.
• Taller stature.
• Presentation usually in adulthood as& infertility.
• Their intelligence shows variability and ranges
from above to below average.
-

• Persons with Klinefelter syndrome can show

behavioral problems, learning disabilities, and
- --

deficits in language.
-
-

- -
 Fragile X syndrome most
- comm
mentl ·x
Prgist
eordaine
• Fragile X accounts for 3% of males with mental
retardation. -
X linked dominant disorder Retise
&

• The main clinical manifestations in affected males are

Generaete
mental retardation, autistic behavior, macro-orchidism
(which may not be evident until puberty), and
characteristic facial features
• The facial features, which include a long face, large
ears, and a prominent square jaw, become more
obvious with age
• Females affected with fragile X show varying degrees of
mental retardation and/or learning disabilities.
 Fragile X syndrome

The main clinical manifestations in affected males are mental retardation,

autistic behavior, macro-orchidism (which may not be evident until
puberty), and characteristic facial features
• The facial features, which include a long face, large ears, and a
prominent square jaw, become more obvious with age
 -

Prader Willi Syndrome -Se I

:
• Prader-Willi syndrome results from the loss of
paternal chromosome 15q11.2-13 locus.
• C/P: hypotonia as infant, developmental delay,
-

mental retardation, obesity, hypogonadism,

- -

short hands and feet, bird{small}

- -
like head
•- Dx; FISH
&

Gri-
agnos
Prader Willi Syndrome
• Obesity
• Short stature
• Mental retardation
• Short hands and feet
• Hypogonadism
loss of paternal chromosome
15q11.2-13 locus.
Thanks
 CHAPTER 154 Principles of Cancer Treatment 601

CHEMOTHERAPY OTHER THERAPIES

Because most pediatric solid tumors have a high risk for micro-
metastatic disease at the time of diagnosis, chemotherapy is used
in almost all cases (Table 154.2). Exceptions include low-stage
neuroblastoma and Wilms tumor (particularly in infants) and
low-grade central nervous system (CNS) tumors. For patients
with localized solid tumors, chemotherapy administered
after removal of the primary tumor is referred to as adjuvant
therapy. Chemotherapy administered while the primary tumor
is still present is referred to as neoadjuvant chemotherapy.
Neoadjuvant chemotherapy has a number of potential benefits,
including an early attack on presumed micrometastatic disease,
shrinkage of the primary tumor to facilitate local control, and
additional time to plan for definitive surgery.
Resistance to particular chemotherapeutic agents can develop
relatively quickly. Thus combinations of chemotherapy drugs are
used, as opposed to sequential single agents, to treat childhood
cancer. The blood-brain barrier prevents the penetration of
chemotherapeutic drugs into the CNS. Thus administration
of the chemotherapeutic agent directly into the cerebrospinal
fluid (by lumbar puncture) is used for leukemia and lym-
phoma. Radiation therapy also circumvents the blood-brain
barrier.
RADIATION THERAPY
Radiation therapy is the process of delivering ionizing
radiation to malignant cells to kill them directly or, more
commonly, prevent them from dividing by interfering
with DNA replication. Conventional radiation therapy uses
photons, but atomic particles such as electrons, protons, and
neutrons can also be used. Not all tumors are radiosensitive,
and radiation therapy is not necessary in all tumors that are
radiosensitive.
Certain cancers have been treated with biological response
modifiers, tyrosine kinase inhibitors, or monoclonal antibodies
in addition to standard treatments. Targeted therapies specifi-
cally target the tumor cells, sparing normal host cells. Imatinib
and dasatinib are tyrosine kinase inhibitors that target the effects
of the t(9;22) translocation (BCR-ABL) of chronic myeloid
leukemia and acute lymphoblastic leukemia. Rituximab is a
monoclonal antibody directed against the cell surface antigen
CD20 expressed in some lymphomas. Dinutuximab is an
anti-GD2 monoclonal antibody used for neuroblastoma. Chimeric
antigen receptor T-cell therapy and bi-specific T-cell engager
therapy are immunotherapies that leverage the patient’s own
T cells to kill cancer cells.
Supportive care also plays an important role in pediatric
oncology, including the use of appropriate antimicrobial agents,
blood products, nutritional support, intensive care, and integra-
tive therapies.
ADVERSE EFFECTS
Because chemotherapy agents are cellular toxins, numerous
adverse effects are associated with their use. Bone marrow
suppression, immunosuppression, nausea, vomiting, and alopecia
are general adverse effects of commonly used chemotherapy
drugs. Each chemotherapy drug also has specific toxicities.
Doxorubicin can cause cardiac damage; cisplatin can cause
renal damage and ototoxicity; cyclophosphamide and ifosfamide
can cause hemorrhagic cystitis; and vincristine can cause
peripheral neuropathy. Radiation therapy produces many adverse
effects such as mucositis, growth retardation, organ dysfunction,
and the later development of secondary cancers. Significant
therapy-related late effects may develop in pediatric cancer
patients (Table 154.3).

