Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran.
Pediatr Rheumatol Online J. 2024 Oct 18;22(1):90. doi: 10.1186/s12969-024-01020-z.
Gain of function (GOF) mutations in NOD-like receptor family CARD-containing 4 protein (NLRC4) gene induce a wide spectrum of autoinflammatory phenotypes. Currently, we categorize them into four groups: familial cold autoinflammatory syndrome (FCAS)4, autoinflammatory infantile enterocolitis (AIFEC), NLRC4-macrophage associated syndrome (MAS), and neonatal-onset multisystem inflammatory disease (NOMID). The rarity and complexity of the disease necessitate the description of new cases and a reexamination of our understanding of the condition.
We present three patients with NLRC4-GOF mutations and AIFEC phenotypes. The first patient is an infant girl with periodic fever, seizure, high inflammatory markers, and an episode of macrophage associated syndrome (MAS). History of recurrent fever episodes since childhood was reported in mother and maternal grandmother. A heterozygous mutation was found in CARD domain of NLRC4: c.A91C: p.Asn31His. The second patient is an adolescent boy with periodic fever, diarrhea, aphthous stomatitis, seizure, and central nervous system (CNS) vasculitis. A heterozygous mutation was found in NLRC4 gene: c.1202T > C. p. Val401Ala. The third patient is a child with chronic diarrhea and elevated inflammatory markers. We found a heterozygous mutation in NLRC4 gene: c.390delG: p.S132Afs*21. All mutations have been reported for the first time as NLRC4 mutations associated with autoinflammation. We introduced novel mutations in the CARD domain and between CARD and NBD domain in the first and third cases, respectively. All three children are under remission following treatment.
NLRC4-GOF mutations can be associated with autoinflammation with diverse symptoms. Given the rarity of the disease and the possibility of new mutations being identified, the existence of a phenotype/genotype correlation has yet to be thoroughly investigated. The variety in manifestations and severity spectrum mandates a variety of treatments. Adalimumab has shown favorable outcomes in our AIFEC cases.
NOD 样受体家族 CARD 结构域包含蛋白 4 基因（NLRC4）的获得性功能（GOF）突变可引起广泛的自身炎症表型。目前，我们将其分为四组：家族性冷自身炎症综合征（FCAS）4、自身炎症性婴儿结肠炎（AIFEC）、NLRC4-巨噬细胞相关综合征（MAS）和新生儿发病的多系统炎症性疾病（NOMID）。该疾病的罕见性和复杂性要求我们描述新病例并重新审视我们对该疾病的理解。
我们介绍了 3 名具有 NLRC4-GOF 突变和 AIFEC 表型的患者。第一例患者是一名患有周期性发热、癫痫、高炎症标志物和巨噬细胞相关综合征（MAS）发作的女婴。患儿母亲和外祖母均有反复发作性发热的病史。在 NLRC4 的 CARD 结构域中发现了杂合突变：c.A91C：p.Asn31His。第二位患者是一名患有周期性发热、腹泻、口疮性口炎、癫痫和中枢神经系统（CNS）血管炎的青少年男性。在 NLRC4 基因中发现了杂合突变：c.1202T > C. p.Val401Ala。第三位患者是一名患有慢性腹泻和炎症标志物升高的儿童。我们在 NLRC4 基因中发现了杂合突变：c.390delG：p.S132Afs*21。所有这些突变均首次被报道与自身炎症相关的 NLRC4 突变有关。在第一例和第三例患者中，我们分别在 CARD 结构域和 CARD 结构域与 NBD 结构域之间发现了新的突变。所有 3 名患儿在接受治疗后均处于缓解期。
NLRC4-GOF 突变可引起具有不同症状的自身炎症。鉴于该疾病的罕见性和可能发现新的突变，表型/基因型相关性尚未得到彻底研究。临床表现和严重程度的多样性需要多种治疗方法。阿达木单抗在我们的 AIFEC 病例中显示出良好的疗效。
