Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries.
Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.
From Laboratory of Human Genetics of Infectious Diseases U980 (LDB, A. Samarina, J. Bustamante, A. Cobat, SBD, J. Feinberg, L. Jannière, YR, MDS, XFK, OFS, A. Chapgier, CP, LA, JLC) and Laboratory of Normal and Pathologic Development of the Immune System U768 (AF), Institut National de la Santé et de la Recherche Médicale, Paris, France; University Paris Descartes (LDB, A. Samarina, J. Bustamante, A. Cobat, SBD, J. Feinberg, L. Jannière, YR, MDS, XFK, OFS, A. Chapgier, CP, AF, LA, JLC), Necker Medical School, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases (A. Samarina, SBD, XFK, LA, JLC), The Rockefeller University, New York, New York; Prince Naif Center for Immunology Research (SAM, SAH, ZAS, AA, JLC) and Department of Pediatrics (SAM, ZAS, AA), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Pediatrics (SAM, SAH, SAJ, HHF, AAG), King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Study Center of Primary Immunodeficiencies (CP) and Pediatric Hematology-Immunology Unit (AF, JLC), Necker Hospital, AP-HP, Paris, France; Department of Pediatric Allergy and Immunology (FD, AI), Ankara University School of Medicine, Ankara, Turkey; Dr Sami Ulus Children Health and Diseases Training and Research Center (GT), Ankara, Turkey; Department of Pediatrics (SAA), King Abdulaziz Medical City, King Fahad National Guard Hospital, Riyadh, Saudi Arabia; Division of Infectious Diseases and Clinical Immunology (PA, DM), National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Teheran, Iran; Laboratory of Cytoimmunology (IBM, RB), Pasteur Institut of Tunis, Tunis-Belvédère, Tunisia; Department of Immunology (JY, M. Oleastro, AB), Juan-Pedro Garrahan National Hospital of Pediatrics, Buenos Aires, Argentina; Department of Pediatrics (BZG), Schneider Children's Medical Center of Israel, Petah Tiqva, Israel; Department of Immunology (CRG), Gran Canaria Dr Negrin University Hospital, Las Palmas de Gran Canaria, Spain; Laboratory of Immunology (IC), Vall d'Hebron Hospital, Barcelona, Spain; Department of Pediatrics (NK, GA), Ege University Medical School, Izmir, Turkey; Department of Clinical Biochemistry and Immunology (DSK, S. Patel, RD), Addenbrookes Hospital, Cambridge, United Kingdom; Immunology Laboratory and Respiratory Infection, Inflammation and Immunology Unit, Departments of Pathology and Thoracic Medicine (A. Exley), Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom; Astrid Lindgren Childrens Hospital Karolinska University Hospital (OJ), Huddinge, Sweden; Department of Immunology (JR) and Department of Infectious Diseases (DN), University Children's Hospital of Zurich, Zurich, Switzerland; Lviv Regional Specialized Children's Hospital (YB), Lviv, Ukraine; Department of Immunology (BP, MP), Children's Memorial Health Institute, Warsaw, Poland; Department of Pediatrics (S. Anderson, ML), Imperial College School of Medicine, St Mary's Hospital, London, United Kingdom; Immunobiology Clinic (LS, A. Efira, FM) and Immunodeficiency Department (KS), Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Vaccinology and Mucosal Immunity (FM), Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Virus Control (MM), Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Internal Medicine (TS), National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; Department of Pediatrics (CAS), University of Geneva, Geneva, Switzerland; Department of International Relations (KF), Ministry of Health, Bratislava, Slovak Republic; Department of Pediatric Hematology and Oncology (RBS), Giessen, Germany; Department of Pediatric Pulmonology and Neonatology (J. Bernhöft), Hannover Medical School, Hannover, Germany; Department of Pediatrics (J. Freihorst, UB), University Hospital Center-Rebro, Zagreb, Croatia; Department of Pediatric Pulmonology and Immunology (FH, FDB), University Hospital