TABLE 154.2 Cancer Chemotherapy

DRUG ACTION INDICATION ACUTE TOXICITY*
ANTIMETABOLITES
Methotrexate Folic acid antagonist; ALL, lymphoma, Myelosuppression (nadir 7-10 days),
inhibits dihydrofolate medulloblastoma, mucositis, dermatitis, hepatitis, renal

=
reductase
6-Mercaptopurine Purine analog
Cytosine arabinoside Pyrimidine analog;
(Ara-C) inhibits DNA polymerase
ALKYLATING AGENTS
Cyclophosphamide Alkylates guanine;
inhibits DNA synthesis
Ifosfamide Similar to
cyclophosphamide
Carmustine (BCNU), Carbamylation of DNA;
lomustine (CCNU) inhibits DNA synthesis
osteosarcoma
ALL
ALL, AML, lymphoma
ALL, lymphoma, sarcoma,
brain tumors
Lymphoma, Wilms tumor,
sarcoma, germ cell and
testicular tumors
CNS tumors, lymphoma,
Hodgkin disease
and CNS effects with high-dose
administration; prevent with hydration
and leucovorin, monitor levels
Myelosuppression; hepatitis; mucositis;
allopurinol increases toxicity
Myelosuppression, conjunctivitis,
mucositis, neurotoxicity
Myelosuppression; hemorrhagic cystitis
Similar to cyclophosphamide;
neurotoxicity, cardiac toxicity
Delayed myelosuppression (4-6 wk);
pulmonary fibrosis, carcinogenic,
stomatitis
Continued
602 SECTION 21 ONCOLOGY

