Revisiting Human IL-12R beta 1 Deficiency A Survey of 141 Patients From

Abstract

Interleukin-12 receptor beta 1 (IL-12R beta 1) 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-Guerin (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-12R beta 1 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.

C1 [de Beaucoudrey, Ludovic; Samarina, Arina; Bustamante, Jacinta; Cobat, Aurelie; Boisson-Dupuis, Stephanie; Feinberg, Jacqueline; Janniere, Lucile; Rose, Yoann; de Suremain, Maylis; Kong, Xiao-Fei; Filipe-Santos, Orchidee; Chapgier, Ariane; Picard, Capucine; Abel, Laurent; Casanova, Jean-Laurent] INSERM, U980, Lab Human Genet Infect Dis, Paris, France.

[Fischer, Alain] INSERM, U768, Lab Normal & Pathol Dev Immune Syst, Paris, France.

[de Beaucoudrey, Ludovic; Samarina, Arina; Bustamante, Jacinta; Cobat, Aurelie; Boisson-Dupuis, Stephanie; Feinberg, Jacqueline; Janniere, Lucile; Rose, Yoann; de Suremain, Maylis; Kong, Xiao-Fei; Filipe-Santos, Orchidee; Chapgier, Ariane; Picard, Capucine; Fischer, Alain; Abel, Laurent; Casanova, Jean-Laurent] Univ Paris 05, Necker Med Sch, Paris, France.

[Samarina, Arina; Boisson-Dupuis, Stephanie; Kong, Xiao-Fei; Abel, Laurent; Casanova, Jean-Laurent] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10065 USA.

[Al-Muhsen, Saleh; Al-Hajjar, Sami; Alangari, Abdullah; Casanova, Jean-Laurent] King Saud Univ, Coll Med, Prince Naif Ctr Immunol Res, Riyadh 11461, Saudi Arabia.

[Al-Muhsen, Saleh; Alangari, Abdullah] King Saud Univ, Coll Med, Dept Pediat, Riyadh 11461, Saudi Arabia.

[Al-Muhsen, Saleh; Al-Hajjar, Sami; Al-Jumaah, Suliman; Frayha, Husn H.; Al-Ghonaium, Abdulaziz] King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh 11211, Saudi Arabia.

[Picard, Capucine] Hop Necker Enfants Malad, AP HP, Study Ctr Primary Immunodeficiencies, Paris, France.

[Fischer, Alain; Casanova, Jean-Laurent] Hop Necker Enfants Malad, AP HP, Pediat Hematol Immunol Unit, Paris, France.

[Dogu, Figen; Ikinciogullari, Aydan] Ankara Univ, Sch Med, Dept Pediat Allergy & Immunol, TR-06100 Ankara, Turkey.

[Tanir, Gonul] Sami Ulus Children Hlth & Dis Training & Res Ctr, Ankara, Turkey.

[Al-Ajaji, Sulaiman] King Fahad Natl Guard Hosp, Dept Pediat, Riyadh, Saudi Arabia.

[Adimi, Parisa; Mansouri, Davood] Shahid Beheshti Univ Med Sci, Div Infect Dis & Clin Immunol, Natl Res Inst TB & Lung Dis, Tehran, Iran.

[Ben-Mustapha, Imen; Barbouche, Ridha] Pasteur Inst Tunis, Lab Cytoimmunol, Tunis, Tunisia.

[Yancoski, Judith; Oleastro, Matias; Bernasconi, Andrea] Juan Pedro Garrahan Natl Hosp Pediat, Dept Immunol, Buenos Aires, DF, Argentina.

[Garty, Ben-Zion] Schneider Childrens Med Ctr Israel, Dept Pediat, Petah Tiqwa, Israel.

[Rodriguez-Gallego, Carlos] Gran Canaria Dr Negrin Univ Hosp, Dept Immunol, Las Palmas Gran Canaria, Spain.

[Caragol, Isabel] Vall dHebron Hosp, Immunol Lab, Barcelona, Spain.

[Kutukculer, Necil; Aksu, Guzide] Ege Univ, Sch Med, Dept Pediat, Izmir, Turkey.