Ghent, Ghent, Belgium; Infectious Diseases Unit (VN), Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom; MRC Center for Immune Regulation (DL), The Medical School, University of Birmingham, Birmingham, United Kingdom; Department of Pediatric Hematology and Oncology (CV), Cliniques Universitaires Saint Luc et Université Catholique de Louvain, Brussels, Belgium; Department of Pediatrics (DT), Mont-Godinne Clinics, Université Catholique de Louvain, Brussels, Belgium; Department of Internal Medicine/Division of Clinical and Experimental Immunology (CN), Maastricht University Medical Centre, Maastricht, The Netherlands; Unit for Respiratory Infections, Department of Infectious Disease Epidemiology (WHH), Robert Koch Institute, Berlin, Germany; Institut für Klinische und Molekulare Virologie (IMF, BF), Universität Erlangen-Nürnberg, Germany; Pediatric Department (JL), Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel; Department of Pediatric Hematology (RR), Apollo Speciality Hospitals, Chennai, India; Department of Pediatrics (ACC, DBL), Stanford University School of Medicine, Stanford, California; Laboratory of Clinical Infectious Diseases (SMH) and Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses (SR), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Department of Pediatric Allergy (KDY), Immunology and Rheumatology and Department of Medical Research, Chang Gung Children's Hospital, and Chang Gung University, Kaohsiung, Taiwan; Department of Clinical Immunology (Xiaochuan Wang), Children's Hospital of Fudan University, Shanghai, China; Clinical Immunology Laboratory (Xiqiang Yang), Children's Hospital of Chongqing Medical University, Chongqing, China; Department of Paediatrics and Adolescent Medicine (PPWL, KWC, YLL), Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China; Department of Pediatrics (TXC), Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Immunology (GC), Federal University of Bahia, Brazil; University Hospital of Caracas (IN), Caracas, Venezuela; Luis Calvo Mackenna Hospital (A. Codoceo, AK), Santiago, Chile; Department of Immunology (LB, DDG, MIG), Ricardo Gutiérrez Children Hospital, Buenos Aires, Argentina; Laboratory of Investigation in Dermatology and Immunodeficiencies, Department of Dermatology (DDMV, ASG, AJDSD), University of São Paulo Medical School, São Paulo, Brazil; Department of Pulmonology (RA), Children's Hospital Federico Gomez, Mexico City, Mexico; Department of Immunology (FJER), National Institute of Pediatrics, Mexico City, Mexico; National Center of Bone Marrow Graft (MB), Tunis, Tunisia; Clinical Immunology Unit (AAB), Ibn-Rochd Hospital, Casablanca, Morocco; Laboratory of Immunology (JEB), Military Hospital Mohamed V, Hay Riad Rabat, Morocco; Department of Pediatrics (NÖ), Baskent University School of Medicine, Ankara, Turkey; Department of Pediatric Infectious Diseases and Clinical Immunology (MK, A. Somer), Istanbul University Faculty of Medicine, Istanbul, Turkey; Department of Pediatric Infectious Diseases and Immunology (NH, CA), Bakirkoy Maternity and Children's State Hospital, Istanbul, Turkey; Department of Pediatrics (S. Asilsoy, SG), Dr Behçet Uz Children Research and Training Hospital,Izmir, Turkey; Department of Pediatrics, Infectious Diseases, Clinical Immunology and Allergy Division (YC), Cerrahpaşa Medical School, Istanbul University, Cerrahpaşa, Istanbul, Turkey; Immunology Division (TTO, OS), Hacettepe University Children's Hospital, Ankara, Turkey; Division of Pediatric Infectious Disease (M. Ozen), Faculty of Medicine, Inonu University, Malatya, Turkey; Department of Pediatrics (SM, NP), Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Biochemistry (S. Pedraza), INCMNSZ, Ministry of Health, Mexico City, Mexico; Section of Allergy-Immunology, Department of Pediatrics (MSE), Hamad Medical Corporation, Doha, Qatar; and Adult Immunopathology Unit (CF), Saint-Louis Hospital, AP-HP, Paris, France.
