Primary immunodeficiencies: 2009 update

Primary immunodeficiencies: 2009 update:The International Union of Immunological Societies (IUIS) Primary Immunodeficiencies (PID)

Expert Committee

IUIS Expert Committee on Primary Immunodeficiencies:, Luigi D. Notarangelo, M.D.a, AlainFischer, M.D.b, Raif. S. Geha, M.D. [(Co-chairs)]a, Jean-Laurent Casanova, M.D.c, HelenChapel, M.D.d, Mary Ellen Conley, M.D.e, Charlotte Cunningham-Rundles, M.D., Ph.D.f, AmosEtzioni, M.D.g, Lennart Hammartröm, M.D.h, Shigeaki Nonoyama, M.D.i, Hans D. Ochs,M.D.j, Jennifer Puck, M.D.k, Chaim Roifman, M.D.l, Reinhard Seger, M.D.m, and JosiahWedgwood, M.D., Ph.D.n

aDivision of Immunology, Children’s Hospital Boston and Department of Pediatrics, Harvard MedicalSchool, Boston, MA, USA bHopital Necker Enfants Malades, Paris, France cThe RockefellerUniversity, New York City, NY, USA dDepartment of Clinical Immunology, Oxford RadcliffeHospitals, Oxford, UK eThe University of Tennessee and St. Jude Children’s Research Hospital,Memphis, TN, USA fMount Sinai School of Medicine, New York City, NY, USA gMeyer’s ChildrenHospital, Rappaport Faculty of Medicine, Technion, Haifa, Israel hDivision of Clinical Immunology,Karolinska University Hospital Huddinge, Stockholm, Sweden iDepartment of Pediatrics, NationalDefense Medical College, Tokorozawa, Japan jDepartment of Pediatrics, University of WashingtonSchool of Medicine, Seattle, WA, USA kDepartment of Pediatrics, University of California at SanFrancisco, San Francisco, CA, USA lThe Sick Children’s Hospital, Toronto, Canada mUniversitäsKinderklinik, Zurich, Switzerland nNational Institute of Allergy and Infectious Diseases, Bethesda,MD, USA

AbstractMore than 50 years after Ogdeon Bruton’s discovery of congenital agammaglobulinemia, humanprimary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanismsthat govern development and function of the human immune system. This report provides the updatedclassification of PIDs, that has been compiled by the International Union of Immunological Societies(IUIS) Expert Committee of Primary Immunodeficiencies after its biannual meeting, in Dublin(Ireland) in June 2009. Since the appearance of the last classification in 2007, novel forms of PIDhave been discovered, and additional pathophysiology mechanisms that account for PID in humanshave been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompteffective forms of treatment and thus to improve survival and quality of life in patients affected withPIDs.

© 2009 American Academy of Allergy, Asthma and Immunology. Published by Mosby, Inc. All rights reserved.Correspondence to: Luigi Notarangelo: [email protected], Alain Fischer: [email protected] orRaif Geha: raif.geha@childrens Division of Immunology, Children’s Hospital, One Blackfan Circle, Boston, MA 02115, Tel:617-919-2482, Fax: 617-730-0528.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain.

NIH Public AccessAuthor ManuscriptJ Allergy Clin Immunol. Author manuscript; available in PMC 2010 December 1.

Published in final edited form as:J Allergy Clin Immunol. 2009 December ; 124(6): 1161–1178. doi:10.1016/j.jaci.2009.10.013.

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-PA Author Manuscript

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Keywordsprimary immunodeficiencies; T cells; B cells; severe combined immune deficiency; predominantlyantibody deficiencies; DNA repair defects; phagocytes; complement; immune dysregulationsyndromes; innate immunity; autoinflammatory disorders

Since 1970, a Committee of experts in the field of Primary Immunodeficiencies (PID) has metevery two years with the goal of classifying and defining these disorders. The most recentmeeting, organized by the Experts Committee on Primary Immunodeficiencies of theInternational Union of Immunological Societies (IUIS), with support from the Jeffrey ModellFoundation and the National Institute of Allergy and Infectious Diseases (NIAID) of theNational Institutes of Health, took place in Dublin, Ireland, in June 2009. In addition tomembers of the Experts Committee, the meeting gathered more than 30 speakers and over 200participants from six continents. Recent discoveries on the molecular and cellular bases of PIDand advances in the diagnosis and treatment of these disorders were discussed. At the end ofthe meeting, the IUIS Experts Committee on Primary Immunodeficiencies met to update theclassification of PIDs, presented in Table 1–Table 8.

The general outline of the classification has remained substantially unchanged. Novel PIDs,whose molecular basis has been identified and reported in the last two years, have been addedto the list. In Table I (Combined T and B cell immunodeficiencies), coronin-1A deficiency(resulting in impaired thymic egress) has been added to the genetic defects causing T− B+

SCID. The first case of DNA-PKcs deficiency has also been reported, and adds to the list ofdefects of non-homologous end-joining resulting in T− B− SCID. Among calcium flux defects,defects of Stim-1, a Ca++ sensor, have been reported in children with immunodeficiency,myopathy and autoimmunity. Mutations of the gene encoding the dedicator of cytokinesis 8(DOCK8) protein have been shown to cause an autosomal recessive combinedimmunodeficiency with hyper-IgE, also characterized by extensive cutaneous viral infections,severe atopy and increased risk of cancer. In the same Table, mutations of the adenylate kinase2 (AK2) gene have been shown to cause reticular dysgenesis, and mutations in DNA ligase IV,ADA and γc have been added to the list of genetic defects that may cause Omenn syndrome.

In Table II (Predominantly antibody deficiencies), mutations in TACI and in BAFF-receptor(BAFF-R) have been added to the list of gene defects that may cause hypogammaglobulinemia.However, it should be noted that only few TACI mutations appear to be disease-causing.Furthermore, variability of clinical expression has been associated with the rare BAFF-Rdeficiency. Table III lists other well-defined immunodeficiency syndromes. PMS2 deficiencyand ICF syndrome (immunodeficiency with centromeric instability and facial anomalies) havebeen added to the list of DNA repair defects, whereas Comel-Netherton syndrome is nowincluded among the immune-osseous dysplasias, and hyper-IgE syndrome due to DOCK8mutation has also been added. ITK deficiency has been included among the molecular causesof lymphoproliferative syndrome in Table IV (Diseases of immune dysregulation). In the sameTable, CD25 deficiency has been listed, to reflect the occurrence of autoimmuninty in this raredisorder. Progress in the molecular characterization of congenital neutropenia and other innateimmunity defects has resulted in the inclusion of G6PT1 and G6PC3 defects in Table V(Congenital defects of phagocyte number, function, or both), and of MyD88 deficiency(causing recurrent pyogenic bacterial infections) in Table VI (Defects of innate immunity),respectively. These two Tables also include two novel genetic defects that result in clinicalphenotypes distinct from the classical definition of PIDs. In particular, mutations of theCSFR2A gene, encoding for granulocyte macrophage-colony stimulating factor receptor α(GM-CSF Rα), have been shown to cause primary alveolar proteinosis due to defectivesurfactant catabolism by alveolar macrophages (see: Table V). Mutations in APOL-I are

et al.

J Allergy Clin Immunol. Author manuscript; available in PMC 2010 December 1.

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associated with trypanosomiasis, as reported in Table VI. It can be anticipated that a growingnumber of defects in immune-related genes will be shown to be responsible for non-classicalforms of PIDs in the future. Along the same line, the spectrum of genetically definedautoinflammatory disorders (Table VIII) has expanded to include NLRP12 mutations(responsible for familial cold autoinflammatory syndrome) and IL1RN defects (causingdeficiency of the Interleukin-1 receptor antagonist). Again, it is expected that a growing numberof genetic defects will be identified in other inflammatory conditions. Finally, defects of Ficolin3 (that plays an important role in complement activation) have been shown to cause recurrentpyogenic infections in the lung (Table VIII).

While the revised classification of PIDs is meant to assist with the identification, diagnosis andmanagement of patients with these conditions, it should not be used dogmatically. In particular,although the typical clinical and immunological phenotype is reported for each PID, it has beenincreasingly recognized that the phenotypic spectrum of these disorders is wider than originallythought. This variability reflects both the effect of different mutations within PID-causinggenes, and the role of other genetic, epigenetic and environmental factors in modifying thephenotype. For example, germline hypomorphic mutations or somatic mutations in SCID-related genes may result in atypical/leaky SCID or Omenn syndrome, the latter associated withsignificant immunopathology. Furthermore, infections may also significantly modify theclinical and immunological phenotype, even in patients who initially present with typical SCID.Thus, the phenotype associated with single-gene defects listed in the revised classificationshould by no means be considered absolute.

Finally, a new column has been added to the revised classification, to illustrate the relativefrequency of the various PID disorders. It should be noted that these frequency estimates arebased on what has been reported in the literature, since, with few exceptions, no solidepidemiologic data exist that can be reliably used to define the incidence of PID disorders.Furthermore, the frequency of PIDs may vary in different countries. Certain populations (andespecially, some restricted ethnic groups of geographical isolates) have a higher frequency ofspecific PID mutations, due to a founder effect and genetic drift. For example, DCLER1C(Artemis) and ZAP70 defects are significantly more common in Athabascan-speaking NativeAmericans and in members of the Mennonite Church, respectively, than in other populations.Similarly, MHC class II deficiency is more frequent in Northern Africa. Furthermore, thefrequency of autosomal recessive immunodeficiencies is higher among populations with a highconsanguinity rate.

AcknowledgmentsThe Dublin meeting was supported by the Jeffrey Modell Foundation and by the NIAID grant R13-AI-066891.Preparation of this report was supported by NIH grant AI-35714 to R.S.G. and L.N.

et al.


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TAB

LE I

Com

bine

d T

and

B c

ell i

mm

unod

efic

ienc

ies

Dis

ease

Cir

cula

ting

T c

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

es/a

typi

cal

pres

enta

tion

Inhe

rita

nce

Mol

ecul

ar d

efec

t/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s**

1. T

− B+

SCID

*

(a)

γc

defic

ienc

yM

arke

dly

decr

ease

dN

orm

al o

r inc

reas

edD

ecre

ased

Mar

kedl

y de

crea

sed

NK

cel

lsLe

aky

case

s may

pre

sent

with

low

to n

orm

al T

and

/or N

Kce

lls

XL

Def

ect i

n γ

chai

n of

rece

ptor

sfo

r IL-

2, -4

, -7,

-9, -

15, -

21R

are

(b)

JAK

3 de

ficie

ncy

Mar

kedl

y de

crea

sed

Nor

mal

or

incr

ease

dD

ecre

ased

Mar

kedl

y de

crea

sed

NK

cel

lsLe

aky

case

s may

pre

sent

with

varia

ble

T an

d/or

NK

cel

ls

AR

Def

ect i

n Ja

nus a

ctiv

atin

gki

nase

3V

ery

rare

(c)

IL7R

α de

ficie

ncy

Mar

kedl

y de

crea

sed

Nor

mal

or

incr

ease

dD

ecre

ased

Nor

mal

NK

cel

lsA

RD

efec

t in

IL-7

rece

ptor

αch

ain

Ver

y ra

re

(d)

CD

45 d

efic

ienc

yM

arke

dly

decr

ease

dN

orm

alD

ecre

ased

Nor

mal

γ/δ

T c

ells

AR

Def

ect i

n C

D45

Extre

mel

y ra

re

(e)

CD

3δ/C

D3ε

/CD

3ζde

ficie

ncy

Mar

kedl

y D

ecre

ased

Nor

mal

Dec

reas

edN

orm

al N

K c

ells

No γ/δ

T ce

llsA

RD

efec

t in

CD

3δ C

D3ε

or

CD

3ζch

ains

of T

cel

l ant

igen

rece

ptor

com

plex

Ver

y ra

re

(f)

