Introduction
Severe combined immunodeficiency (SCID) is a fatal disorder resulting from various genetic defects. In the Middle East, where consanguineous marriage is prevalent, autosomal recessive mutations in recombination-activating genes (RAG) are a leading cause of SCID. We present a large cohort of SCID patients due to RAG1 or RAG2 mutations.

Methods
Twenty-six patients with RAG1 or RAG2 deficiency, diagnosed at Sheba Medical Center, were retrospectively investigated. Clinical presentation, immunologic phenotype, genetic analysis, treatment, and outcome were analyzed.

Results
Majority of patients were referred from the Palestinian Authority. Most patients were males of Muslim Arab descent, 77% were born to consanguineous parents, and 65% had family history of immunodeficiency. Nearly all patients suffered from various infections before turning 2 months old, eight patients (31%) presented with Omenn and Omenn-like syndrome, and three patients (11%) had maternal engraftment. Notably, seven patients (27%) suffered from vaccine-derived infections, including a rare case of measles encephalitis. Nineteen patients underwent hematopoietic stem cell transplantation (HSCT) at a median age of 6 months, with a successful outcome for 72% of them. Genetic analysis revealed 11 different mutations (7 RAG2, 4 RAG1), two of them novel.

Conclusions
Consanguineous marriages account for a genetic “founder effect.” SCID is a pediatric emergency that dictates immediate precautions and curative treatment with HSCT. Due to lack of newborn screening for SCID within the Palestinian population, most patients in this cohort were diagnosed upon clinical symptoms, which led to a delayed diagnosis, harmful administration of contra-indicated live vaccines, delay in HSCT, and poor outcome.



中文翻译：

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大量RAG1 / 2缺陷型SCID患者—临床，免疫学和预后分析

简介
严重的联合免疫缺陷症（SCID）是由多种遗传缺陷引起的致命性疾病。在近亲结婚普遍的中东地区，重组激活基因（RAG）中的常染色体隐性突变是SCID的主要原因。由于RAG1或RAG2突变，我们提出了一大批SCID患者。

方法
回顾性调查在谢巴医学中心诊断为RAG1或RAG2缺乏症的26例患者。临床表现，免疫表型，遗传分析，治疗和结果进行了分析。

结果
大多数病人是从巴勒斯坦权力机构转来的。大多数患者是阿拉伯穆斯林血统的男性，有近亲父母出生的占77％，有免疫缺陷家族史的占65％。几乎所有患者在2个月大之前就遭受了各种感染，其中8例（31％）出现Omenn和Omenn样综合征，而3例（11％）发生了母体植入。值得注意的是，有7名患者（27％）患有疫苗源性感染，包括罕见的麻疹脑炎病例。19名患者的中位年龄为6个月，接受了造血干细胞移植（HSCT），其中72％成功。遗传分析揭示了11个不同的突变（7个RAG2、4个RAG1），其中两个是新颖的。

结论
血缘婚姻是基因“创始人效应”的原因。SCID是一种小儿急症，要求立即采取预防措施和使用HSCT进行治疗。由于在巴勒斯坦人口中缺乏针对SCID的新生儿筛查，该队列中的大多数患者均根据临床症状被诊断出，从而导致诊断延迟，禁忌使用活疫苗的有害给药，HSCT延迟和预后不良。