An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.
BACKGROUND
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone.


METHODS
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN.


RESULTS
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly.


CONCLUSIONS
We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Aksentijevich
Ivona
I
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Masters
Seth L
SL
Ferguson
Polly J
PJ
Dancey
Paul
P
Frenkel
Joost
J
van Royen-Kerkhoff
Annet
A
Laxer
Ron
R
Tedgård
Ulf
U
Cowen
Edward W
EW
Pham
Tuyet-Hang
TH
Booty
Matthew
M
Estes
Jacob D
JD
Sandler
Netanya G
NG
Plass
Nicole
N
Stone
Deborah L
DL
Turner
Maria L
ML
Hill
Suvimol
S
Butman
John A
JA
Schneider
Rayfel
R
Babyn
Paul
P
El-Shanti
Hatem I
HI
Pope
Elena
E
Barron
Karyl
K
Bing
Xinyu
X
Laurence
Arian
A
Lee
Chyi-Chia R
CC
Chapelle
Dawn
D
Clarke
Gillian I
GI
Ohson
Kamal
K
Nicholson
Marc
M
Gadina
Massimo
M
Yang
Barbara
B
Korman
Benjamin D
BD
Gregersen
Peter K
PK
van Hagen
P Martin
PM
Hak
A Elisabeth
AE
Huizing
Marjan
M
Rahman
Proton
P
Douek
Daniel C
DC
Remmers
Elaine F
EF
Kastner
Daniel L
DL
Goldbach-Mansky
Raphaela
R
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1