Cor

onin

-1A

def

icie

ncy

Mar

kedl

y de

crea

sed

Nor

mal

Dec

reas

edD

etec

tabl

e th

ymus

AR

Def

ectiv

e th

ymic

egr

ess o

f Tce

lls a

nd T

cel

l loc

omot

ion

Extre

mel

y ra

re

2. T

− B−

SCID

*

(a

) RA

G 1

/2 d

efic

ienc

yM

arke

dly

decr

ease

dM

arke

dly

decr

ease

dD

ecre

ased

Def

ectiv

e V

DJ r

ecom

bina

tion

May

pre

sent

with

Om

enn

synd

rom

e

AR

Def

ect o

f rec

ombi

nase

activ

atin

g ge

ne (R

AG

) 1 o

r 2R

are

(b)

DC

LRE1

C (A

rtem

is)

defic

ienc

yM

arke

dly

decr

ease

dM

arke

dly

decr

ease

dD

ecre

ased

Def

ectiv

e V

DJ r

ecom

bina

tion,

radi

atio

n se

nsiti

vity

May

pre

sent

with

Om

enn

synd

rom

e

AR

Def

ect i

n A

rtem

is D

NA

reco

mbi

nase

-rep

air p

rote

inV

ery

rare

(c)

DN

A P

Kcs

def

icie

ncy

Mar

kedl

y de

crea

sed

Mar

kedl

y de

crea

sed

Dec

reas

ed[w

idel

y st

udie

d sc

id m

ouse

defe

ct]

AR

Def

ect i

n D

NA

PKcs

Rec

ombi

nase

repa

ir pr

otei

nEx

trem

ely

rare

(d)

Ade

nosi

ne d

eam

inas

e(A

DA

) def

icie

ncy

Abs

ent f

rom

birt

h(n

ull m

utat

ions

) or

prog

ress

ive

decr

ease

Abs

ent f

rom

birt

hor

pro

gres

sive

decr

ease

Prog

ress

ive

decr

ease

Cos

toch

ondr

al ju

nctio

nfla

ring,

neur

olog

ical

feat

ures

, hea

ring

impa

irmen

t, lu

ng a

nd li

ver

man

ifest

atio

ns. C

ases

with

parti

al A

DA

act

ivity

may

hav

ea de

laye

d or

mild

er p

rese

ntat

ion

AR

Abs

ent A

DA

, ele

vate

dly

mph

otox

ic m

etab

olite

s(d

ATP

, S-a

deno

syl

hom

ocys

tein

e)

Rar

e

(e)

Ret

icul

ar d

ysge

nesi

sM

arke

dly

decr

ease

dD

ecre

ased

or n

orm

alD

ecre

ased

Gra

nulo

cyto

peni

a, d

eafn

ess

AR

Def

ectiv

e m

atur

atio

n of

T, B

and

mye

loid

cel

ls (s

tem

cel

lde

fect

)D

efec

t in

mito

chon

dria

l

Extre

mel

y ra

re

et al.


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Dis

ease

Cir

cula

ting

T c

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

es/a

typi

cal

pres

enta

tion

Inhe

rita

nce

Mol

ecul

ar d

efec

t/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s**

aden

ylat

e ki

nase

2.

3. O

men

n sy

ndro

me*

**Pr

esen

t; re

stric

ted

hete

roge

neity

Nor

mal

or

decr

ease

dD

ecre

ased

, exc

ept

incr

ease

d Ig

EEr

ythr

oder

ma,

eos

inop

hilia

,ad

enop

athy

,he

pato

sple

nom

egal

y

AR

Hyp

omor

phic

mut

atio

ns in

RA

G1/

2, A

rtem

is, I

L-7R

α,R

MR

P, A

DA

, DN

A L

igas

eIV

,γc

Rar

e

4. D

NA

liga

se IV

defic

ienc

yD

ecre

ased

Dec

reas

edD

ecre

ased

Mic

roce

phal

y, fa

cial

dysm

orph

ism

s, ra

diat

ion

sens

itivi

tyM

ay p

rese

nt w

ith O

men

nsy

ndro

me

or w

ith a

del

ayed

clin

ical

ons

et.

AR

DN

A li

gase

IV d

efec

t,im

paire

dno

nhom

olog

ous e

nd jo

inin

g(N

HEJ

)

Ver

y ra

re

5. C

ernu

nnos

def

icie

ncy

Dec

reas

edD

ecre

ased

Dec

reas

edM

icro

ceph

aly,

in u

tero

gro

wth

reta

rdat

ion,

radi

atio

nse

nsiti

vity

AR

Cer

nunn

os d

efec

t, im

paire

dN

HEJ

Ver

y ra

re

6. C

D40

liga

nd d

efic

ienc

yN

orm

alIg

M+

and

IgD

+ B

cells

pre

sent

, oth

eris

otyp

es a

bsen

t

IgM

incr

ease

d or

norm

al, o

ther

isot

ypes

decr

ease

d

Neu

trope

nia,

thro

mbo

cyto

peni

a;he

mol

ytic

ane

mia

, bili

ary

tract

and

liver

dis

ease

, opp

ortu

nist

icin

fect

ions

XL

Def

ects

in C

D40

liga

nd(C

D40

L) c

ause

defe

ctiv

eis

otyp

e sw

itchi

ng a

ndim

paire

dde

ndrit

ic c

ell s

igna

ling

Rar

e

7. C

D40

def

icie

ncy

Nor

mal

IgM

+ an

d Ig

D+

Bce

lls p

rese

nt, o

ther

isot

ypes

abs

ent

IgM

incr

ease

d or

norm

al, o

ther

isot

ypes

decr

ease

d

Neu

trope

nia,

gas

troin

test

inal

and

liver

/bili

ary

tract

dis

ease

,op

portu

nist

ic in

fect

ions

AR

Def

ects

in C

D40

cau

sede

fect

ive

isot

ype

switc

hing

and

impa

ired

dend

ritic

cel

lsi

gnal

ing

Extre

mel

y ra

re

8. P

urin

e nu

cleo

side

phos

phor

ylas

e de

ficie

ncy

(PN

P)

Prog

ress

ive

decr

ease

Nor

mal

Nor

mal

or d

ecre

ased

Aut

oim

mun

e ha

emol

ytic

anae

mia

, neu

rolo

gica

lim

pairm

ent

AR

Abs

ent P

NP,

T-c

ell a

ndne

urol

ogic

def

ects

from

elev

ated

toxi

c m

etab

olite

s(e

.g. d

GTP

)

Ver

y ra

re

9. C

D3γ

def

icie

ncy

Nor

mal

, but

redu

ced

TCR

exp

ress

ion

Nor

mal

Nor

mal

AR

Def

ect i

n C

D3 γ

Extre

mel

y ra

re

10. C

D8

defic

ienc

yA

bsen

t CD

8, n

orm

alC

D4

cells

Nor

mal

Nor

mal

AR

Def

ects

of C

D8 α

chai

nEx

trem

ely

rare

11. Z

AP-

70 d

efic

ienc

yD

ecre

ased

CD

8,no

rmal

CD

4 ce

llsN

orm

alN

orm

alA

RD

efec

ts in

ZA

P-70

sign

alin

gki

nase

Ver

y ra

re

12. C

a++ c

hann

elde

ficie

ncy

Nor

mal

cou

nts,

defe

ctiv

e TC

Rm

edia

ted

activ

atio

n

Nor

mal

cou

nts

Nor

mal

Aut

oim

mun

ity, a

nhyd

rotic

ecto

derm

ic d

yspl

asia

, non

-pr

ogre

ssiv

e m

yopa

thy

AR

AR

Def

ect i

n O

rai-1

, a C

a++

chan

nel c

ompo

nent

Def

ect i

n St

im-I

, a C

a++

sens

or

Extre

mel

y ra

re

13. M

HC

clas

s I d

efic

ienc

yD

ecre

ased

CD

8,no

rmal

CD

4N

orm

alN

orm

alV

ascu

litis

AR

Mut

atio

ns in

TAP

1, T

AP2

orTA

PBP

(tapa

sin)

gen

esgi

ving

MH

C c

lass

I de

ficie

ncy

Ver

y ra

re

14. M

HC

cla

ss II

defic

ienc

yN

orm

al n

umbe

r,de

crea

sed

CD

4 ce

llsN

orm

alN

orm

al o

r dec

reas

edA

RM

utat

ion

in tr

ansc

riptio

nfa

ctor

s for

MH

C c

lass

IIR

are

et al.


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Dis

ease

Cir

cula

ting

T c

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

es/a

typi

cal

pres

enta

tion

Inhe

rita

nce

Mol

ecul

ar d

efec

t/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s**

prot

eins

(C2T

A, R

FX5,

RFXA

P, R

FXAN

K g

enes

)

15. W

inge

d he

lixde

ficie

ncy

(Nud

e)

Mar

kedl

y de

crea

sed

Nor

mal

Dec

reas

edA

lope

cia,

abn

orm

al th

ymic

epith

eliu

m, i

mpa

ired

T ce

llm

atur

atio

n [w

idel

y st

udie

dnu

dem

ouse

def

ect]

AR

Def

ects

in fo

rkhe

ad b

ox N

1tra

nscr

iptio

n fa

ctor

enc

oded

by FOXN

1, th

e ge

ne m

utat

ed in

nude

mic

e

Extre

mel

y ra

re

16. C

D25

def

icie

ncy

Nor

mal

to m

odes

tlyde

crea

sed

Nor

mal

Nor

mal

Lym

phop

rolif

erat

ion

(lym

phad

enop

athy

,he

pato

sple

nom

egal

y),

auto

imm

unity

(may

rese

mbl

eIP

EX sy

ndro

me)

, im

paire

d T-

cell

prol

ifera

tion

AR

Def

ects

in IL

-2Rα

chai

nEx

trem

ely

rare

17. S

TA

T5b

def

icie

ncy

Mod

estly

dec

reas

edN

orm

alN

orm

alG

row

th-h

orm

one

inse

nsiti

vedw

arfis

m, d

ysm

orph

icfe

atur

es,

ecze

ma,

lym

phoc

ytic

inte

rstit

alpn

eum

oniti

s, au

toim

mun

ity

AR

Def

ects

of S

TAT5

b, im

paire

dde

velo

pmen

t and

func

tion

ofγδ

T ce

lls, T

reg

and

NK

cel

ls,

impa

ired

T-ce

ll pr

olife

ratio

n

Extre

mel

y ra

re

18. I

tk d

efic

ienc

yM

odes

tlyde

crea

sed

Nor

mal

Nor

mal

or

decr

ease

dA

REB

V a

ssoc

iate

dly

mph

opro

lifer

atio

nEx

trem

ely

rare

19. D

OC

K8

defic

ienc

yD

ecre

ased

Dec

reas

edLo

w Ig

M, i

ncre

ased

IgE

Rec

urre

nt re

spira

tory

infe

ctio

ns.

Exte

nsiv

e cu

tane

ous v

iral a

ndba

cter

ial (

stap

h.) i

nfec

tions

,su

scep

tibili

ty to

can

cer,

hype

reos

inop

hilia

, sev

ere

atop

y,lo

w N

K c

ells

AR

Def

ect i

n D

OC

K8

Ver

y ra

re

Abbr

evia

tions

: SC

ID, s

ever

e co

mbi

ned

imm

une

defic

ienc

ies;

XL,

X-li

nked

inhe

ritan

ce; A

R, a

utos

omal

rece

ssiv

e in

herit

ance

; NK

, nat

ural

kill

er c

ells

.* A

typi

cal c

ases

of S

CID

may

pre

sent

with

T c

ells

bec

ause

of h

ypom

orph

ic m

utat

ions

or s

omat

ic m

utat

ions

in T

cel

l pre

curs

ors.

**Fr

eque

ncy

: may

var

y fr

om re

gion

to re

gion

or e

ven

amon

g co

mm

uniti

es i.

e. M

enno

nite

, Inn

uit e

tc.

