Severe Combined Immunodeficiency - PowerPoint Presentation

Slide1

Severe Combined Immunodeficiency

Introduction

Benjamin L.

Wright, MDSlide2

Disclosures

I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity. Slide3
Slide4

Objectives

Discuss the pathogenesis of SCID.

Provide an overview of the molecular defects.

Discuss clinical presentation

Explain the implications of newborn screening.

Review treatment strategies.

Address outcomes of treatment.Slide5

Severe Combined Immunodeficiency (SCID)

A fa

t

al

syndro

m

e

of

d

i

verse

genetic origin,

chara

c

te

r

ized

by

absenc

e

of T

and

B ce

l

l (and

some

t

imes NK

cel

l

) function

s

.Slide6

Blood ComponentsSlide7
Slide8
Slide9
Slide10

The FactorySlide11
Slide12

The School HouseSlide13

School House Lessons

Recognize self

Recognize non-selfSlide14

TRECsSlide15

Newborn Screening for SCIDSlide16
Slide17

Flow

C

ytometrySlide18
Slide19
Slide20

Mut

a

ti

ons

in

at

L

e

a

st

13

Di

f

fe

r

e

n

t

Gene

s

:

SCID

L

ymp

h

o

cyte Phenotypes

Lymphocyte

Profile

Molecular

Defect

T

-

B+ N

K

-

c-deficient,

Jak

3-deficient

T

-

B+ NK+

IL-7Ra-deficient, CD3-deficient, CD3-deficient, CD3-deficient, CD45-deficient

T

-

B

-

NK

-

AD

A

-defi

ci

ent

T- B- NK+

RAG1/RAG2-deficient, Artemis-deficient, Ligase 4-deficient, DNA-

PKcs

,

CernunosSlide21

T cell receptorSlide22
Slide23

Clinical Presentation

Common infections

otitis media

pneumonia

Opportunistic infections:

thrush

P

.

jiroveci

, fungus,

mycobacteria.

Chronic diarrhea

Failure to thriveSlide24

Absent

thymic

shadowSlide25

Oral thrushSlide26

Positive Screens: Referral

Referral to an immunologist

Reason: the TREC test picks up other T cell

lymphopenic

conditions in addition to SCID, many of which do not require a transplant.

No need to hospitalize positively screened newborn but parents should implement reverse precautions at home.Slide27

Diagnostic Evaluation

CBC with differential

Flow

cytometry

to assess lymphocyte subsets

T cell proliferation to mitogens

Genetic testingSlide28

Management

Transfusion precautions (CMV-, irradiated)

Antibiotic prophylaxis (

bactrim

/

pentamidine

for PJP)

Avoid live viral vaccines

IVIG

Contact precautionsSlide29

Treatment

Hematopoietic stem cell transplant (bone marrow, cord blood, peripheral blood)

Gene therapySlide30

Thymus growth after transplantSlide31

S

CID

Case

s

r

epo

r

t

ed

f

r

om

T

r

anspla

n

t

Ce

nt

e

r

s

d

y

s

g

e

n

e

s

is,

c

o

n

g

e

n

ital

Un

k

no

w

n

3%

I

L

2

R

G

50%

R

A

G1

1%

A

D

A 14%

IL7R 10%

JAK3 7%

RMRP 1%TTC7A 1%

RAG2 1%

abnormalities, ~1% each

Com

bined estimates from published series (Duke, European, PIDTC)

Un

k

no

w

n/un

- s

p

ecifi

e

d

23%

I

L

2

R

G

19%

R

A

G1

15%

A

DA

10%

I

L

7R

1

1%

P

redicted Incidence 1 perCD45, FOXN1, CD3D1, 00,000CD3E, Reticular

SCID Cases found in 11 States by Newborn ScreeningAverage Incidence: 52 cases in 3Million Infants,1.715 per 100,000, or 1/58,000 Survival 92%

Chromosome abnormality2%TTC7A 2%CD3D 2%DCLRE1C 2%RAG2 2%

Kwan et

al., JA

M

A

3

12:

72

9

-

7

3

8,

2014Slide32

Other conditions det

e

cted

by

TREC

s

cree

n

ing

Multisystem syndromes with variable T cell deficiency

57

%

DiGeorge

/chromosome 22q11.2

deletion

15

% Trisomy

21

3

% Ataxia

telangiectasia

2

% CHARGE syndromeSlide33

Other

conditions

det

e

cted by

TREC

scree

n

ing

Secondary

T

l

y

mp

h

openia

25% Congenital cardiac anomalies

38% Other congenital anomalies

13% Vascular leakage, third spacing

hydrops

3% Neonatal leukemiaSlide34

Other conditions det

e

cted

by

TREC

s

cree

n

ing

Extreme

preterm

birth

alone—T

cel

l

s

become

normal

o

v

er

time.

“

Variant SCID” or Idiopathic T lymphopeniaLow T cells and TRECs, low naïv

e

C

D

45

R

A

T

cells

no

maternal

eng

r

af

t

men

t

impaired

T

c

e

ll

or antibody responses, no known gene defectSlide35

T

cell

d

eficiencies

with

n

ormal

TREC

l

eve

l

s

Zap70

MHC

c

l

a

s

s

II

def

i

c

i

e

ncy

X-linked Hyper IgMWis

ko

tt

Ald

r

ic

h

S

y

n

d

r

o

me

HIV/AIDSSlide36

Estimated

prevalence of SCID

in US is 1:58,000

85,352

births in

AZ, 1,296

births i

n

the Navajo

Nation.

1.47

babies/

yr

born

with SCID in

AZ

0.48

babies/

yr

born

with SCID in the Navajo Nation

alone.

Estimated total babies born in AZ with SCID

–

1.95/

yr

NBS in AZ for SCIDSlide37

11.75

babies/

yr

with other causes of T cell

lymphopenia

in AZ

36

referrals/

yr

for confirmatory

testing

NBS in AZ for SCIDSlide38
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