TABLE 154.2 Cancer Chemotherapy—cont’d

DRUG ACTION INDICATION ACUTE TOXICITY*
Cisplatin Inhibits DNA synthesis Osteosarcoma, Nephrotoxic; myelosuppression,
neuroblastoma, CNS tumors, ototoxicity, neurotoxicity, hemolytic
germ cell tumors uremic syndrome
Carboplatin Inhibits DNA synthesis Same as for cisplatin Myelosuppression
TOPOISOMERASE INHIBITORS
Doxorubicin and Intercalation, DNA ALL, AML, osteosarcoma, Cardiomyopathy, red urine, tissue
daunorubicin strand breaks Ewing sarcoma, lymphoma, necrosis on extravasation,
neuroblastoma myelosuppression, conjunctivitis,
radiation dermatitis, arrhythmia
Dactinomycin Intercalation, DNA Wilms tumor, Tissue necrosis on extravasation,
strand breaks rhabdomyosarcoma, Ewing myelosuppression, hepatopathy with
sarcoma thrombocytopenia, stomatitis
Etoposide (VP-16) DNA strand breaks ALL, AML, lymphoma, germ Myelosuppression, secondary
cell tumor, sarcoma leukemia, allergic reaction
Topotecan DNA strand breaks Neuroblastoma, Myelosuppression, diarrhea, mucositis
rhabdomyosarcoma
TUBULIN INHIBITORS
Vincristine Inhibits microtubule ALL, lymphoma, Wilms tumor, Local cellulitis, peripheral neuropathy,
r formation Hodgkin disease, Ewing constipation, ileus, jaw pain,
sarcoma, neuroblastoma, inappropriate ADH secretion, seizures,
rhabdomyosarcoma, brain ptosis, minimal myelosuppression
tumors
Vinblastine Inhibits microtubule Hodgkin disease, Langerhans Local cellulitis, myelosuppression
formation cell histiocytosis
ENZYME
Asparaginase Depletion of asparagine ALL, AML Allergic reaction; pancreatitis,
hyperglycemia, platelet dysfunction
and coagulopathy, encephalopathy,
stroke, thrombosis
HORMONES
Prednisone, Direct lymphocyte ALL; Hodgkin disease, Cushing syndrome, cataracts, diabetes,
dexamethasone cytotoxicity lymphoma hypertension, myopathy, osteoporosis,
infection, peptic ulceration, irritability,
psychosis, hunger, fluid retention
MONOCLONAL ANTIBODIES
Rituximab Anti-CD20 CD20+ B-cell leukemia, Fever, chills, allergy
lymphoma
Brentuximab Anti-CD30 CD30+ lymphomas Myelosuppression, peripheral
neuropathy, fatigue, fever
Blinatumomab Anti-CD19 and anti-CD3 CD19+ refractory Cytokine release syndrome,
B-lymphoblastic leukemia neurotoxicity
Dinutuximab Anti-GD2 High-risk neuroblastoma Neuropathic pain, hypotension,
hypoxia, fever, capillary leak syndrome,
hypersensitivity reactions
SMALL MOLECULE PATHWAY INHIBITORS
Imatinib Inhibits BCR-ABL, VEGF, Ph+ CML, ALL Nausea, vomiting, fatigue, headache
c-KIT kinases
Dasatinib Inhibits BCR-ABL, c-KIT, Ph+ CML, ALL Fluid retention, rash, nausea
and other kinases
MISCELLANEOUS
Tretinoin (all-trans Promotes differentiation Acute promyelocytic leukemia Fever, respiratory distress, leukocytosis
retinoic acid) and (ATRA); neuroblastoma (CRA) (ATRA); dry mouth, hair loss,
isotretinoin (cis- pseudotumor cerebri (CRA)
retinoic acid)
Arsenic Promotes differentiation, Acute promyelocytic leukemia Transaminitis, nausea, vomiting,
apoptosis abdominal pain, QTc prolongation

*Many drugs produce nausea and vomiting during administration; many cause alopecia with repeated doses.
ADH, Antidiuretic hormone; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; CML, chronic myeloid leukemia; CNS,
central nervous system; VEGF, vascular endothelial growth factor.
 CHAPTER 155 Leukemia 603