*** So

me

case

s of O

men

n sy

ndro

me

rem

ain

gene

tical

ly u

ndef

ined

****

Som

e m

etab

olic

dis

orde

rs su

ch m

ethy

lmal

onic

aci

duria

may

pre

sent

with

pro

foun

d ly

mph

open

ia in

add

ition

to th

eir t

ypic

al p

rese

ntin

g fe

atur

es.

et al.


NIH


NIH


NIH


Tabl

e II

Pred

omin

antly

Ant

ibod

y D

efic

ienc

ies

Dis

ease

Seru

m Ig

Ass

ocia

ted

Feat

ures

Inhe

rita

nce

Gen

etic

Def

ects

/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s

1. S

ever

e re

duct

ion

in a

ll se

rum

imm

unog

lobu

lin is

otyp

es w

ithpr

ofou

ndly

dec

reas

ed o

r abs

ent B

cel

ls

a)

Btk

def

icie

ncy

All

isot

ypes

dec

reas

edSe

vere

bac

teria

l inf

ectio

ns;

norm

al n

umbe

rs o

f pro

-B c

ells

XL

Mut

atio

ns in

BTK

rare

b) μ

heav

y ch

ain

defic

ienc

yA

ll is

otyp

es d

ecre

ased

Seve

re b

acte

rial i

nfec

tions

;no

rmal

num

bers

of p

ro-B

cel

lsA

RM

utat

ions

in μ

hea

vy c

hain

very

rare

c) λ

5 de

ficie

ncy

All

isot

ypes

dec

reas

edSe

vere

bac

teria

l inf

ectio

ns;

norm

al n

umbe

rs o

f pro

-B c

ells

AR

Mut

atio

ns in

λ5

extre

mel

yra

re

d)

Igα

defic

ienc

yA

ll is

otyp

es d

ecre

ased

Seve

re b

acte

rial i

nfec

tions

;no

rmal

num

bers

of p

ro-B

cel

lsA

RM

utat

ions

in Igα

extre

mel

y ra

re

e)

Ig β

def

icie

ncy

All

isot

ypes

dec

reas

edSe

vere

bac

teria

l inf

ectio

nsno

rmal

num

bers

of p

ro-B

cel

lsA

RM

utat

ions

in Igβ

extre

mel

yra

re

f)

BLN

K d

efic

ienc

yA

ll is

otyp

es d

ecre

ased

Seve

re b

acte

rial i

nfec

tions

norm

al n

umbe

rs o

f pro

-B c

ells

AR

Mut

atio

ns in

BLN

Kex

trem

ely

rare

g)

Thym

oma

with

imm

unod

efic

ienc

yA

ll is

otyp

es d

ecre

ased

Bac

teria

l and

opp

ortu

nist

icin

fect

ions

;au

toim

mun

ity

Non

eU

nkno

wn

rare

2. S

ever

e re

duct

ion

in a

t lea

st 2

seru

mim

mun

oglo

bulin

isot

ypes

with

nor

mal

or

low

num

bers

of B

cel

ls

a)

Com

mon

var

iabl

eim

mun

odef

icie

ncy

diso

rder

s*Lo

w Ig

G a

nd Ig

A a

nd/o

rIg

MC

linic

al p

heno

type

s var

y: m

ost h

ave

recu

rren

t bac

teria

l inf

ectio

ns, s

ome

have

aut

oim

mun

e,ly

mph

opro

lifer

ativ

ean

d/or

gra

nulo

mat

ous d

isea

se

Var

iabl

eU

nkno

wn

rela

tivel

yco

mm

on

b)

ICO

S de

ficie

ncy

Low

IgG

and

IgA

and

/or

IgM

-A

RM

utat

ions

in IC

OS

extre

mel

yra

re

c)

CD

19 d

efic

ienc

yLo

w Ig

G, a

nd Ig

A a

nd/o

rIg

M-

AR

Mut

atio

ns in

CD

19ex

trem

ely

rare

d)

TAC

I def

icie

ncy*

*Lo

w Ig

G a

nd Ig

A a

nd/o

rIg

M-

AD

or A

R o

rco

mpl

exM

utat

ions

in T

NFR

SF13

B(T

AC

I)ve

ry c

omm

on

e)

BA

FF re

cept

or d

efic

ienc

y**

Low

IgG

and

IgM

Var

iabl

e cl

inic

al e

xpre

ssio

nA

RM

utat

ions

in T

NFR

SF13

C(B

AFF

-R)

extre

mel

yra

re

et al.


NIH


NIH


NIH


Dis

ease

Seru

m Ig

Ass

ocia

ted

Feat

ures

Inhe

rita

nce

Gen

etic

Def

ects

/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s

3. S

ever

e re

duct

ion

in se

rum

IgG

and

IgA

with

nor

mal

/ele

vate

d Ig

M a

ndno

rmal

num

bers

of B

cel

ls

a)

CD

40L

defic

ienc

y***

IgG

and

IgA

dec

reas

ed; I

gMm

ay b

e no

rmal

or i

ncre

ased

;B

cel

l num

bers

may

be

norm

al o

r inc

reas

ed

Opp

ortu

nist

ic in

fect

ions

,ne

utro

peni

a,au

toim

mun

e di

seas

e

XL

Mut

atio

ns in

CD

40L

(als

oca

lled

TNFS

F5 o

r CD

154)

rare

b)

CD

40 d

efic

ienc

y***

Low

IgG

and

IgA

; nor

mal

or

rais

ed Ig

MO

ppor

tuni

stic

infe

ctio

ns,

neut

rope

nia,

auto

imm

une

dise

ase

AR

Mut

atio

ns in

CD

40 (a

lso

calle

dTN

FRSF

5)ex

trem

ely

rare

c)

AID

def

icie

ncy*

****

IgG

and

IgA

dec

reas

ed; I

gMin

crea

sed

Enla

rged

lym

ph n

odes

and

ger

min

alce

nter

sA

RM

utat

ions

in A

ICD

A ge

neve

ry ra

re

d)

UN

G d

efic

ienc

y***

*Ig

G an

d Ig

A d

ecre

ased

; IgM

incr

ease

dEn

larg

ed ly

mph

nod

es a

nd g

erm

inal

cent

ers

AR

Mut

atio

n in

UN

Gex

trem

ely

rare

4. Is

otyp

e or

ligh

t cha

in d

efic

ienc

ies w

ithno

rmal

num

bers

of B

cel

ls

a)

Ig h

eavy

cha

in m

utat

ions

and

dele

tions

One

or m

ore

IgG

and

/or I

gAsu

bcla

sses

as w

ell a

s IgE

may

be

abse

nt

May

be

asym

ptom

atic

AR

Mut

atio

n or

chr

omos

omal

dele

tion

at14

q32

Rel

ativ

ely

com

mon

b) κ

chai

n de

ficie

ncy

All

imm

unog

lobu

lins h

ave

lam

bda

light

cha

inA

sym

ptom

atic

AR

Mut

atio

n in

Kap

pa c

onst

ant

gene

Extre

mel

yra

re

c)

Isol

ated

IgG

subc

lass

defic

ienc

yR

educ

tion

in o

ne o

r mor

eIg

Gsu

bcla

ss

Usu

ally

asy

mpt

omat

ic; m

ay h

ave

recu

rren

t vira

l/ ba

cter

ial i

nfec

tions

Var

iabl

eU

nkno

wn

Rel

ativ

ely

com

mon

d)

IgA

with

IgG

subc

lass

defic

ienc

yR

educ

ed Ig

A w

ith d

ecre

ase

in o

ne o

r mor

e IgG

subc

lass

;R

ecur

rent

bac

teria

l inf

ectio

ns in

maj

ority

Var

iabl

eU

nkno

wn

Rel

ativ

ely

com

mon

e)

Sele

ctiv

e Ig

A d

efic

ienc

yIg

A d

ecre

ased

/ abs

ent

Usu

ally

asy

mpt

omat

ic; m

ay h

ave

recu

rren

t inf

ectio

ns w

ith p

oor

antib

ody

resp

onse

s to

carb

ohyd

rate

ant

igen

s;m

ay h

ave

alle

rgie

s or a

utoi

mm

une

dise

ase.

A fe

w c

ases

pro

gres

s to

CV

ID,

othe

rs co

exis

t with

CV

ID in

the s

ame

fam

ily.

Var

iabl

eU

nkno

wn

Mos

t com

mon

5. S

peci

fic a

ntib

ody

defic

ienc

y w

ithno

rmal

Ig c

once

ntra

tions

and

nor

mal

num

bers

of B

cel

ls

Nor

mal

Inab

ility

to m

ake

antib

odie

s to

spec

ific

antig

ens

Var

iabl

eU

nkno

wn

Rel

ativ

ely

com

mon

et al.


NIH


NIH


NIH


Dis

ease

Seru

m Ig

Ass

ocia

ted

Feat

ures

Inhe

rita

nce

Gen

etic

Def

ects

/pre

sum

edpa

thog

enes

isR

elat

ive

freq

uenc

yam

ong

PID

s

6. T

rans

ient

hyp

ogam

mag

lobu

linem

ia o

fin

fanc

y w

ith n

orm

al n

umbe

rs o

f B c

ells

IgG

and

IgA

dec

reas

edR

ecur

rent

mod

erat

e ba

cter

ial

infe

ctio

nsV

aria

ble

Unk

now

nco

mm

on

XL, X

-link

ed in

herit

ance

; AR,

aut

osom

al re

cess

ive

inhe

ritan

ce; A

D, a

utos

omal

dom

inan

t inh

erita

nce;

BTK

, Bur

ton

tyro

sine

kin

ase;

BLN

K, B

cel

l lin

ker p

rote

in; A

ID, a

ctiv

atio

n-in

duce

d cy

tidin

e de

amin

ase;

UN

G, u

raci

l-DN

A g

lyco

syla

se; I

CO

S, in

duci

ble

cost

imul

ator

; Ig(ĸ)

, im

mun

oglo

bulin

of ĸ

ligh

t-cha

in ty

pe;

* Com

mon

var

iabl

e im

mun

odef

icie

ncy

diso

rder

s: th

ere

are

seve

ral d

iffer

ent c

linic

al p

heno

type

s, pr

obab

ly re

pres

entin

g di

stin

guis

habl

e di

seas

es w

ith d

iffer

ing

imm

unop

atho

gene

ses

**A

ltera

tions

in T

NFR

SF13

B (T

ACI)

and

TN

FRSF

13C

(BAF

F-R)

sequ

ence

may

repr

esen

t dis

ease

mod

ifyin

g m

utat

ions

rath

er th

an d

isea

se c

ausi

ng m

utat

ions

*** C

D40

L an

d C

D40

def

icie

ncy

are

also

incl

uded

in T

able

I**

*** D

efic

ienc

y of

activ

atio

n in

duce

d cy

tidin

e dea

min

se (A

ID) o

r ura

cil-D

NA

gly

cosy

lase

(UN

G) p

rese

nt as

form

s of t

he h

yper

-IgM

synd

rom

e but

diff

er fr

om C

D40

L an

d C

D40

def

icie

ncie

s in

that

the p

atie

nts

have

larg

e ly

mph

nod

es w

ith g

erm

inal

cen

ters

and

are

not

susc

eptib

le to

opp

ortu

nist

ic in

fect

ions

.

et al.


NIH


NIH


NIH


Tabl

e III

Oth

er w

ell-d

efin

ed im

mun

odef

icie

ncy

synd

rom

es.

