The first child of a consanguineous family of Turkish descent developed recurrent fevers a few hours after birth and oral ulcers at the age of 10 days. The newborn was repeatedly evaluated for infectious causes of fever and received several courses of antibiotics as per guidelines for fever in newborns,¹ but no causative organisms could be detected and there was no long-lasting effect of antimicrobial treatment (Figure 1A,B,D). Specific diagnostics for potential infectious causes of the ulcers such as infections of the toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex (TORCH) complex as well for gastrointestinal pathogens failed to show any significant findings except for a one-off positive adenovirus antigen test in stools. She developed bloody stools at 6 weeks, extensive perianal ulcers at 7 weeks of age, and failed to thrive. The course of the symptoms, the main laboratory findings, and the therapeutic measures are shown in Figure 1.

Due to the recurrent nature of the symptoms and lack of a plausible infectious cause, the child was evaluated for an autoinflammatory disease. Fecal calprotectin was found to be considerably elevated (Figure 1C). Esophagogastroduodenoscopy and rectosigmoidoscopy were performed, and histological findings showed a chronic inflammation of the esophagus with lymphocyte infiltration and an acute proctocolitis with regenerating epithelial changes with preserved crypt architecture without being conclusive of the cause. An inborn error of immunity leading to very early-onset inflammatory bowel disease was suspected.

At 9 weeks of age, trio exome sequencing revealed homozygous previously described but functionally not verified likely deleterious mutations in interleukin 10 receptor subunit alpha (IL10RA; NM_001558.4: c.133T > G, p.Trp45Gly).² Functional validation of a defect in the interleukin 10 (IL10)/signal transducer and activator of transcription (STAT3) pathway was obtained by demonstrating significantly decreased STAT3 phosphorylation in lymphocytes with IL10 stimulation in comparison with a healthy control (Figure 2A–C, details on the assay in the Appendix S1).

At the age of 8 weeks, the child had been empirically started on increasing doses of oral prednisolone (1–1.5 mg/kg), which initially led to some improvement, but not a complete clinical response with recurrent inflammatory episodes as well as painful perianal ulcers persisting. This was similar to other reported cases of confirmed IL10 pathway defects, as only a negligible fraction (2.4%) of patients treated with steroids have shown a clinical response according to a recent review by Sharifinejad et al.³ The child continued to have fevers; Enterococcus faecalis had been detected in blood cultures at the age of 7 weeks and Enterobacterium cloacae in urine cultures at the age of 11 weeks. At the age of 11 weeks, she developed signs of an upper respiratory tract infection for the first time and tested positive for rhino/enterovirus in multiplex polymerase chain reaction from a nasopharyngeal aspirate. At the same time, cytomegalovirus viraemia was detected and treated with gan- and then valganciclovir. Due to recurrent vomiting, perceived painful defecation and poor weight gain, partial parenteral feeding was started at age 12 weeks.

Since no medical therapy has been shown to be superior to others in IL10 pathway defects,³ the choice of additional anti-inflammatory agents was challenging. As enteric bacteria had been detected in blood and urine cultures, gut decontamination was started to reduce translocation of enteral bacteria as well as to scale down inflammation by reducing microbial stimulation via the inflamed gut. A regimen consisting of colistin (50,000 U/kg every 8 h), gentamicin (2.5 mg/kg every 8 h), vancomycin (10 mg/kg every 8 h), and amphotericin B (3 mg/kg twice a week) was started at age 13 weeks.

Antitumor necrosis factor (TNF) alpha antibody treatment was opted for as the next therapeutic agent due to its success in non-monogenic inflammatory bowel disease⁴ as well as a theoretical beneficial effect via the reduction in abnormally high TNF-alpha levels known to occur in patients with IL10R deficiency.⁵ Infliximab was started at 14 weeks of age at an initial dose of 5 mg/kg, resulting in a serum trough level of 13 μg/mL 2 weeks later. The second dose of 10 mg/kg resulted in a trough level of >20 μg/mL 4 weeks later, when the third dose (also 10 mg/kg) was administered. Under this combination, the patient showed significant improvement. The inflammatory episodes ceased, and calprotectin levels dropped dramatically (Figure 1A,C,E). The perianal ulcers showed a clear response after the first dose of infliximab and resolved after the second dose (Figure 2D,E).

