探讨X连锁ELF4缺陷病(DEX)患儿的临床特征、遗传学特点及诊治方案。

选择2022年9月于苏州大学附属儿童医院住院治疗的1例DEX患儿(先证者)及其家系成员(父母、同卵双胎哥哥及大哥)为研究对象。采用回顾性分析方法，对先证者临床资料进行分析，包括临床表现、实验室检查、影像学特点、基因检测、治疗及随访结果等。采用全外显子组测序(WES)结合Sanger测序验证先证者的ELF4基因变异及其来源，并依据美国医学遗传学与基因组学学会(ACMG)指南进行ELF4基因变异的致病性评估。以"ELF4缺陷""ELF4基因变异""ELF4 deficiency""ELF4 mutation"分别为中、英文关键词，在万方数据知识服务平台、中国知网、中华医学期刊网及PubMed数据库中进行DEX患儿相关研究的文献检索。本次检索年限设定为各数据库建库至2025年12月30日。本研究遵循的程序通过苏州大学附属儿童医院医学伦理委员会批准(审批文号：2024CS087)，并与受试儿监护人均签署临床研究知情同意书。

①先证者为男性DEX患儿，4岁10个月，同卵双胎弟弟，主要临床表现为肛周脓肿、反复发热、腹痛、口腔溃疡，肠镜检查结果显示回盲部巨大溃疡。WES结果显示ELF4基因(NM_001421.3)c.799C>T(p.R267W)错义变异，位于ETS结构域。经Sanger测序证实先证者ELF4基因变异为母源遗传，依据ACMG指南将该变异评估为可能致病性。免疫学检查提示，先证者部分T、B淋巴细胞亚群异常。对先证者采取糖皮质激素、免疫抑制剂及生物制剂联合治疗后，病情逐渐缓解。先证者的同卵双胎哥哥仅表现为反复口腔溃疡，症状较轻。②文献复习结果：采用本研究设定文献检索策略，共检索到关于DEX患儿研究文献为15篇，共纳入29例DEX患儿(加上本研究先证者)的临床特征、遗传学特点及诊治方案进行综合分析的结果显示，89.7%(26/29) DEX患儿为男性，64.3%(18/28) DEX患儿的发病年龄≤6岁。DEX患儿临床表现主要为口腔溃疡(86.2%，25/29)，胃肠道症状(69.0%，20/29)，发热(58.6%，17/29)。其治疗药物主要为糖皮质激素和生物制剂，72.4%(21/29)患儿治疗后达临床缓解，76.2%(16/21)需联合用药达缓解，1例无药维持缓解，1例合并多种不同类型淋巴瘤导致死亡。这29例DEX患儿中，共检出ELF4基因23种变异，其中以错义变异和移码变异为主，占比为39.1%(9/23)；87.0%(20/23)变异累及ETS结构域，而且累及该结构域的患儿更易表现为自身炎症表型。

DEX患儿的临床表现具有明显异质性，多需要联合治疗。DEX患儿以自身炎症表型为主，可表现为炎症性肠病或白塞病样表型。ELF4基因变异多集中于ETS结构域，ETS结构域变异可能与自身炎症表型相关。DEX患儿常需多药联合治疗方可控制病情。对于早发、临床表现不典型，或治疗反应欠佳的该病患儿，应尽早开展基因检测，以明确诊断并指导对其采取个体化治疗措施。

To investigate the clinical characteristics, genetic features, and diagnostic and therapeutic strategies of deficiency in ELF4, X-linked (DEX).

A child with DEX who was hospitalized at the Children′s Hospital of Soochow University in September 2022 was enrolled as the proband. Clinical data, including clinical manifestations, laboratory findings, imaging features, genetic testing results, treatment, and follow-up outcomes, were retrospectively analyzed. Whole-exome sequencing (WES) was performed to identify ELF4 gene variants, which were subsequently confirmed by Sanger sequencing, and their pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). A literature search was conducted using the keywords " " ELF4 deficiency" and " ELF4 mutation" in Chinese and English across the Wanfang Data, China National Knowledge Infrastructure (CNKI), Chinese Medical Journal Network, and PubMed databases. The search period ranged from inception to December 30, 2025. This study was approved by the Medical Ethics Committee of the Children′s Hospital of Soochow University (Approval No. 2024CS087), and written informed consent was obtained from the patient′s guardian.

①The proband was a 4-year-10-month-old boy, the second-born of a twin pregnancy. His main clinical manifestations included perianal abscess, recurrent fever, abdominal pain, and oral ulcers. Colonoscopy revealed a large ulcer in the ileocecal region. WES identified a missense variant in the ELF4 gene (NM_001421.3), c.799C>T (p.R267W), located within the ETS domain. Sanger sequencing confirmed that the variant was maternally inherited, and it was classified as likely pathogenic according to the ACMG guidelines. Immunological evaluation indicated abnormalities in certain T- and B-lymphocyte subsets. The patient′s condition gradually improved following combined treatment with glucocorticoids, immunosuppressants, and biologic agents. His monozygotic twin brother presented only with recurrent oral ulcers and had milder symptoms. ②Literature review: A total of 29 pediatric patients with DEX were included. Among them, 89.7% (26/29) were male, and 64.3% (18/28) had disease onset at ≤6 years of age. The main clinical manifestations included oral ulcers (86.2%, 25/29), gastrointestinal symptoms (69.0%, 20/29), and fever (58.6%, 17/29). Glucocorticoids and biologic agents were the main therapeutic options. Overall, 72.4% (21/29) of patients achieved clinical remission after treatment, of whom 76.2% (16/21) required combination therapy. One patient maintained remission without medication, and one patient died due to multiple lymphomas. A total of 23 distinct ELF4 gene variants were identified in the 29 patients, with missense and frameshift variants being the most common, each accounting for 39.1% (9/23). Notably, 87.0% (20/23) of the variants involved the ETS domain, and variants affecting this domain were more likely to be associated with an autoinflammatory phenotype.

DEX exhibits marked clinical heterogeneity, and most patients require combination therapy for disease control. The disease predominantly presents with autoinflammatory features and may manifest as inflammatory bowel disease-like or Behçet′s disease-like phenotypes. ELF4 variants are mainly clustered in the ETS domain and variants involving the ETS domain of ELF4 may be associated with an autoinflammatory phenotype. Given that effective disease control often requires multi-drug therapy, early genetic testing should be considered in patients with early onset, atypical clinical manifestations, or poor response to treatment to establish a definitive diagnosis and guide individualized therapy.