Dis

ease

Cir

cula

ting

Tce

llsC

ircu

latin

gB

cel

lsSe

rum

IgA

ssoc

iate

d fe

atur

esIn

heri

tanc

e

Gen

etic

defe

cts/

Pres

umed

Path

ogen

esis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

1. W

isko

tt-A

ldric

h sy

ndro

me

(WA

S)Pr

ogre

ssiv

ede

crea

se,

Abn

orm

ally

mph

ocyt

ere

spon

ses t

oan

ti-C

D3

Nor

mal

Dec

reas

ed Ig

M: a

ntib

ody

topo

lysa

ccha

rides

par

ticul

arly

decr

ease

d; o

ften

incr

ease

dIg

A a

nd Ig

E

Thro

mbo

cyto

peni

a w

ithsm

all

plat

elet

s; e

czem

a;ly

mph

omas

;au

toim

mun

e di

seas

e;Ig

Ane

phro

path

y; b

acte

rial

and

vira

lin

fect

ions

. XL

thro

mbo

cyto

peni

a is

am

ild fo

rm o

f WA

S, a

ndX

Lne

utro

peni

a is

cau

sed

bym

isse

nse

mut

atio

ns in

the

GTP

ase

bind

ing

dom

ain

of W

ASP

XL

Mut

atio

ns in

WAS

P;cy

tosk

elet

al d

efec

taf

fect

ing

haem

atop

oiet

icst

em c

ell d

eriv

ativ

es

Rar

e

2. D

NA

repa

ir de

fect

s (ot

her

than

thos

e in

Tab

le 1

)

(a

) Ata

xia-

tela

ngie

ctas

iaPr

ogre

ssiv

ede

crea

seN

orm

alO

ften

decr

ease

d Ig

A, I

gEan

d Ig

G su

bcla

sses

;in

crea

sed

IgM

mon

omer

s;an

tibod

ies v

aria

bly

decr

ease

d

Ata

xia;

tela

ngie

ctas

ia;

pulm

onar

yin

fect

ions

; lym

pho-

retic

ular

and

oth

erm

alig

nanc

ies;

incr

ease

dal

pha

feto

prot

ein

and

X-r

ayse

nsiti

vity

;ch

rom

osom

al in

stab

ility

AR

Mut

atio

ns in

ATM

;di

sord

erof

cel

l cyc

le c

heck

-poi

ntan

d D

NA

dou

ble-

stra

ndbr

eak

repa

ir

Rel

ativ

ely

com

mon

(b

) Ata

xia-

tela

ngie

ctas

ialik

e di

seas

e (A

TLD

)Pr

ogre

ssiv

ede

crea

seN

orm

alA

ntib

odie

s var

iabl

yde

crea

sed

Mod

erat

e at

axia

;pu

lmon

ary

infe

ctio

ns; s

ever

ely

incr

ease

dra

dios

ensi

tivity

AR

Hyp

omor

phic

mut

atio

nsin M

RE11

; dis

orde

r of c

ell

cycl

e ch

eckp

oint

and

DN

Ado

uble

- stra

nd b

reak

repa

ir

Ver

y ra

re

(c

) Nijm

egen

bre

akag

esy

ndro

me

Prog

ress

ive

decr

ease

Var

iabl

yre

duce

dO

ften

decr

ease

d Ig

A, I

gEan

d Ig

G su

bcla

sses

;in

crea

sed

IgM

; ant

ibod

ies

varia

bly

decr

ease

d

Mic

roce

phal

y; b

ird-li

kefa

ce;

lym

phom

as; s

olid

tum

ors;

ioni

zing

radi

atio

n se

nsiti

vity

;ch

rom

osom

alin

stab

ility

AR

Hyp

omor

phic

mut

atio

nsin N

BS1

(Nib

rin)

; dis

orde

rof ce

ll cy

cle c

heck

poin

t and

DN

A d

oubl

e- st

rand

brea

kre

pair

Rar

e

et al.


NIH


NIH


NIH


Dis

ease

Cir

cula

ting

Tce

llsC

ircu

latin

gB

cel

lsSe

rum

IgA

ssoc

iate

d fe

atur

esIn

heri

tanc

e

Gen

etic

defe

cts/

Pres

umed

Path

ogen

esis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

(d

) Blo

om S

yndr

ome

Nor

mal

Nor

mal

Red

uced

Shor

t sta

ture

; bird

like

face

; sun

-se

nsiti

ve e

ryth

ema;

mar

row

failu

re;

leuk

emia

; lym

phom

a;ch

rom

osom

alin

stab

ility

AR

Mut

atio

ns in

BLM

; Rec

Qlik

e he

licas

eR

are

(e

) Im

mun

odef

icie

ncy

with

cent

rom

eric

inst

abili

ty a

ndfa

cial

ano

rmal

ies (

ICF)

Dec

reas

ed o

rno

rmal

Dec

reas

ed o

rno

rmal

Hyp

ogam

mag

lobu

linem

ia;

varia

ble

antib

ody

defic

ienc

yFa

cial

dys

mor

phic

feat

ures

;m

acro

glos

sia;

bac

teria

l/op

portu

nist

icin

fect

ions

;m

alab

sorp

tion;

mul

tirad

ial

conf

igur

atio

ns o

fch

rom

osom

es 1

, 9,

16; n

o D

NA

bre

aks

AR

Mut

atio

ns in

DN

Am

ethy

ltran

sfer

ase

DN

MT3

B, re

sulti

ng in

defe

ctiv

e D

NA

met

hyla

tion

Ver

y ra

re

(f

) PM

S2 D

efic

ienc

y(C

lass

Sw

itch

reco

mbi

natio

n[C

SR] d

efic

ienc

y du

e to

defe

ctiv

e m

ism

atch

repa

ir)

Nor

mal

Switc

hed

and

non-

switc

hed

Bce

lls a

rere

duce

d

Low

IgG

and

IgA

, ele

vate

dIg

M, a

bnor

mal

ant

ibod

yre

spon

ses

Rec

urre

nt in

fect

ions

;ca

fé-a

u-la

itsp

ots;

lym

phom

a,co

lore

ctal

carc

inom

a, b

rain

tum

or

AR

Mut

atio

ns in

PM

S2,

resu

lting

in d

efec

tive

CSR

-in

duce

d D

NA

dou

ble

stra

nd b

reak

s in

Igsw

itch

regi

ons

Ver

y ra

re

3. T

hym

ic d

efec

ts

D

iGeo

rge

anom

aly

(Chr

omos

ome

22q1

1.2

dele

tion

synd

rom

e

Dec

reas

edor

Nor

mal

Nor

mal

Nor

mal

or d

ecre

ased

Con

otru

ncal

mal

form

atio

n; a

bnor

mal

faci

es; l

arge

del

etio

n(3

Mb)

in22

q11.

2 (o

r rar

ely

ade

letio

n in

10p

)

De

novo

defe

ct o

rA

D

Con

tiguo

us g

ene

defe

ctin 90

% a

ffec

ting

thym

icde

velo

pmen

t; m

utat

ion

in TBX1

Com

mon

4. Im

mun

e-os

seou

sdy

spla

sias

(a

) Car

tilag

e ha

ir hy

popl

asia

Dec

reas

edor

Nor

mal

;im

paire

dly

mph

ocyt

epr

olife

ratio

n*

Nor

mal

Nor

mal

or r

educ

ed.

Ant

ibod

ies v

aria

bly

decr

ease

d

Shor

t-lim

bed

dwar

fism

with

met

aphy

seal

dys

osto

sis,

spar

se h

air,

bone

mar

row

failu

re,

auto

imm

unity

,su

scep

tibili

ty to

lym

phom

a an

d ot

her

canc

ers,

impa

ired

sper

mat

ogen

esis

,ne

uron

al d

yspl

asia

of t

hein

test

ine

AR

Mut

atio

ns in

RM

RP(R

Nas

e M

RP

RN

A)

Invo

lved

in p

roce

ssin

gof m

itoch

ondr

ial R

NA

and

cell

cycl

e co

ntro

l

Rar

e

(b

) Sch

imke

synd

rom

eD

ecre

ased

Nor

mal

Nor

mal

Shor

t sta

ture

,sp

ondi

loep

iphy

seal

AR

Mut

atio

ns in

SMAR

CAL

1V

ery

rare

et al.


NIH


NIH


NIH


Dis

ease

Cir

cula

ting

Tce

llsC

ircu

latin

gB

cel

lsSe

rum

IgA

ssoc

iate

d fe

atur

esIn

heri

tanc

e

Gen

etic

defe

cts/

Pres

umed

Path

ogen

esis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

dysp

lasi

a, in

traut

erin

egr

owth

reta

rdat

ion,

neph

ropa

thy;

bac

teria

l,vi

ral,

fung

al in

fect

ions

;m

ay p

rese

ntas

SC

ID; b

one

mar

row

failu

re

Invo

lved

in c

hrom

atin

rem

odel

ing

5. C

omel

-Net

herto

nSy

ndro

me

Nor

mal

Switc

hed

and

non-

switc

hed

Bce

lls a

rere

duce

d

Elev

ated

IgE

and

IgA

Ant

ibod

y va

riabl

yde

crea

sed

Con

geni

tal i

chth

yosi

s,ba

mbo

o ha

ir,at

opic

dia

thes

is,

incr

ease

d ba

cter

ial

infe

ctio

ns, f

ailu

re to

thriv

e

AR

Mut

atio

ns in

SPI

NK

5re

sulti

ng in

lack

of t

hese

rine

prot

ease

inhi

bito

rLE

KTI

, exp

ress

ed in

epith

elia

l cel

ls

Rar

e

6. H

yper

-IgE

synd

rom

es(H

IES)

(a

) AD

-HIE

S(J

ob S

yndr

ome)

Nor

mal

Th-1

7 ce

llsde

crea

sed

Nor

mal

Elev

ated

IgE;

spec

ific

antib

ody

prod

uctio

nde

crea

sed

Dis

tinct

ive

faci

alfe

atur

es (b

road

nasa

l brid

ge),

ecze

ma,

oste

opor

osis

and

frac

ture

s, sc

olio

sis,

failu

re/d

elay

of sh

eddi

ng p

rimar

yte

eth,

hype

rext

ensi

ble

join

ts,

bact

eria

lin

fect

ions

(ski

n an

dpu

lmon

ary

absc

esse

s/pn

eum

atoc

eles

) due

toSt

aphy

loco

ccus

aur

eus,

cand

idia

sis

AD

Ofte

n de

novo

def

ect

Dom

inan

t-neg

ativ

ehe

tero

zygo

us m

utat

ions

in STAT

3

Rar

e

(b

) AR

-HIE

SN

o sk

elet

al a

ndco

nnec

tive

tissu

eab

norm

aliti

es;

AR

Nor

mal

Nor

mal

Elev

ated

IgE

i)

susc

eptib

ility

to

intra

cellu

lar

bact

eria

(Myc

obac

teria

,

Salm

onel

la),

fung

ian

d

viru

ses

Mut

atio

n in

TYK

2Ex

trem

ely

rare

Red

uced

Red

uced

Elev

ated

IgE,

low

IgM

ii)

recu

rren

t res

pira

tory

infe

ctio

ns;

exte

nsiv

e

cuta

neou

s vira

l and

stap

hylo

cocc

al

infe

ctio

ns,

incr

ease

d

Mut

atio

n in

DO

CK

8V

ery

rare

et al.