At age 25 weeks, the patient underwent hematopoietic stem cell transplantation (HSCT) with CD34+ selected peripheral blood stem cells and a CD3+ add-back from a 10/10 human leucocyte antigen matched unrelated donor after a reduced intensity conditioning regimen with busulfan (cumulative area under the curve 69 mg/L × h), fludarabine (180 mg/m²), and alemtuzumab (1.0 mg/kg). Ciclosporin A and mycophenolate mofetil were used for prophylaxis of graft-versus-host-disease. Neutrophile engraftment took place on Day +18 and 100% donor chimerism in CD14+ and CD15+ cells were seen on Day +19. There was a cytomegalovirus reactivation at age Day +19 and a new norovirus infection on Day +22. Pulmonary hypertension was diagnosed at one-month post-HSCT and treated with 1 mg/kg prednisolone; this resolved quickly and the steroids were tapered over a period of 1 month. There were recurrent episodes of mild hemochezia at 2.5 to 4 months after HSCT. A recurrence of the disease due to waning chimerism was considered as donor CD3+ chimerism sank to 20% at this point. Repeat esophagogastroduodenoscopy and rectosigmoidoscopy and histology showed no signs of enteral graft-versus-host-disease. The hematochezia was thought to be infectious with persistence of norovirus in the stools and ceased after immunosuppression was reduced.

As building up enteral feeds was challenging due to frequent vomiting and refusal to eat, the child was still partially parentally fed at 14 months of age as she developed a central line infection. Further course was otherwise unremarkable, the patient remained free of inflammatory episodes as well as ulcers and had normal stools with 80% CD3+ and 100% CD14+ and CD15+ donor chimerism in peripheral blood on last follow-up 10 months of post-HSCT.

In summary, our patient showed a good response to anti-TNF alpha antibody treatment and medium dose corticosteroids in combination with gut decontamination with antimicrobials as a bridge to transplantation (Figures 1A–E and 2D,E). Despite a range of different substances being tried out in similar patients to date, most reports state IL10 and IL10 receptor defects to be resistant to immunosuppression.^{3, 6} Infliximab has been the most commonly used biological agent in these patients, but the effect response rates have been reported to be low.^{3, 7} Which of the three therapeutic components contributed the most to achieving remission in our patient, is impossible to say. Early genetic diagnosis, leading to definitive diagnosis at a very young age, and therefore short duration of disease before starting therapy might have substantially contributed to achieving remission. This approach might prove useful in similar patients.

土耳其血统近亲家庭的第一个孩子在出生后数小时内出现反复发烧，并在10天大时出现口腔溃疡。对新生儿反复评估发热的感染原因，并按照新生儿发热指南 1 接受了几个疗程的抗生素治疗，¹但未检测到致病微生物，抗菌治疗也没有长期效果（图 1A、B、D） ）。对溃疡潜在感染原因的具体诊断，例如弓形虫病、其他感染、风疹、巨细胞病毒、单纯疱疹病毒（TORCH）复合体感染以及胃肠道病原体感染，除了一次性腺病毒抗原检测呈阳性外，没有显示出任何显着的发现。凳子。她在 6 周时出现血便，在 7 周时出现广泛的肛周溃疡，并且无法生长。症状的过程、主要实验室检查结果和治疗措施如图1所示。

由于症状反复出现且缺乏合理的感染原因，该儿童接受了自身炎症性疾病评估。发现粪便钙卫蛋白显着升高（图 1C）。进行了食管胃十二指肠镜检查和直肠乙状结肠镜检查，组织学结果显示食管慢性炎症伴淋巴细胞浸润，以及急性直肠结肠炎伴再生上皮变化且隐窝结构保留，但病因尚不清楚。怀疑是先天性免疫缺陷导致极早发的炎症性肠病。

9 周龄时，三重外显子组测序显示，白细胞介素 10 受体亚基 α 中可能存在先前描述但功能上未经验证的纯合子突变（IL10RA；NM_001558.4：c.133T > G，p.Trp45Gly）。²通过证明与健康对照相比，IL10 刺激后淋巴细胞中 STAT3 磷酸化显着降低，对白细胞介素 10 (IL10)/信号转导器和转录激活剂 (STAT3) 通路缺陷进行了功能验证（图 2A-C，详细信息）附录 S1 中的测定）。

