Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds
Inherited IL-12p40 Deficiency Genetic, Immunologic, and Clinical Features of 49 Patients From 30 Kindreds
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DOI：
10.1097/md.0b013e31828a01f9
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发表时间：
2013-03-01
期刊：
影响因子：
1.6
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
--
作者：
Prando, Carolina;Samarina, Arina;Casanova, Jean-Laurent
常染色体隐性白细胞介素（IL）-12 p40（IL-12 p40）缺乏症是孟德尔分枝杆菌病（MSMD）易感性的一种罕见遗传病因。我们报告了来自5个国家（印度、伊朗、巴基斯坦、沙特阿拉伯和突尼斯）的30例肾功能不全的49例患者的遗传学、免疫学和临床特征。IL 12 B基因只有9种不同的突变等位基因：2个小插入，3个小缺失，2个剪接位点突变和1个大缺失，每个都引起移码并导致提前终止密码子，以及1个无义突变。这9种变异中有4种是复发性的，由于特定国家的创始人效应，影响了30种报告的kinases中的25种。所有患者均为纯合子，并显示完全的IL-12 p40缺陷。因此，患者缺乏可检测的IL-12 p70和IL-12 p40，并且具有低水平的干扰素γ（IFN-γ）。临床特征以儿童期卡介苗（减毒牛分枝杆菌株）和沙门氏菌感染为特征，沙门氏菌病复发率（36.4%）高于分枝杆菌病复发率（25%）。卡介苗接种导致41例患者中40例（97.5%）的卡介苗疾病。多重分枝杆菌感染是罕见的，仅在3例患者中观察到，而沙门氏菌病和分枝杆菌病的关联在9例患者中观察到。还诊断出其他一些感染，包括慢性粘膜皮肤念珠菌病（n = 3）、诺卡氏菌病（n = 2）和克雷伯菌病（n = 1）。IL-12 p40缺乏症具有高但不完全的临床表现率，其中33.3%的指示病例的遗传影响亲属没有表现出症状。然而，预后很差，死亡率高达28.6%。总的来说，IL-12 p40缺乏症的临床表型与白细胞介素12受体β 1（IL-12 R β 1）缺乏症非常相似。总之，IL-12 p40缺乏症比最初认为的更常见，在MSMD和其他巨噬细胞内感染性疾病（特别是沙门氏菌病）患者中应予以考虑。（医学2013; 92：109-122）
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-gamma). The clinical features are characterized by childhood onset of bacille Calmette-Guerin (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 beta 1 (IL-12R beta 1) 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. (Medicine 2013; 92: 109-122)