NIH


NIH


NIH


Dis

ease

Cir

cula

ting

Tce

llsC

ircu

latin

gB

cel

lsSe

rum

IgA

ssoc

iate

d fe

atur

esIn

heri

tanc

e

Gen

etic

defe

cts/

Pres

umed

Path

ogen

esis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

risk

of c

ance

r,se

vere

atop

y w

ithan

aphy

laxi

s

Nor

mal

Nor

mal

Elev

ated

IgE

iii

) C

NS

hem

orrh

age,

fung

al a

nd v

iral

infe

ctio

ns

Unk

now

nEx

trem

ely

rare

7. C

hron

ic m

ucoc

utan

eous

cand

idia

sis

Nor

mal

Nor

mal

Nor

mal

Chr

onic

muc

ocut

aneo

usca

ndid

iasi

s,im

paire

d de

laye

d-ty

pehy

pers

ensi

tivity

toca

ndid

a an

tigen

s,au

toim

mun

ity, n

oec

tode

rmal

dysp

lasi

a

AD

, AR

,sp

orad

icU

nkno

wn

Ver

y ra

re

8. H

epat

ic v

enoo

ccul

usiv

edi

seas

e w

ithim

mun

odef

icie

ncy

(VO

DI)

Nor

mal

(Dec

reas

edm

emor

y T

cells

)

Nor

mal

(Dec

reas

edm

emor

y B

cells

)

Dec

reas

ed Ig

G, I

gA, I

gMH

epat

ic v

eno-

occu

lusi

vedi

seas

e;Pn

eum

ocys

tis ji

rove

cipn

eum

onia

;th

rom

bocy

tope

nia;

hepa

tosp

leno

meg

aly

AR

Mut

atio

ns in

SP1

10Ex

trem

ely

rare

9. X

L-D

yske

rato

sis c

onge

nita

(Hoy

eraa

l-Hre

idar

sson

Synd

rom

e)

Prog

ress

ive

decr

ease

Prog

ress

ive

decr

ease

Var

iabl

eIn

traut

erin

e gr

owth

reta

rdat

ion,

mic

roce

phal

y, n

ail

dyst

roph

y,re

curr

ent i

nfec

tions

,di

gest

ive

tract

invo

lvem

ent,

panc

ytop

enia

, red

uced

num

ber a

nd fu

nctio

n of

NK

cel

ls

XL

Mut

atio

ns in

Dys

kerin

(DK

C1)

Ver

y ra

re

* Patie

nts w

ith c

artil

age-

hair

hypo

plas

ia c

an p

rese

nt a

lso

with

typi

cal S

CID

or w

ith O

men

n sy

ndro

me

et al.


NIH


NIH


NIH


TAB

LE IV

Dis

ease

s of i

mm

une

Dys

regu

lato

n

Dis

ease

Cir

cula

ting

T C

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

esIn

heri

-ta

nce

Gen

etic

def

ects

,Pr

esum

ed P

atho

gene

sis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

1. Im

mun

o-de

ficie

ncy

with

/hy

popi

gmen

tatio

n

(a) C

hedi

ak-H

igas

hi sy

ndro

me

Nor

mal

Nor

mal

Nor

mal

Parti

al a

lbin

ism

, gia

nt ly

soso

mes

,lo

wN

K a

nd C

TL a

ctiv

ities

, hei

ghte

ned

acut

e-ph

ase

reac

tion,

late

-ons

etpr

imar

y en

ceph

alop

athy

AR

Def

ects

in L

YST,

impa

ired

lyso

som

al tr

affic

king

Rar

e

(b) G

risce

lli S

yndr

ome,

type

2N

orm

alN

orm

alN

orm

alPa

rtial

alb

inis

m, l

ow N

K a

nd C

TLac

tiviti

es, h

eigh

tene

d ac

ute

phas

ere

actio

n, e

ncep

halo

path

y in

som

epa

tient

s

AR

Def

ects

in R

AB27

Aen

codi

ng a

GTP

ase

inse

cret

ory

vesc

icle

s

Rar

e

(c) H

erm

ansk

y-Pu

dlak

synd

rom

e, ty

pe 2

Nor

mal

Nor

mal

Nor

mal

Parti

al a

lbin

ism

, neu

trope

nia,

low

NK

and

CTL

act

ivity

, inc

reas

ed b

leed

ing

AR

Mut

atio

ns o

f AP3

B1

gene

,en

codi

ng fo

r the

βsu

buni

tof

the

AP-

3 co

mpl

ex

Extre

mel

y ra

re

2. F

amili

al h

emop

hago

cytic

lym

phoh

istio

cyto

sis (

FHL

)sy

ndro

mes

(a) P

erfo

rin d

efic

ienc

yN

orm

alN

orm

alN

orm

alSe

vere

infla

mm

atio

n, fe

ver,

decr

ease

d N

K a

nd C

TL a

ctiv

ities

AR

Def

ects

in P

RF1;

perf

orin

,a

maj

or c

ytol

ytic

pro

tein

Rar

e

(b) M

unc

13-D

defic

ienc

yN

orm

alN

orm

alN

orm

alSe

vere

infla

mm

atio

n, fe

ver,

decr

ease

d N

K a

nd C

TL a

ctiv

ities

AR

Def

ects

in M

UN

C13

Dre

quire

d to

prim

eve

scic

les

for f

usio

n

Rar

e

(c) S

ynta

xin

11 d

efic

ienc

yN

orm

alN

orm

alN

orm

alSe

vere

infla

mm

atio

n, fe

ver,

decr

ease

d N

K a

ctiv

ityA

RD

efec

ts in

STX

11,

invo

lved

in v

esci

cle

traff

icki

ngan

dfu

sion

Ver

y ra

re

3. L

ymph

opro

lifer

ativ

esy

ndro

mes

(a) X

LP1,

SH

2D1A

def

icie

ncy

Nor

mal

Nor

mal

or

redu

ced

Nor

mal

or l

owim

mun

o-gl

obul

ins

Clin

ical

and

imm

unol

ogic

abno

rmal

ities

trig

gere

d by

EB

Vin

fect

ion,

incl

udin

g he

patit

is, a

plas

tican

aem

ia, l

ymph

oma

XL

Def

ects

in S

H2D

1Aen

codi

ng a

n ad

apto

rpr

otei

n re

gula

ting

intra

cellu

lar s

igna

ls

Rar

e

(b) X

LP2,

XIA

P de

ficie

ncy

Nor

mal

Nor

mal

or

redu

ced

Nor

mal

or l

owim

mun

o-gl

obul

ins

Clin

ical

and

imm

unol

ogic

abno

rmal

ities

trig

gere

d by

EB

Vin

fect

ion,

incl

udin

g sp

leno

meg

aly,

XL

Def

ects

in X

IAP

enco

ding

an in

hibi

tor o

f apo

ptos

is

Ver

y ra

re

et al.


NIH


NIH


NIH


Dis

ease

Cir

cula

ting

T C

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

esIn

heri

-ta

nce

Gen

etic

def

ects

,Pr

esum

ed P

atho

gene

sis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

hepa

titis

, hem

opha

gocy

tic sy

ndro

me,

lym

phom

a

(c) I

TK d

efic

ienc

yM

odes

tly d

ecre

ased

Nor

mal

Nor

mal

or

decr

ease

dEB

V-a

ssoc

iate

d ly

mph

opro

lifer

atio

nA

RM

utat

ions

in IT

KEx

trem

ely

rare

4. S

yndr

omes

with

auto

imm

unity

(a) A

utoi

mm

une

lym

phop

rolif

erat

ive

synd

rom

e(A

LPS)

(i) C

D95

(Fas

) def

ects

, ALP

Sty

pe 1

aIn

crea

sed

CD

4−C

D8−

dou

ble

nega

tive

(DN

) Tce

lls

Nor

mal

Nor

mal

or

incr

ease

dSp

leno

meg

aly,

ade

nopa

thy,

auto

imm

une

bloo

d cy

tope

nias

,de

fect

ive

lym

phoc

yte

apop

tosi

sin

crea

sed

lym

phom

a ris

k

AD

(rar

ese

vere

AR

case

s)

Def

ects

in T

NFR

SF6,

cell

surf

ace

apop

tosi

sre

cept

or;

in a

dditi

on to

ger

mlin

em

utat

ions

, som

atic

mut

atio

ns c

ause

a si

mila

rph

enot

ype

Rar

e

(ii) C

D95

L (F

as li

gand

)de

fect

s,A

LPS

type

1b

Incr

ease

d D

N T

cells

Nor

mal

Nor

mal

Sple

nom

egal

y, a

deno

path

y,au

toim

mun

e bl

ood

cyto

peni

as,

defe

ctiv

e lym

phoc

yte a

popt

osis

, SLE

AD

AR

Def

ects

in T

NFS

F6,

ligan

dfo

r CD

95 a

popt

osis

rece

ptor

Extre

mel

y ra

re

(iii)

Cas

pase

10

defe

cts,

ALP

Sty

pe 2

aIn

crea

sed

DN

Tce

llsN

orm

alN

orm

alA

deno

path

y, sp

leno

meg

aly,

auto

imm

une

dise

ase,

def

ectiv

ely

mph

ocyt

e ap

opto

sis

AD

Def

ects

in C

ASP1

0,in

trace

llula

r apo

ptos

ispa

thw

ay

Extre

mel

y ra

re

(iv) C

aspa

se 8

def

ects

, ALP

Sty

pe 2

bSl

ight

ly in

crea

sed

DN

T c

ells

Nor

mal

Nor

mal

or

decr

ease

dA

deno

path

y, sp

leno

meg

aly,

recu

rren

tba

cter

ial a

nd v

iral i

nfec

tions

,de

fect

ive

lym

phoc

yte a

popt

osis

and

activ

atio

n;

AD

Def

ects

in C

ASP8

,in

trace

llula

r apo

ptos

isan

dac

tivat

ion

path

way

s

Extre

mel

y ra

re

(v) A

ctiv

atin

g N

-Ras

def

ect,

N-

Ras

ALP

SIn

crea

sed

DN

Tce

llsEl

evat

ion

ofC

D5

B c

ells

Nor

mal

Ade

nopa

thy,

sple

nom

egal

y,le

ukem

ia,

lym

phom

a, d

efec

tive

lym

phoc

yte

apop

tosi

s fol

low

ing

IL-2

with

draw

al

AD

Def

ect i

n N

RAS

enco

ding

a GTP

bin

ding

pro

tein

with

dive

rse

sign

alin

gfu

nctio

ns,

activ

atin

g m

utat

ions

impa

irm

itoch

ondr

ial a

popt

osis

Extre

mel

y ra

re

(b) A

PEC

ED, a

utoi

mm

une

poly

endo

crin

opat

hy w

ithca

ndid

iasi

s and

ect

oder

mal

dyst

roph

y

Nor

mal

Nor

mal

Nor

mal

Aut

oim

mun

e di

seas

e, p

artic

ular

ly o

fpa

rath

yroi

d, a

dren

al a

nd o

ther

endo

crin

e or

gans

plu

s can

didi

asis

,de

ntal

ena

mel

hyp

opla

sia

and

othe

rab

norm

aliti

es

AR

Def

ects

in A

IRE,

enco

ding

a tra

nscr

iptio

n re

gula

tor

need

ed to

est

ablis

hth

ymic

self-

tole

ranc

e

Rar

e

(c) I

PEX

, im

mun

edy

sreg

ulat

ion,

Lack

of C

D4+

CD

25+

FOX

P3+

Nor

mal

Elev

ated

IgA

,Ig

EA

utoi

mm

une

diar

rhea

, ear

ly o

nset

diab

etes

, thy

roid

itis,

hem

olyt

icX

LD

efec

ts in

FO

XP3,

enco

ding

a T

cel

lR

are

et al.


NIH


NIH


NIH


Dis

ease

Cir

cula

ting

T C

ells

Cir

cula

ting

Bce

llsSe

rum

IgA

ssoc

iate

d Fe

atur

esIn

heri

-ta

nce

Gen

etic

def

ects

,Pr

esum

ed P

atho

gene

sis

Rel

ativ

efr

eque

ncy

amon

g PI

Ds

poly

endo

crin

opat

hy,

ente

ropa

thy

(X-li

nked

)

regu

lato

ry T

cel

lsan

emia

, thr

ombo

cyto

peni

a, e

czem

atra

nscr

iptio

n fa

ctor

(d) C

D25

def

icie

ncy

Nor

mal

to m

odes

tlyde

crea

sed

Nor

mal

Nor

mal

Lym

phor

polif

erat

ion,

aut

oim

mun

ity,

impa

ired

T ce

ll pr

olife

ratio

nA

RD

efec

ts in

IL-2

Rα

chai

nEx

trem

ely

rare

AR

: aut

osom

al re

cess

ive;

XL:

X-li

nked

; AD

: aut

osom

al d

omin

ant;

DN

: dou

ble-

nega

tive;

SLE

; sys

tem

ic lu

pus e

ryth

emat

osus

et al.


