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Revisiting human IL-12R?1 deficiency: a survey of 141 patients from 30 countries.

ABSTRACT: Interleukin-12 receptor ?1 (IL-12R?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-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-12R?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.

SUBMITTER: de Beaucoudrey L

PROVIDER: S-EPMC3129625 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries.

de Beaucoudrey Ludovic L Samarina Arina A Bustamante Jacinta J Cobat Aurélie A Boisson-Dupuis Stéphanie S Feinberg Jacqueline J Al-Muhsen Saleh S Jannière Lucile L Rose Yoann Y de Suremain Maylis M Kong Xiao-Fei XF Filipe-Santos Orchidée O Chapgier Ariane A Picard Capucine C Fischer Alain A Dogu Figen F Ikinciogullari Aydan A Tanir Gonul G Al-Hajjar Sami S Al-Jumaah Suliman S Frayha Husn H HH AlSum Zobaida Z Al-Ajaji Sulaiman S Alangari Abdullah A Al-Ghonaium Abdulaziz A Adimi Parisa P Mansouri Davood D Ben-Mustapha Imen I Yancoski Judith J Garty Ben-Zion BZ Rodriguez-Gallego Carlos C Caragol Isabel I Kutukculer Necil N Kumararatne Dinakantha S DS Patel Smita S Doffinger Rainer R Exley Andrew A Jeppsson Olle O Reichenbach Janine J Nadal David D Boyko Yaryna Y Pietrucha Barbara B Anderson Suzanne S Levin Michael M Schandené Liliane L Schepers Kinda K Efira André A Mascart Françoise F Matsuoka Masao M Sakai Tatsunori T Siegrist Claire-Anne CA Frecerova Klara K Blüetters-Sawatzki Renate R Bernhöft Jutta J Freihorst Joachim J Baumann Ulrich U Richter Darko D Haerynck Filomeen F De Baets Frans F Novelli Vas V Lammas David D Vermylen Christiane C Tuerlinckx David D Nieuwhof Chris C Pac Malgorzata M Haas Walther H WH Müller-Fleckenstein Ingrid I Fleckenstein Bernhard B Levy Jacob J Raj Revathi R Cohen Aileen Cleary AC Lewis David B DB Holland Steven M SM Yang Kuender D KD Wang Xiaochuan X Wang Xiaohong X Jiang Liping L Yang Xiqiang X Zhu Chaomin C Xie Yuanyuan Y Lee Pamela Pui Wah PPW Chan Koon Wing KW Chen Tong-Xin TX Castro Gabriela G Natera Ivelisse I Codoceo Ana A King Alejandra A Bezrodnik Liliana L Di Giovani Daniela D Gaillard Maria Isabel MI de Moraes-Vasconcelos Dewton D Grumach Anete Sevciovic AS da Silva Duarte Alberto Jose AJ Aldana Ruth R Espinosa-Rosales Francisco Javier FJ Bejaoui Mohammed M Bousfiha Ahmed Aziz AA Baghdadi Jamila El JE Özbek Namik N Aksu Guzide G Keser Melike M Somer Ayper A Hatipoglu Nevin N Aydogmus Çigdem Ç Asilsoy Suna S Camcioglu Yildiz Y Gülle Saniye S Ozgur Tuba T TT Ozen Meteran M Oleastro Matias M Bernasconi Andrea A Mamishi Setareh S Parvaneh Nima N Rosenzweig Sergio S Barbouche Ridha R Pedraza Sigifredo S Lau Yu Lung YL Ehlayel Mohammad S MS Fieschi Claire C Abel Laurent L Sanal Ozden O Casanova Jean-Laurent JL

Medicine 20101101 6

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 tuber ...[more]

PMID: 21057261

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Project description:Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor β1 (IL-12Rβ1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.

Project description:BackgroundStatins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners' (GPs) advice to stop statins in oldest-old patients.ObjectiveTo investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs' advice to stop statins in oldest-old patients.DesignWe invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment.Main measuresCases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs' advice to stop.Key resultsTwo thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45-47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89-90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6-15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5-1.7) and with frailty (ORadj 4.1, 95%CI 3.8-4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5-56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19-42) to 98% (95% CI 96-99).ConclusionsThe absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs' advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs' advice to stop statins.

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Revisiting human IL-12R?1 deficiency: a survey of 141 patients from 30 countries.

Publications

Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries.

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