8周大时，根据经验，孩子开始增加口服泼尼松龙剂量（1-1.5 mg/kg），最初带来了一些改善，但没有完全的临床缓解，伴有反复炎症发作以及肛周疼痛。溃疡持续存在。这与其他报告的已确诊的 IL10 通路缺陷的病例类似，因为根据 Sharifinejad 等人最近的一篇综述，只有一小部分（2.4%）接受类固醇治疗的患者表现出临床反应。³孩子持续发烧；7周龄时的血培养中检测到了粪肠球菌， 11周龄时的尿培养中检测到了阴沟肠杆菌。11周岁时，她首次出现上呼吸道感染的症状，并在鼻咽抽吸物的多重聚合酶链反应中检测出鼻/肠道病毒呈阳性。同时，检测到巨细胞病毒血症并用gan-治疗，然后用缬更昔洛韦治疗。由于反复呕吐、排便疼痛和体重增加缓慢，12 周龄时开始部分肠外喂养。

由于在 IL10 通路缺陷方面没有任何药物治疗被证明优于其他治疗，³选择其他抗炎药物具有挑战性。由于在血液和尿液培养物中检测到肠道细菌，因此开始进行肠道净化，以减少肠道细菌的移位，并通过减少发炎肠道的微生物刺激来减少炎症。治疗方案由粘菌素（每 8 小时 50,000 U/kg）、庆大霉素（每 8 小时 2.5 mg/kg）、万古霉素（每 8 小时 10 mg/kg）和两性霉素 B（3 mg/kg 每周两次）组成。从 13 周开始。

抗肿瘤坏死因子 (TNF) α 抗体治疗被选择作为下一个治疗药物，因为它在非单基因炎症性肠病⁴中取得了成功，并且通过减少已知发生在肠道中的异常高的 TNF-α 水平而产生了理论上的有益效果。 IL10R缺乏症患者。⁵英夫利昔单抗在 14 周龄时开始使用，初始剂量为 5 mg/kg，2 周后血清谷水平为 13 μg/mL。4 周后，当给予第三剂（也是 10 mg/kg）时，第二剂 10 mg/kg 导致谷值>20 μg/mL。在这种组合下，患者表现出显着的改善。炎症发作停止，钙卫蛋白水平急剧下降（图 1A、C、E）。肛周溃疡在第一剂英夫利昔单抗后显示出明显的反应，并在第二剂后消退（图 2D、E）。

25 周时，患者接受了造血干细胞移植 (HSCT)，使用 CD34+ 选定的外周血干细胞和来自 10/10 人白细胞抗原匹配的无关供体的 CD3+ 加回，并采用白消安（累积面积曲线下（69 mg/L × h）、氟达拉滨（180 mg/m ²）和阿仑单抗（1.0 mg/kg）。环孢素 A 和吗替麦考酚酯用于预防移植物抗宿主病。中性粒细胞植入发生在第+18天，并且在第+19天观察到CD14+和CD15+细胞中100%供体嵌合。第+19天出现巨细胞病毒重新激活，第+22天出现新的诺如病毒感染。HSCT后1个月诊断为肺动脉高压，并接受1 mg/kg泼尼松龙治疗；这个问题很快就解决了，类固醇在 1 个月内逐渐减少。HSCT后2.5至4个月反复出现轻度便血。由于此时供体 CD3+ 嵌合性下降至 20%，因此认为由于嵌合性减弱而导致疾病复发。重复食管胃十二指肠镜检查和直肠乙状结肠镜检查以及组织学检查未发现肠移植物抗宿主病的迹象。便血被认为是由于粪便中持续存在诺如病毒而具有传染性，并在免疫抑制减少后停止。

由于频繁呕吐和拒绝进食，建立肠内喂养具有挑战性，因此该孩子在 14 个月大时仍接受部分家长喂养，因为她出现了中心导管感染。进一步的病程在其他方面并不显着，在 HSCT 后 10 个月的最后一次随访中，患者没有炎症发作和溃疡，粪便正常，外周血中有 80% CD3+ 和 100% CD14+ 和 CD15+ 供体嵌合体。

总之，我们的患者对抗 TNF α 抗体治疗和中等剂量皮质类固醇联合抗菌药物肠道净化作为移植的桥梁表现出良好的反应（图 1A-E 和 2D、E）。尽管迄今为止在类似患者中尝试了一系列不同的物质，但大多数报告都指出 IL10 和 IL10 受体缺陷对免疫抑制具有抵抗力。^{3, 6}英夫利昔单抗是这些患者最常用的生物制剂，但据报道效果反应率较低。^{3, 7}三种治疗成分中哪一种对我们患者的缓解贡献最大，目前还无法确定。早期基因诊断可以在很小的时候就做出明确的诊断，因此开始治疗前的疾病持续时间很短，可能对实现缓解有很大贡献。这种方法可能对类似的患者有用。