NIH


NIH


NIH


TAB

LE V

Con

geni

tal d

efec

ts o

f pha

gocy

te n

umbe

r, fu

nctio

n, o

r bot

h

Dis

ease

Affe

cted

cells

Affe

cted

func

ton

Ass

ocia

ted

feat

ures

Inhe

rita

nce

Gen

e de

fect

– p

resu

med

path

ogen

esis

Rel

ativ

e fr

eque

ncy

amon

g PI

Ds

1.–2

.Se

vere

con

geni

tal n

eutro

peni

asN

Mye

loid

diff

eren

tiatio

nSu

bgro

up w

ith m

yelo

dysp

lasi

aA

DEL

A2: m

istra

ffic

king

of e

last

ase

Rar

e

NM

yelo

id d

iffer

entia

tion

B/T

lym

phop

enia

AD

GFI

1: re

pres

sion

of e

last

ase

Extre

mel

y ra

re

3.K

ostm

ann

Dis

ease

NM

yelo

id d

iffer

entia

tion

Cog

nitiv

e an

d ne

urol

ogic

alde

fect

s*A

RH

AX1:

cont

rol o

f apo

ptos

isR

are

4N

eutro

peni

a w

ith c

ardi

ac a

ndur

ogen

ital m

alfo

rmat

ions

N +

FM

yelo

id d

iffer

entia

tion

Stru

ctur

al h

eart

defe

cts,

urog

enita

lab

norm

aliti

es, a

nd v

enou

san

giec

tasi

as o

f tru

nks a

ndlim

bs

AR

G6P

C3:

abo

lishe

d en

zym

atic

activ

ity o

fgl

ucos

e-6-

phos

phat

ase

and

enha

nced

apop

tosi

s of N

and

F

Ver

y ra

re

5G

lyco

gen

stor

age

dise

ase

type

1bN

+ M

Kill

ing,

che

mot

axis

,O

2− p

rodu

ctio

nFa

stin

g hy

pogl

ycem

ia, l

actic

acid

osis

, hyp

erlip

idem

ia,

hepa

tom

egal

y, n

eutro

peni

a

AR

G6P

T1: G

luco

se-6

-pho

spha

tetra

nspo

rter 1

Ver

y ra

re

6.C

yclic

neu

trope

nia

N?

Osc

illat

ions

of o

ther

leuk

ocyt

es a

ndpl

atel

ets

AD

ELA2

: mis

traff

icki

ng o

f ela

stas

eV

ery

rare

7.X

-link

ed n

eutro

peni

a/m

yelo

dysp

lasi

aN

+ M

?M

onoc

ytop

enia

XL

WAS

P: R

egul

ator

of a

ctin

cyto

skel

eton

(loss

of a

utoi

nhib

ition

)

Extre

mel

y ra

re

8.P1

4 de

ficie

ncy

N+L

Mel

Endo

som

e bi

ogen

esis

Neu

trope

nia

Hyp

ogam

mag

lobu

linem

ia↓C

D8

cyto

toxi

city

Parti

al a

lbin

ism

Gro

wth

failu

re

AR

MAP

BPIP

: End

osom

al a

dapt

orpr

otei

n14

Extre

mel

y ra

re

9.Le

ukoc

yte

adhe

sion

def

icie

ncy

type

1N

+ M

+L

+ N

KA

dher

ence

Che

mot

axis

Endo

cyto

sis

T/N

K c

ytot

oxic

ity

Del

ayed

cor

d se

para

tion,

skin

ulce

rsPe

riodo

ntiti

sLe

ukoc

ytos

is

AR

INTG

B2: A

dhes

ion

prot

ein

Ver

y ra

re

10.

Leuk

ocyt

e ad

hesi

on d

efic

ienc

yty

pe 2

N +

MR

ollin

gC

hem

otax

isM

ild L

AD

type

1 fe

atur

espl

us h

h-bl

ood

grou

p pl

usm

enta

l and

grow

th re

tard

atio

n

AR

FUC

T1: G

DP-

Fuco

se tr

ansp

orte

rEx

trem

ely

rare

11.

Leuk

ocyt

e ad

hesi

on d

efic

ienc

yty

pe 3

N +

M +

L +

NK

Adh

eren

ceLA

D ty

pe 1

plu

s ble

edin

gte

nden

cyA

RK

IND

LIN

3:R

ap1-

activ

atio

n of

β1–

3 in

tegr

ins

Extre

mel

y ra

re

12.

Rac

2 d

efic

ienc

yN

Adh

eren

ceC

hem

otax

isO

2− p

rodu

ctio

n

Poor

wou

nd h

ealin

g,le

ukoc

ytos

isA

DRA

C2:

Reg

ulat

ion

of a

ctin

cyto

skel

eton

Extre

mel

y ra

re:

Reg

ulat

ion

of a

ctin

cyto

skel

eton

13.

β-ac

tin d

efic

ienc

yN

+ M

Mot

ility

Men

tal r

etar

datio

n, sh

ort

stat

ure

AD

ACTB

: Cyt

opla

smic

Act

inEx

trem

ely

rare

14.

Loca

lized

juve

nile

Per

iodo

ntiti

sN

Form

ylpe

ptid

e in

duce

dch

emot

axis

Perio

dont

itis o

nly

AR

FPR1

: Che

mok

ine

rece

ptor

Ver

y ra

re

et al.


NIH


NIH


NIH


Dis

ease

Affe

cted

cells

Affe

cted

func

ton

Ass

ocia

ted

feat

ures

Inhe

rita

nce

Gen

e de

fect

– p

resu

med

path

ogen

esis

Rel

ativ

e fr

eque

ncy

amon

g PI

Ds

15.

Papi

llon-

Lefè

vre

Synd

rom

eN

+ M

Che

mot

axis

Perio

dont

itis,

palm

opla

ntar

hype

rker

atos

is**

AR

CTS

C: C

athe

psin

C a

ctiv

atio

n of

serin

epr

otea

ses

Ver

y ra

re

16.

Spec

ific

gran

ule

defic

ienc

yN

Che

mot

axis

N w

ith b

ilobe

d nu

clei

AR

C/E

BPE:

mye

loid

tran

scrip

tion

fact

orEx

trem

ely

rare

17.

Shw

achm

an-D

iam

ond

Synd

rom

eN

Che

mot

axis

Panc

ytop

enia

, exo

crin

epa

ncre

atic

insu

ffic

ienc

y,ch

ondr

odys

plas

ia

AR

SBD

SR

are

18.

X-li

nked

chr

onic

gran

ulom

atou

sdi

seas

e (C

GD

)

N +

MK

illin

g (f

aulty

O2−

pro

duct

ion)

McL

eod

phen

otyp

e in

asu

bgro

up o

fpa

tient

s

XL

CYB

B: E

lect

ron

trans

port

prot

ein

(gp9

1pho

x)R

elat

ivel

y co

mm

on

19.–

21.

Aut

osom

al C

GD

’sN

+ M

Kill

ing

(fau

ltyO

2− p

rodu

ctio

n)A

RC

YBA:

Ele

ctro

n tra

nspo

rt pr

otei

n(p

22ph

ox)

NC

F1: A

dapt

er p

rote

in(p

47ph

ox)

NC

F2: A

ctiv

atin

g pr

otei

n(p

67ph

ox)

Rel

ativ

ely

com

ùmo,

n

22.

IL-1

2 an

d IL

-23

rece

ptor

β1

chai

nde

ficie

ncy

L +

NK

IFN

-γ se

cret

ion

Susc

eptib

ility

to M

ycob

acte

ria

and

Salm

onel

la

AR

IL12

RB1:

IL-1

2 an

d IL

-23

rece

ptor

β1

chai

nR

are

23.

IL-1

2p40

def

icie

ncy

MIF

N-γ

secr

etio

nSu

scep

tibili

ty to

Myc

obac

teri

aan

dSa

lmon

ella

AR

IL12

B: su

buni

t of I

L12/

IL23

Ver

y ra

re

24.

IFN

-γ re

cept

or 1

def

icie

ncy

M +

LIF

N-γ

bin

ding

and

sign

alin

gSu

scep

tibili

ty to

Myc

obac

teri

aan

dSa

lmon

ella

AR

, AD

IFN

GR1

:IF

N-γ

R li

gand

bin

ding

cha

inR

are

25.

IFN

-γ re

cept

or 2

def

icie

ncy

M +

LIF

N-γ

sign

alin

gSu

scep

tibili

ty to

Myc

obac

teri

aan

dSa

lmon

ella

AR

IFN

GR2

: IFN

-γR

acce

ssor

y ch

ain

Ver

y ra

re

26.

STA

T1 d

efic

ienc

y (2

form

s)M

+ L

IFN

α/β

, IFN

-γ, I

FN-λ

and

IL-2

7 si

gnal

ing

Susc

eptib

ility

toM

ycob

acte

ria,

Sal

mon

ella

and

viru

ses

AR

STAT

1Ex

trem

ely

rare

IFN

-γ si

gnal

ling

Susc

eptib

ility

toM

ycob

acte

ria

and

Salm

onel

la

AD

STAT

1Ex

trem

ely

rare

27.

AD

hyp

er-I

gE sy

ndro

me

L+M

+N+

epith

elia

lIL

-6/1

0/22

/23

sign

allin

gD

istin

ctiv

e fa

cial

feat

ures

(bro

adna

sal b

ridge

); ec

zem

a;os

teop

oros

isan

d fr

actu

res;

scol

iosi

s; fa

ilure

/de

lay

of sh

eddi

ng p

rimar

y te

eth;

hype

rext

ensi

ble

join

ts;

bact

eria

lin

fect

ions

(ski

n an

d pu

lmon

ary

AD

STAT

3R

are

et al.


NIH


NIH


NIH


Dis

ease

Affe

cted

cells

Affe

cted

func

ton

Ass

ocia

ted

feat

ures

Inhe

rita

nce

Gen

e de

fect

– p

resu

med

path

ogen

esis

Rel

ativ

e fr

eque

ncy

amon

g PI

Ds

absc

esse

s/pn

eum

atoc

eles

) due

to Stap

hylo

cocc

us a

ureu

s;ca

ndid

iasi

s

28.

AR

hyp

er-I

gE (T

YK

2de

ficie

ncy)

L+M

+N+

othe

rsIL

-6/1

0/12

/23/

IFN

-α/

IFN

-βsi

gnal

ling

Susc

eptib

ility

to in

trace

llula

rba

cter

ia(M

ycob

acte

ria, S

alm

onel

la),

stap

hylo

cocc

us a

nd v

iruse

s.

AR

TYK

2Ex

trem

ely

rare

AD, a

utos

omal

dom

inan

t; XL

, X-li

nked

inhe

ritan

ce; A

R, a

utos

omal

rece

ssiv

e in

herit

ance

; N, n

eutro

phils

; M, m

onoc

ytes

-mac

roph

ages

; L, l

ymph

ocyt

es; N

K, n

atur

al k

iller

cel

ls; M

el, m

elan

ocyt

es; F

, fib

robl

asts

;ST

AT1,

sign

al tr

ansd

ucer

and

act

ivat

or o

f tra

nscr

iptio

n 1;

* cogn

itive

ane

neu

rolo

gica

l def

ects

are

obs

erve

d in

a fr

actio

n of

pat

ient

s;**

perio

dont

itis m

ay b

e is

olat

ed.

et al.