TABLE 154.3 Long-Term Sequelae of Cancer Therapy EPIDEMIOLOGY

PROBLEM ETIOLOGICAL AGENT(S) ALL accounts for approximately 75%, acute myeloid leukemia
Infertility Alkylating agents; radiation (AML) accounts for approximately 20%, and CML accounts
for less than 5% of leukemia cases in the pediatric population.
Second cancers Genetic predisposition; radiation;
alkylating agents, etoposide, Other chronic leukemias, including juvenile myelomonocytic
topoisomerase II inhibitors leukemia, chronic myelomonocytic leukemia, and chronic
Sepsis Splenectomy
lymphocytic leukemia, are rare in childhood. ALL is the most
common childhood cancer, comprising 25% of cancer prior
Hepatotoxicity Methotrexate, 6-mercaptopurine; to the age of 15 years (40 per 1 million children under the age
radiation
of 15 years) and 19% of cancer prior to the age of 20 years.
Hepatic venoocclusive High-dose, intensive chemotherapy ALL is classified according to lymphoid lineage as either
disease (busulfan, cyclophosphamide) ± B cell or T cell. The incidence of B-lineage ALL peaks at 2-5
bone marrow transplant
years of age and is slightly more common in boys than in girls.
Scoliosis Radiation T-cell ALL is associated with male predominance and an older
Pulmonary (fibrosis) Radiation; bleomycin, busulfan age of onset. In the United States, ALL is more common in
Cardiomyopathy Doxorubicin, daunorubicin; radiation whites than in African American children. The incidence of
AML is relatively higher in the neonatal period, then drops
Leukoencephalopathy Cranial radiation, methotrexate
and stabilizes until adolescence when there is a slight increase,
Cognition/intelligence Cranial radiation, methotrexate which continues into adulthood (especially beyond 55 years of
Pituitary dysfunction Cranial radiation age). Males and females are equally affected by AML. Hispanic
(growth hormone and African American children have a slightly higher incidence
deficiency, of AML than white children.
panhypopituitarism)
Psychosocial Stress, anxiety, death of peers;
conditioned responses to CLINICAL MANIFESTATIONS
chemotherapy
Thyroid dysfunction Radiation Decision-Making Algorithms
Osteonecrosis Corticosteroids Available @ StudentConsult.com

Arthritis
Extremity Pain
Lymphadenopathy
Anemia
Bleeding

155
CHAPTER
Leukemia
ETIOLOGY
The etiology of childhood leukemia is unknown and is thought
to be multifactorial with both genetics and environmental factors
contributing to malignant transformation. In chronic myeloid
leukemia (CML) and, less commonly, in acute lymphoblastic
leukemia (ALL), a translocation involving chromosomes 9 and
22 (Philadelphia [Ph] chromosome) creates a novel fusion gene
called BCR-ABL. This results in the production of a constitu-
tively activated tyrosine kinase that drives the development of
CML and Ph-positive ALL. In addition, a number of genetic
syndromes/diseases including Down syndrome (Trisomy
21), Fanconi anemia, Bloom syndrome, ataxia-telangiectasia,
Wiskott-Aldrich syndrome, neurofibromatosis type 1, and
rare familial leukemia syndromes can predispose children to
the development of acute leukemia. Siblings of children with
leukemia are at an increased risk of developing leukemia with an
approximately two- to fourfold risk above the general pediatric
population (approximately 25% risk for monozygotic twins).
Environmental factors that may increase the risk of leukemia
include ionizing radiation and chemical exposures including
certain chemotherapy agents (particularly the topoisomerase
II inhibitors).
Signs and symptoms of acute leukemia are related to the
infiltration of leukemic cells into normal tissues, resulting in
either bone marrow failure (anemia, neutropenia, thrombocy-
topenia) and/or specific tissue infiltration (lymph nodes, liver,
spleen, brain, bone, skin, gingiva, testes). Common presenting
symptoms are fever, pallor, petechiae and/or ecchymoses,
lethargy, malaise, anorexia, and bone/joint pain. Physical
examination frequently reveals lymphadenopathy and hepato-
splenomegaly. The testes and central nervous system (CNS)
are common extramedullary sites for ALL involvement; neu-
rological symptoms or a painless enlargement of one or both
testes may be seen. Patients with T-cell ALL often have high
white blood cell (WBC) counts, an anterior mediastinal mass
(mediastinal adenopathy and/or thymic infiltration), cervical
lymphadenopathy, hepatosplenomegaly, and CNS involvement.
In patients with AML, extramedullary soft tissue tumors may
be found in various sites.
LABORATORY AND IMAGING STUDIES
The diagnosis of acute leukemia is confirmed by findings of
immature blast cells on the peripheral blood smear, bone
marrow aspirate, or both. Most patients have abnormal blood
counts; anemia and thrombocytopenia are common. The WBC
count may be low, normal, or high; 15-20% of patients have a