目标:铁粒幼细胞性贫血,免疫缺陷,周期性发烧,发育迟缓(SIFD)是由tRNA核苷酸转移酶1(TRNT1)的双等位基因功能丧失变体引起的常染色体隐性综合征。缺乏治疗SIFD的有效方法。我们确定了TRNT1中的两个新突变和SIFD的有效和新颖疗法。
方法:我们回顾性总结了来自不同家庭的两名SIFD患者的临床记录,并回顾了所有已发表的SIFD病例。
结果:两名患者都有周期性发热,发育迟缓,皮疹,小细胞性贫血,和B细胞淋巴细胞减少与感染。患者1的全外显子组测序鉴定了先前未报告的TRNT1纯合突变(c.706G>A/p。Glu236Lys)。他接受了静脉注射免疫球蛋白(IVIG)替代治疗和抗生素,但在1岁时死亡。患者2的基因检测显示复合杂合突变(c.907C>G/p。Gln303Glu和c.88A>G/p。Met30Val)在TRNT1中,前者是一种新的突变。阿达木单抗治疗和IVIG替代治疗后的第一个月,周期性发热得到控制。但在第二个月复发。停用阿达木单抗并替换为沙利度胺,有效控制周期性发热并使炎症标志物正常化。对报告病例的回顾性分析显示,69例SIFD患者携带46个突变。男女比例为1:1,平均发病年龄为3.0个月。SIFD患者最常见的临床表现是小细胞性贫血(82.6%),低球蛋白血症/B细胞淋巴细胞减少(75.4%),周期性发热(66.7%),和发育迟缓(60.0%)。除了典型的四联症,SIFD具有涉及多个系统的几种异质症状。皮质类固醇,免疫抑制剂,和anakinra疗效低,而依那西普抑制了发热并改善了贫血。骨髓移植可用于治疗严重的SIFD,但风险很高。总的来说,28.2%(20/71)的报告患者死亡,主要是因为多器官衰竭。位于外显子1-内含子5的双等位基因突变导致更严重的表型和更高的死亡率。此外,15.5%(11/71)的患者存活到成年。五名患者的症状可以自发缓解。
结论:沙利度胺可以控制SIFD的炎症,是一种新的SIFD治疗方法。
Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (
TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in
TRNT1 and an efficacious and novel therapy for SIFD.
We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD.
Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of
TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in
TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients.
Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.