NIH


NIH


NIH


Tabl

e VI

Def

ects

in In

nate

Imm

unity

Dis

ease

Affe

cted

Cel

lFu

nctio

nal D

efec

tA

ssoc

iate

d Fe

atur

esIn

heri

tanc

eG

ene

Def

ect/P

resu

med

path

ogen

esis

Rel

ativ

e fr

eque

ncy

amon

g PI

Ds

Anh

idro

tic e

ctod

erm

al d

yspl

asia

with

imm

unod

efic

ienc

y (E

DA

-ID

)

Lym

phoc

ytes

+M

onoc

ytes

NFκ

B si

gnal

ling

path

way

anhi

drot

ic e

ctod

erm

aldy

spla

sia

+ sp

ecifi

c an

tibod

yde

ficie

ncy

(lack

of A

bre

spon

seto

pol

ysac

char

ides

)va

rious

infe

ctio

ns(m

ycob

acte

ria a

nd p

yoge

ns)

XR

Mut

atio

ns o

f NEM

O(I

KBK

G),

am

odul

ator

of N

F-κB

activ

atio

n

Rar

e

Anh

idro

tic e

ctod

erm

al d

yspl

asia

with

imm

unod

efic

ienc

y (E

DA

-ID

)

Lym

phoc

ytes

+M

onoc

ytes

NFκ

B si

gnal

ling

path

way

anhi

drot

ic e

ctod

erm

aldy

spla

sia

+ T

cell

defe

ct +

vario

us in

fect

ions

AD

Gai

n-of

-fun

ctio

nm

utat

ion

ofIK

BA, r

esul

ting

inim

paire

dac

tivat

ion

of N

F-κB

Extre

mel

y ra

re

Inte

rleuk

in-1

Rec

epto

r Ass

ocia

ted

kina

se 4

(IR

AK

4) d

efic

ienc

yLy

mph

ocyt

es +

Mon

ocyt

esTI

R-I

RA

K si

gnal

ling

patw

hay

Bac

teria

l inf

ectio

ns (p

yoge

ns)

AR

Mut

atio

n of

IRAK

4, a

com

pone

nt o

f TLR

- and

IL-1

R-

sign

alin

g pa

thw

ay

Ver

y ra

re

MyD

88 d

efic

ienc

yly

mph

ocyt

es +

Mon

ocyt

esTI

R-M

yD88

sign

allin

g pa

thw

ayB

acte

rial i

nfec

tions

(pyo

gens

)A

RM

utat

ion

of M

YD

88, a

com

pone

nt o

f the

TLR

and

IL-

1R si

gnal

ing

path

way

Ver

y ra

re

WH

IM (W

arts

,H

ypog

amm

aglo

bulin

emia

infe

ctio

ns,M

yelo

kath

exis

) syn

drom

e

Gra

nulo

cyte

s +Ly

mph

ocyt

esIn

crea

sed

resp

onse

of t

heC

XC

R4

chem

okin

e re

cept

orto

its l

igan

d C

XC

L12

(SD

F-1)

Hyp

ogam

mag

lobu

linem

ia,

redu

ced

B c

ell n

umbe

r, se

vere

redu

ctio

n of

neu

troph

il co

unt,

war

ts/H

PV in

fect

ion

AD

Gai

n-of

-fun

ctio

nm

utat

ions

of

CXC

R4, t

he re

cept

or fo

rC

XC

L12

Ver

y ra

re

Epid

erm

odys

plas

ia v

erru

cifo

rmis

Ker

atin

ocyt

es a

ndle

ukoc

ytes

?H

uman

Pap

illom

a vi

rus

(gro

upB

1) in

fect

ions

and

can

cer o

fth

e sk

in

AR

Mut

atio

ns o

f EVE

R1,

EVER

2Ex

trem

ely

rare

Her

pes s

impl

ex e

ncep

halit

is (H

SE)

Cen

tral n

ervo

ussy

stem

resi

dent

cel

ls,

epith

elia

lce

lls a

ndle

ukoc

ytes

UN

C-9

3B–d

epen

dent

IFN

-α, -β,

and

–λ, i

nduc

tion

Her

pes s

impl

ex v

irus 1

ence

phal

itis a

nd m

enin

gitis

AR

Mut

atio

ns o

f UN

C93

B1Ex

trem

ely

rare

*

Her

pes s

impl

ex e

ncep

halit

is (H

SE)

Cen

tral n

ervo

ussy

stem

resi

dent

cel

ls,

epith

elia

lce

lls, d

endr

itic

cells

,cy

toto

xic

lym

phoc

ytes

TLR

3-de

pend

ent I

FN-α

, -β,

and

-λ, i

nduc

tion

Her

pes s

impl

ex v

irus 1

ence

phal

itis a

nd m

enin

gitis

AD

Mut

atio

ns o

f TLR

3Ex

trem

ely

rare

*

et al.


NIH


NIH


NIH


Dis

ease

Affe

cted

Cel

lFu

nctio

nal D

efec

tA

ssoc

iate

d Fe

atur

esIn

heri

tanc

eG

ene

Def

ect/P

resu

med

path

ogen

esis

Rel

ativ

e fr

eque

ncy

amon

g PI

Ds

Tryp

anos

omia

sis

APO

L-I

Tryp

anos

omia

sis

AD

Mut

atio

n in

APO

L-I

Extre

mel

y ra

re*

NF-κB

: nuc

lear

fact

or K

appa

B; T

IR: T

oll a

nd In

terle

ukin

1 R

ecep

tor;

IFN

: int

erfe

ron;

HPV

: hum

an p

apill

oma

viru

s; T

LR: T

oll-l

ike

rece

ptor

* Onl

y a

few

pat

ient

s hav

e be

en g

enet

ical

ly in

vest

igat

ed, a

nd th

ey re

pres

ente

d a

smal

l fra

ctio

n of

all

patie

nts t

este

d, b

ut th

e cl

inic

al p

heno

type

bei

ng c

omm

on, t

hese

gen

etic

dis

orde

rs m

ay a

ctua

lly b

e m

ore

com

mon

.

et al.


NIH


NIH


NIH


Tabl

e VI

I

Aut

oinf

lam

mat

ory

Dis

orde

rs

Dis

ease

Affe

cted

cel

lsFu

nctio

nal d

efec

tsA

ssoc

iate

d Fe

atur

esIn

heri

tanc

eG

ene

defe

cts

Rel

ativ

efr

eque

ncy

amon

gPI

Ds

Fam

ilial

Med

iterr

anea

n Fe

ver

Mat

ure

gran

uloc

ytes

,cy

toki

ne-

activ

ated

mon

ocyt

es.

Dec

reas

ed p

rodu

ctio

n of

pyr

inpe

rmits

ASC

-indu

ced

IL-1

proc

essi

ng a

nd in

flam

mat

ion

follo

win

g su

bclin

ical

sero

sal

inju

ry;

mac

roph

age

apop

tosi

sde

crea

sed.

Rec

urre

nt fe

ver,

sero

sitis

and

infla

mm

atio

nre

spon

sive

to c

olch

icin

e.Pr

edis

opos

es to

vas

culit

isan

d in

flam

mat

ory

bow

eldi

seas

e.

AR

Mut

atio

ns o

f MEF

V

com

mon

TNF

rece

ptor

-ass

ocia

ted

perio

dic

synd

rom

e (T

RA

PS)

PMN

s, m

onoc

ytes

Mut

atio

ns o

f 55-

kD T

NF

rece

ptor

lead

ing

to in

trace

llula

rre

cept

orre

tent

ion

or d

imin

ishe

d so

lubl

ecy

toki

ne re

cept

or a

vaila

ble

tobi

ndTN

F

Rec

urre

nt fe

ver,

sero

sitis

,ra

sh, a

nd o

cula

r or j

oint

infla

mm

atio

n

AD

Mut

atio

ns o

f TN

FRSF

1A

rare

Hyp

er Ig

D sy

ndro

me

Mev

alon

ate

kina

se d

efic

ienc

yaf

fect

ing

chol

este

rol s

ynth

esis

;pa

thog

enes

is o

f dis

ease

uncl

ear

Perio

dic

feve

r and

leuk

ocyt

osis

with

hig

h Ig

Dle

vels

AR

Mut

atio

ns o

f MVK

rare

Muc

kle-

Wel

ls sy

ndro

me*

PMN

s Mon

ocyt

esD

efec

t in

cryo

pyrin

, inv

olve

din le

ukoc

yte

apop

tosi

s and

NFk

Bsi

gnal

ling

and

IL-1

pro

cess

ing

Urti

caria

, SN

HL,

amyl

oido

sis.

Res

pons

ive

toIL

-1R

/ant

agon

ist

AD

Mut

atio

ns o

f CIA

S1 (a

lso

calle

d PY

PAF1

or N

ALP

3)ra

re

Fam

ilial

col

d au

toin

flam

mat

ory

synd

rom

e*PM

Ns,

mon

ocyt

essa

me

as a

bove

Non

-pru

ritic

urti

caria

,ar

thrit

is, c

hills

, fev

er a

ndle

ukoc

ytos

is a

fter c

old

expo

sure

. Res

pons

ive

toIL

-1R

/ant

agon

ist (

Ana

kinr

a)

AD

Mut

atio

ns o

f CIA

S1M

utat

ions

of N

LRP1

2V

ery

rare

Neo

nata

l ons

et m

ultis

yste

min

flam

mat

ory

dise

ase

(NO

MID

)or

chr

onic

infa

ntile

neu

rolo

gic

cuta

neou

s and

arti

cula

rsy

ndro

me

(CIN

CA

)*

PMN

s, ch

ondr

ocyt

essa

me

as a

bove

Neo

nata

l ons

et ra

sh,

chro

nic

men

ingi

tis, a

ndar

thro

path

y w

ith fe

ver a

ndin

flam

mat

ion

resp

onsi

ve to

IL-1

R a

ntag

onis

t (A

naki

nra)

AD

Mut

atio

ns o

f CIA

S1V

ery

rare

Pyog

enic

ster

ile a

rthrit

is,

pyod

erm

a ga

ngre

nosu

m, a

cne

(PA

PA) s

yndr

ome

hem

atop

oiet

ic ti

ssue

s,up

regu

late

d in

activ

ated

T-c

ells

Dis

orde

red

actin

reor

gani

zatio

nle

adin

g to

com

prom

ised

phys

iolo

gic

sign

alin

g du

ring

infla

mm

ator

yre

spon

se

Des

truct

ive

arth

ritis

,in

flam

mat

ory

skin

rash

,m

yosi

tis

AD

Mut

atio

ns o

f PST

PIP1

(als

o ca

lled

C2B

P1)

Ver

y ra

re

Bla

u sy

ndro

me

Mon

ocyt

esM

utat

ions

in n

ucle

otid

ebi

ndin

g si

teU

veiti

s, gr

anul

omat

ous

syno

vitis

, cam

ptod

acty

ly,

rash

and

cra

nial

AD

Mut

atio

ns o

f NO

D2

(als

oca

lled

CA

RD

15)

rare

et al.


NIH


NIH


NIH


Dis

ease

Affe

cted

cel

lsFu

nctio

nal d

efec

tsA

ssoc

iate

d Fe

atur

esIn

heri

tanc

eG

ene

defe

cts

Rel

ativ

efr

eque

ncy

amon

gPI

Ds

of C

AR

D15

, pos

sibl

ydi

srup

ting

inte

ract

ions

with

lipop

olys

acch

arid

esan

d N

F-κB

sign

allin

g

neur

opat

hies

, 30%

dev

elop

Cro

hn’s

dis

ease

Chr

onic

recu

rren

t mul

tifoc

alos

teom

yelit

is a

nd c

onge

nita

ldy

sery

thro

poie

tic a

nem

ia(M

ajee

d sy

ndro

me)

Neu

troph

ils, b

one

mar

row

cel

lsun

defin

edC

hron

ic re

curr

ent m

ultif

ocal

oste

omye

litis

, tra

nsfu

sion

-de

pend

ent a

nem

ia,

cuta

neou

s inf

lam

mat

ory

diso

rder

s

AR

Mut

atio

ns o

f LPI

N2

Ver

y ra

re

DIR

A(D

efic

ienc

y of

the

Inte

rleuk

in 1

Rec

epto

rA

ntag

onis

t)

PMN

s, M

onoc

ytes

Mut

atio

ns in

the

IL1

rece

ptor

anta

goni

st a

llow

s uno

ppos

edac

tion

of In

terle

ukin

1

Neo

nata

l ons

et o

f ste

rile

mul

tifoc

al o

steo

mye

litis

,pe

riost

itis a

nd p

ustu

losi

s.