[Kumararatne, Dinakantha S.; Patel, Smita; Doffinger, Rainer] Addenbrookes Hosp, Dept Clin Biochem & Immunol, Cambridge, England.

[Exley, Andrew] Papworth Hosp NHS Fdn Trust, Inflammat & Immunol Unit, Dept Pathol, Cambridge, England.

[Exley, Andrew] Papworth Hosp NHS Fdn Trust, Inflammat & Immunol Unit, Dept Thorac Med, Cambridge, England.

[Jeppsson, Olle] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Huddinge, Sweden.

[Reichenbach, Janine] Univ Childrens Hosp Zurich, Dept Immunol, Zurich, Switzerland.

[Nadal, David] Univ Childrens Hosp Zurich, Dept Infect Dis, Zurich, Switzerland.

[Boyko, Yaryna] Lviv Reg Specialized Childrens Hosp, Lvov, Ukraine.

[Pietrucha, Barbara; Pac, Malgorzata] Childrens Mem Hlth Inst, Dept Immunol, Warsaw, Poland.

[Anderson, Suzanne; Levin, Michael] St Marys Hosp, Imperial Coll Sch Med, Dept Pediat, London, England.

[Schandene, Liliane; Efira, Andre; Mascart, Francoise] Univ Libre Bruxelles, Immunobiol Clin, Hop Erasme, Brussels, Belgium.

[Schepers, Kinda] Univ Libre Bruxelles, Immunodeficiency Dept, Hop Erasme, Brussels, Belgium.

[Mascart, Francoise] Univ Libre Bruxelles, Lab Vaccinol & Mucosal Immun, Brussels, Belgium.

[Matsuoka, Masao] Kyoto Univ, Inst Virus Res, Lab Virus Control, Kyoto 606, Japan.

[Sakai, Tatsunori] Natl Hosp Org Kumamoto Med Ctr, Dept Internal Med, Kumamoto, Japan.

[Siegrist, Claire-Anne] Univ Geneva, Dept Pediat, Geneva, Switzerland.

[Frecerova, Klara] Minist Hlth, Dept Int Relat, Bratislava, Slovakia.

[Blueetters-Sawatzki, Renate] Dept Pediat Hematol & Oncol, Giessen, Germany.

[Bernhoeft, Jutta] Hannover Med Sch, Dept Pediat Pulmonol & Neonatol, D-3000 Hannover, Germany.

[Freihorst, Joachim; Baumann, Ulrich] Univ Hosp Ctr Rebro, Dept Pediat, Zagreb, Croatia.

[Haerynck, Filomeen; De Baets, Frans] Ghent Univ Hosp, Dept Pediat Pulmonol & Immunol, B-9000 Ghent, Belgium.

[Novelli, Vas] Great Ormond St Hosp Sick Children, Infect Dis Unit, London WC1N 3JH, England.

[Lammas, David] Univ Birmingham, Sch Med, MRC, Ctr Immune Regulat, Birmingham, W Midlands, England.

[Vermylen, Christiane] Clin Univ St Luc, Dept Pediat Hematol & Oncol, B-1200 Brussels, Belgium.

Catholic Univ Louvain, B-1200 Brussels, Belgium.

[Tuerlinckx, David] Catholic Univ Louvain, Dept Pediat, Mt Godinne Clin, B-1200 Brussels, Belgium.

[Nieuwhof, Chris] Maastricht Univ, Med Ctr, Dept Internal Med, Div Clin & Expt Immunol, Maastricht, Netherlands.

[Haas, Walther H.] Robert Koch Inst, Dept Infect Dis Epidemiol, Unit Resp Infect, D-1000 Berlin, Germany.

[Mueller-Fleckenstein, Ingrid; Fleckenstein, Bernhard] Univ Erlangen Nurnberg, Inst Klin & Mol Virol, D-8520 Erlangen, Germany.

[Levy, Jacob] Ben Gurion Univ Negev, Fac Hlth Sci, Soroka Med Ctr, Dept Pediat, Beer Sheva, Israel.

[Raj, Revathi] Apollo Special Hosp, Dept Pediat Hematol, Madras, Tamil Nadu, India.

[Cohen, Aileen Cleary; Lewis, David B.] Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA.

[Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA.