Ludovic
L
de Beaucoudrey
Arina
A
Samarina
Jacinta
J
Bustamante
Aurélie
A
Cobat
Stéphanie
S
Boisson-Dupuis
Jacqueline
J
Feinberg
Saleh
S
Al-Muhsen
Lucile
L
Jannière
Yoann
Y
Rose
Maylis
M
de Suremain
Xiao-Fei
XF
Kong
Orchidée
O
Filipe-Santos
Ariane
A
Chapgier
Capucine
C
Picard
Alain
A
Fischer
Figen
F
Dogu
Aydan
A
Ikinciogullari
Gonul
G
Tanir
Sami
S
Al-Hajjar
Suliman
S
Al-Jumaah
Husn H
HH
Frayha
Zobaida
Z
AlSum
Sulaiman
S
Al-Ajaji
Abdullah
A
Alangari
Abdulaziz
A
Al-Ghonaium
Parisa
P
Adimi
Davood
D
Mansouri
Imen
I
Ben-Mustapha
Judith
J
Yancoski
Ben-Zion
BZ
Garty
Carlos
C
Rodriguez-Gallego
Isabel
I
Caragol
Necil
N
Kutukculer
Dinakantha S
DS
Kumararatne
Smita
S
Patel
Rainer
R
Doffinger
Andrew
A
Exley
Olle
O
Jeppsson
Janine
J
Reichenbach
David
D
Nadal
Yaryna
Y
Boyko
Barbara
B
Pietrucha
Suzanne
S
Anderson
Michael
M
Levin
Liliane
L
Schandené
Kinda
K
Schepers
André
A
Efira
Françoise
F
Mascart
Masao
M
Matsuoka
Tatsunori
T
Sakai
Claire-Anne
CA
Siegrist
Klara
K
Frecerova
Renate
R
Blüetters-Sawatzki
Jutta
J
Bernhöft
Joachim
J
Freihorst
Ulrich
U
Baumann
Darko
D
Richter
Filomeen
F
Haerynck
Frans
F
De Baets
Vas
V
Novelli
David
D
Lammas
Christiane
C
Vermylen
David
D
Tuerlinckx
Chris
C
Nieuwhof
Malgorzata
M
Pac
Walther H
WH
Haas
Ingrid
I
Müller-Fleckenstein
Bernhard
B
Fleckenstein
Jacob
J
Levy
Revathi
R
Raj
Aileen Cleary
AC
Cohen
David B
DB
Lewis
Steven M
SM
Holland
Kuender D
KD
Yang
Xiaochuan
X
Wang
Xiaohong
X
Wang
Liping
L
Jiang
Xiqiang
X
Yang
Chaomin
C
Zhu
Yuanyuan
Y
Xie
Pamela Pui Wah
PPW
Lee
Koon Wing
KW
Chan
Tong-Xin
TX
Chen
Gabriela
G
Castro
Ivelisse
I
Natera
Ana
A
Codoceo
Alejandra
A
King
Liliana
L
Bezrodnik
Daniela
D
Di Giovani
Maria Isabel
MI
Gaillard
Dewton
D
de Moraes-Vasconcelos
Anete Sevciovic
AS
Grumach
Alberto Jose
AJ
da Silva Duarte
Ruth
R
Aldana
Francisco Javier
FJ
Espinosa-Rosales
Mohammed
M
Bejaoui
Ahmed Aziz
AA
Bousfiha
Jamila El
JE
Baghdadi
Namik
N
Özbek
Guzide
G
Aksu
Melike
M
Keser
Ayper
A
Somer
Nevin
N
Hatipoglu
Çigdem
Ç
Aydogmus
Suna
S
Asilsoy
Yildiz
Y
Camcioglu
Saniye
S
Gülle
Tuba T
TT
Ozgur
Meteran
M
Ozen
Matias
M
Oleastro
Andrea
A
Bernasconi
Setareh
S
Mamishi
Nima
N
Parvaneh
Sergio
S
Rosenzweig
Ridha
R
Barbouche
Sigifredo
S
Pedraza
Yu Lung
YL
Lau
Mohammad S
MS
Ehlayel
Claire
C
Fieschi
Laurent
L
Abel
Ozden
O
Sanal
Jean-Laurent
JL
Casanova
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous / Q000453:epidemiology / Q000235:genetics; D009163:Mycobacterium bovis / Q000302:isolation & purification; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D009170:Nontuberculous Mycobacteria / Q000302:isolation & purification; D016019:Survival Analysis
D016207:Cytokines; D053711:Interleukin-12 Receptor beta 1 Subunit