AR

Mut

atio

ns o

f IL1

RNV

ery

rare

* All

thre

e sy

ndro

mes

ass

ocia

ted

with

sim

ilar C

IAS1

mut

atio

ns; d

isea

se p

heno

type

in a

ny in

divi

dual

app

ears

to d

epen

d on

mod

ifyin

g ef

fect

s of o

ther

gen

es a

nd e

nviro

nmen

tal f

acto

rs.

Abb

revi

atio

ns: P

MN

, pol

ymor

phon

ucle

ar c

ells

; AD

, aut

osom

al d

omin

ant i

nher

itanc

e. A

SC, a

popt

osis

-aso

cate

d sp

eck-

like

prot

ein

with

a c

aspa

se re

crui

tmen

t dom

ain;

CA

RD

, cas

pase

recr

uitm

ent d

omai

n;C

D2B

P1, C

D2

bind

ing

prot

ein-

1; P

STPI

P1, P

rolin

e/se

rine/

thre

onin

e ph

osph

atas

e-in

tera

ctin

g pr

otei

n 1;

SN

HL

- sen

sorin

eura

l hea

ring

loss

;CIA

S1- c

old-

indu

ced

auto

infla

mm

ator

y sy

ndro

me

1

et al.


NIH


NIH


NIH


Tabl

e VI

II

Com

plem

ent d

efic

ienc

ies

Dis

ease

Func

tiona

l Def

ect

Ass

ocia

ted

Feat

ures

Inhe

rita

nce

Gen

eD

efec

tsR

elat

ive

freq

uenc

yam

ong

PID

s

C1q

def

icie

ncy

-Abs

ent C

hem

olyt

ic a

ctiv

ity, D

efec

tive

MA

C *

-Fau

lty d

isso

lutio

n of

imm

une

com

plex

es-F

aulty

cle

aran

ce o

f apo

ptot

ic c

ells

SLE–

like

synd

rom

e,rh

eum

atoi

d di

seas

e,in

fect

ions

AR

C1q

Ver

y ra

re

C1r

def

icie

ncy*

-Abs

ent C

hem

olyt

ic a

ctiv

ity, D

efec

tive

MA

C-F

aulty

dis

solu

tion

of im

mun

e co

mpl

exes

SLE–

like

synd

rom

e,rh

eum

atoi

d di

seas

e,in

fect

ions

AR

C1r

*V

ery

rare

C1s

def

icie

ncy

-Abs

ent C

hem

olyt

ic a

ctiv

itySL

E-lik

e sy

ndro

me;

mul

tiple

auto

imm

une

dise

ases

AR

C1s

*Ex

trem

ely

rare

C4

defic

ienc

y-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Fau

lty d

isso

lutio

n of

imm

une

com

plex

es-D

efec

tive

hum

oral

imm

une

resp

onse

SLE–

like

synd

rom

e,rh

eum

atoi

d di

seas

e,in

fect

ions

AR

C4A

and

C4B

§V

ery

rare

C2

defic

ienc

y**

-Abs

ent C

hem

olyt

ic a

ctiv

ity, D

efec

tive

MA

C-F

aulty

dis

solu

tion

of im

mun

e co

mpl

exes

SLE–

like

synd

rom

e,va

scul

itis,

poly

myo

sitis

,py

ogen

ic in

fect

ions

AR

C2*

*R

are

C3

defic

ienc

y-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Def

ectiv

e B

acte

ricid

al a

ctiv

ity-D

efec

tive

hum

oral

imm

une

resp

onse

Rec

urre

nt p

yoge

nic

infe

ctio

nsA

RC

3V

ery

rare

C5

defic

ienc

y-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Def

ectiv

e B

acte

ricid

al a

ctiv

ityN

eiss

eria

l inf

ectio

ns, S

LEA

RC

5V

ery

rare

C6

defic

ienc

y-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Def

ectiv

e B

acte

ricid

al a

ctiv

ityN

eiss

eria

l inf

ectio

ns, S

LEA

RC

6R

are

C7

defic

ienc

y-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Def

ectiv

e B

acte

ricid

al a

ctiv

ityN

eiss

eria

l inf

ectio

ns, S

LE,

vasc

uliti

sA

RC

7R

are

C8a

def

icie

ncy*

**-A

bsen

t C h

emol

ytic

act

ivity

, Def

ectiv

e M

AC

-Def

ectiv

e B

acte

ricid

al a

ctiv

ityN

eiss

eria

l inf

ectio

ns, S

LEA

RC

8αV

ery

rare

C8b

def

icie

ncy

-Abs

ent C

hem

olyt

ic a

ctiv

ity, D

efec

tive

MA

C-D

efec

tive

Bac

teric

idal

act

ivity

Nei

sser

ial i

nfec

tions

, SLE

AR

C8β

Ver

y ra

re

C9

defic

ienc

y-R

educ

ed C

hem

olyt

ic a

ctiv

ity, D

efec

tive

MA

C-D

efec

tive

Bac

teric

idal

act

ivity

Nei

sser

ial i

nfec

tions

****

AR

C9

Rar

e

C1

inhi

bito

r def

icie

ncy

-Spo

ntan

eous

act

ivat

ion

of th

e co

mpl

emen

t pat

hway

with

con

sum

ptio

n of

C4/

C2

-Spo

ntan

eous

act

ivat

ion

of th

e co

ntac

t sys

tem

with

gene

ratio

n of

bra

dyki

nin

from

hig

h m

olec

ular

wei

ght

kini

noge

n

Her

edita

ry a

ngio

edem

aA

DC

1 in

hibi

tor

Rel

ativ

eco

mm

on

Fact

or I

defic

ienc

y-S

pont

aneo

us a

ctiv

atio

n of

the

alte

rnat

ive

com

plem

ent

path

way

with

con

sum

ptio

n of

C3

Rec

urre

nt p

yoge

nic

infe

ctio

ns, g

lom

erul

onep

hriti

s,he

mol

ytic

-ure

mic

synd

rom

e

AR

Fact

or I

Ver

y ra

re

et al.


NIH


NIH


NIH


Dis

ease

Func

tiona

l Def

ect

Ass

ocia

ted

Feat

ures

Inhe

rita

nce

Gen

eD

efec

tsR

elat

ive

freq

uenc

yam

ong

PID

s

Fact

or H

def

icie

ncy

-Spo

ntan

eous

act

ivat

ion

of th

e al

tern

ativ

e co

mpl

emen

tpa

thw

ay w

ith c

onsu

mpt

ion

of C

3H

emol

ytic

-ure

mic

synd

rom

e,m

embr

anop

rolif

erat

ive

glom

erul

onep

hriti

s

AR

Fact

or H

Rar

e

Fact

or D

def

icie

ncy

-Abs

ent h

emol

ytic

act

ivity

by

the

alte

rnat

e pa

thw

ayN

eiss

eria

l inf

ectio

nA

RFa

ctor

DV

ery

rare

Prop

erdi

n de

ficie

ncy

-Abs

ent h

emol

ytic

act

ivity

by

the

alte

rnat

e pa

thw

ayN

eiss

eria

l inf

ectio

nX

LPr

oper

din

Rar

e

MB

P de

ficie

ncy

****

*-D

efec

tive

man

nose

reco

gniti

on-D

efec

tive

hem

olyt

ic a

ctiv

ity b

y th

e le

ctin

pat

hway

.Py

ogen

ic in

fect

ions

with

very

low

pen

etra

nce

mos

tlyas

ympt

amat

ic

AR

MB

P **

***

Rel

ativ

eco

mm

on

MA

SP2

defic

ienc

y-A

bsen

t hem

olyt

ic a

ctiv

ity b

y th

e le

ctin

pat

hway

SLE

synd

rom

e, p

yoge

nic

infe

ctio

nA

RM

ASP

2Ex

trem

ely

rare

Com

plem

ent R

ecep

tor

3 (C

R3)

def

icie

ncy

-see

LA

D1

in T

able

V, a

bove

AR

INTG

B2

Rar

e

Mem

bran

e C

ofac

tor

Prot

ein

(CD

46)

defic

ienc

y

-Inh

ibito

r of c

ompl

emen

t alte

rnat

e pa

thw

ay, d

ecre

ased

C3b

bin

ding

Glo

mer

ulon

ephr

itis,

atyp

ical

hem

olyt

ic u

rem

ic sy

ndro

me

AD

MC

PV

ery

rare

Mem

bran

e A

ttack

Com

plex

Inhi

bito

r(C

D59

) def

icie

ncy

-Ery

thro

cyte

s hig

hly

susc

eptib

le to

com

plem

ent-

med

iate

d ly

sis

Hem

olyt

ic a

nem

ia,

thro

mbo

sis

AR

CD

59Ex

trem

ely

rare

Paro

xysm

al n

octu

rnal

hem

oglo

binu

ria-C

ompl

emen

t-med

iate

d he

mol

ysis

Rec

urre

nt h

emol

ysis

Acq

uire

d X

-lin

ked

mut

atio

n

PIG

AR

elat

ive

com

mon

Imm

unod

efic

ienc

yas

soci

ated

with

Fic

olin

3 de

ficie

ncy

Abs

ence

of c

ompl

emen

t act

ivat

ion

by th

e Fi

colin

3pa

thw

ayR

ecur

rent

seve

re p

yoge

nic

infe

ctio

ns m

ainl

y in

the

lung

s

AR

FCN

3Ex

trem

ely

rare

* The

C1r

and

C1s

gen

es a

re lo

cate

d w

ithin

9.5

kb

of e

ach

othe

r. In

man

y ca

ses o

f C1r

def

icie

ncy,

C1s

is a

lso

defic

ient

.§ G

ene

dupl

icat

ion

has r

esul

ted

in tw

o ac

tive

C4A

gen

es lo

cate

d w

ithin

10

kb. C

4 de

ficie

ncy

requ

ires a

bnor

mal

ities

in b

oth

gene

s, us

ually

the

resu

lt of

del

etio

ns.

**Ty

pe 1

C2

defic

ienc

y is

in li

nkag

e di

sequ

ilibr

ium

with

HLA

-A25

, B18

and

-DR

2 an

d co

mpl

otyp

e, S

O42

(slo

w v

aria

nt o

f Fac

tor B

, abs

ent C

2, ty

pe 4

C4A

, typ

e 2

C4B

) and

is c

omm

on in

Cau

casi

ans (

abou

t1

per 1

0,00

0). I

t res

ults

from

a 2

8-bp

del

etio

n re

sulti

ng in

a p

rem

atur

e st

op c

odon

in th

e C

2 ge

ne; C

2 m

RN

A is

not

pro

duce

d. T

ype

2 C

2 de

ficie

ncy

is v

ery

rare

and

invo

lves

am

ino

acid

subs

titut

ions

whi

chre

sult

in C

2 se

cret

ory

bloc

k.**

* C8a

lpha

def

icie

ncy

is a

lway

s ass

ocia

ted

with

C8g

amm

a de

ficie

ncy.

The

gen

e en

codi

ng C

8gam

ma

map

s to

chro

mos

ome

9 an

d is

nor

mal

. C8g

amm

a is

cov

alen

tly b

ound

to C

8alp

ha.

****

Ass

ocia

tion

is w

eake

r tha

n w

ith C

5, C

6, C

7 an

d C

8 de

ficie

ncie

s. C

9 de

ficie

ncy

occu

rs in

abo

ut 1

per

1,0

00 Ja

pane

se.

****

* Popu

latio

n st

udie

s rev

eal n

o de

tect

able

incr

ease

in in

fect

ions

in M

BP

defic

ient

adu

lts.

Abb

revi

atio

ns: M

AC

= M

embr

ane

atta

ck c

ompl

ex S

LE: s

yste

mic

lupu

s ery

them

atos

us; M

BP:

Man

nose

bin

ding

Pro

tein

; MA

SP-2

: MB

P as

soci

ated

serin

e pr

otea

se 2

.

et al.


NIH


NIH


NIH


Primary immunodeficiencies: 2009 update

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Transcript of Primary immunodeficiencies: 2009 update