Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, No. 56 Nanlishi Road, Beijing, 100045, China.
J Clin Immunol. 2023 May;43(4):780-793. doi: 10.1007/s10875-023-01441-7. Epub 2023 Feb 2.
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.
铁粒幼细胞性贫血、免疫缺陷、周期性发热和发育迟缓（SIFD）是一种常染色体隐性综合征，由 tRNA 核苷酸转移酶 1（TRNT1）的双等位基因失活变异引起。目前缺乏有效的 SIFD 治疗方法。我们鉴定了 TRNT1 的两个新突变，并找到了一种有效的新型 SIFD 治疗方法。
我们回顾性总结了来自不同家庭的 2 例 SIFD 患者的临床记录，并复习了所有已发表的 SIFD 病例。
两名患者均有周期性发热、发育迟缓、皮疹、小细胞性贫血和 B 细胞淋巴细胞减少伴感染。患者 1 的全外显子组测序发现了 TRNT1 先前未报道的纯合突变（c.706G> A/p.Glu236Lys）。他接受了静脉注射免疫球蛋白（IVIG）替代和抗生素治疗，但在 1 岁时死亡。患者 2 的基因检测显示 TRNT1 复合杂合突变（c.907C> G/p.Gln303Glu 和 c.88A> G/p.Met30Val），前者为新突变。阿达木单抗治疗和 IVIG 替代后第一个月控制了周期性发热，但第二个月复发。停用阿达木单抗，改用沙利度胺，有效控制了周期性发热并使炎症标志物正常化。对已报道病例的回顾性分析显示，69 例 SIFD 患者携带 46 种突变。男女比例为 1:1，发病的平均年龄为 3.0 个月。SIFD 患者最常见的临床表现是小细胞性贫血（82.6%）、低丙种球蛋白血症/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%）。除了典型的四联征外，SIFD 还具有多种涉及多个系统的异质性症状。皮质类固醇、免疫抑制剂和阿那白滞素疗效较低，而依那西普可抑制发热并改善贫血。骨髓移植可用于治疗严重的 SIFD，但风险较高。总共 28.2%（20/71）的报道患者死亡，主要是多器官衰竭。双等位基因突变位于外显子 1-内含子 5 导致更严重的表型和更高的死亡率。此外，15.5%（11/71）的患者存活至成年。5 例患者的症状可自行缓解。
沙利度胺可控制 SIFD 的炎症，是 SIFD 的一种新治疗方法。