[Rosenzweig, Sergio] NIAID, Infect Dis Susceptibil Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA.

[Yang, Kuender D.] Chang Gung Childrens Hosp, Dept Pediat Allergy, Kaohsiung, Taiwan.

Chang Gung Childrens Hosp, Dept Med Res, Kaohsiung, Taiwan.

Chang Gung Univ, Kaohsiung, Taiwan.

[Wang, Xiaochuan] Fudan Univ, Dept Clin Immunol, Childrens Hosp, Shanghai 200433, Peoples R China.

[Yang, Xiqiang] Chongqing Med Univ, Childrens Hosp, Clin Immunol Lab, Chongqing, Peoples R China.

[Lee, Pamela Pui Wah; Chan, Koon Wing; Lau, Yu Lung] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Li Ka Shing Fac Med, Pokfulam, Hong Kong, Peoples R China.

[Chen, Tong-Xin] Shanghai Jiao Tong Univ, Xinhua Hosp, Shanghai Inst Pediat Res, Dept Pediat,Sch Med, Shanghai 200030, Peoples R China.

[Castro, Gabriela] Univ Fed Bahia, Dept Immunol, BR-41170290 Salvador, BA, Brazil.

[Natera, Ivelisse] Univ Hosp Caracas, Caracas, Venezuela.

[Codoceo, Ana; King, Alejandra] Hosp Ninos Luis Calvo Mackenna, Santiago, Chile.

[Bezrodnik, Liliana; Di Giovani, Daniela; Isabel Gaillard, Maria] Ricardo Gutierrez Children Hosp, Dept Immunol, Buenos Aires, DF, Argentina.

[de Moraes-Vasconcelos, Dewton; Grumach, Anete Sevciovic; da Silva Duarte, Alberto Jose] Univ Sao Paulo, Sch Med, Dept Dermatol, Lab Invest Dermatol & Immunodeficiencies, Sao Paulo, Brazil.

[Aldana, Ruth] Childrens Hosp Federico Gomez, Dept Pulmonol, Mexico City, DF, Mexico.

[Javier Espinosa-Rosales, Francisco] Natl Inst Pediat, Dept Immunol, Mexico City, DF, Mexico.

[Bejaoui, Mohammed] Natl Ctr Bone Marrow Graft, Tunis, Tunisia.

[Bousfiha, Ahmed Aziz] Ibn Rochd Hosp, Clin Immunol Unit, Casablanca, Morocco.

[El Baghdadi, Jamila] Mil Hosp Mohamed V, Immunol Lab, Hay Riad Rabat, Morocco.

[Ozbek, Namik] Baskent Univ, Sch Med, Dept Pediat, TR-06490 Ankara, Turkey.

[Keser, Melike; Somer, Ayper] Istanbul Univ, Fac Med, Dept Pediat Infect Dis & Clin Immunol, Istanbul, Turkey.

[Hatipoglu, Nevin; Aydogmus, Cigdem] Bakirkoy Matern & Childrens State Hosp, Dept Pediat Infect Dis & Immunol, Istanbul, Turkey.

[Asilsoy, Suna; Gulle, Saniye] Dr Behcet Uz Children Res & Training Hosp, Dept Pediat, Izmir, Turkey.

[Camcioglu, Yildiz] Istanbul Univ, Dept Pediat, Infect Dis Clin Immunol & Allergy Div, Cerrahpasa Med Sch, Istanbul, Turkey.

[Ozgur, Tuba T.; Sanal, Ozden] Hacettepe Univ, Childrens Hosp, Div Immunol, Ankara, Turkey.

[Ozen, Meteran] Inonu Univ, Fac Med, Div Pediat Infect Dis, Malatya, Turkey.

[Mamishi, Setareh; Parvaneh, Nima] Univ Tehran Med Sci, Infect Dis Res Ctr, Dept Pediat, Tehran, Iran.

[Pedraza, Sigifredo] Minist Hlth, Dept Biochem, INCMNSZ, Mexico City, DF, Mexico.

[Ehlayel, Mohammad S.] Hamad Med Corp, Dept Pediat, Doha, Qatar.

[Fieschi, Claire] St Louis Hosp, AP HP, Adult Immunopathol Unit, Paris, France.