探讨SCN11A基因突变所致家族性发作性疼痛综合征3型(FEPS3)患儿及其家系患者的临床特点。

选择2017年7月于首都医科大学附属首都儿童医学中心门诊就诊，经基因检测确诊的1例FEPS3患儿(先证者)及其家系7例FEPS3患者共计8例FEPS3患者[先证者，先证者父亲及奶奶，先证者父亲的姨表弟，先证者奶奶的姐姐、哥哥及妹妹，以及奶奶的母亲(死亡)]为研究对象。采用回顾性分析方法，对这8例FEPS3患者的临床表现、基因检测结果、治疗及转归等进行分析。检索国内外数据库中关于FEPS3家系相关研究文献进行复习，总结该病临床特点。本研究经首都医科大学附属首都儿童医学中心伦理委员会批准(审批文号：SHERLL2020012)。

①先证者为男性，就诊时年龄为2岁3个月，因"发作性哭闹、四肢疼痛1^＋年"门诊就诊，既往体健。就诊时体格检查和实验室检查结果均无明显异常，基因检测结果提示SCN11A基因c.665G>A(p.R222H)突变(致病性错义突变)。根据其临床表现及基因检测结果，将其确诊为FEPS3患儿。嘱其避免寒冷、剧烈活动等诱因，疼痛时给予布洛芬口服镇痛。患儿目前10^＋岁，剧烈活动后仍出现发作性四肢疼痛，以双肘、双膝关节远端明显。②先证者家系4代成员中，先证者父亲、父亲姨表弟、奶奶与其同辈(4例)，以及奶奶的母亲，共7例存在与先证者类似疼痛发作症状。先证者父亲、先证者奶奶均被检测到SCN11A基因致病性突变c.665G>A(p.R222H)，而被确诊为FEPS3患者；其余5例家系成员根据临床表现及本病遗传特点，被临床诊断为FEPS3患者。7例家系成员均曾被采取避免寒冷等相关诱因，疼痛时口服布洛芬或其他非甾体类抗炎药(NSAID)缓解措施；并且于18~30岁四肢疼痛症状开始减轻，约40岁可完全缓解。③文献检索结果：共计检索到6篇关于FEPS3患者的相关研究文献，共报道15个经基因检测结果确诊的FEPS3家系。对包括本研究在内的16个FEPS3家系的综合分析结果显示，多数该病患者于婴儿期起病，临床表现以四肢发作性疼痛为主，寒冷、劳累、疾病时疼痛明显，可伴有多汗、便秘、腹泻及腹痛等症状。这16个FEPS3家系均为SCN11A基因杂合错义突变，共报道9个基因突变位点。口服NSAID可短暂缓解疼痛，多数患者随着年龄增长，疼痛症状可明显缓解或消失。

SCN11A基因突变所致FEPS3患者表现为早发性、发作性四肢疼痛，结合基因检测结果可早期诊断该病。FEPS3具有家族遗传性，口服NSAID可缓解患者疼痛，随着患者年龄增长疼痛症状可明显缓解或消失。

To explorer the clinical features of pediatric and adult patients with familial episodic pain syndrome type 3 (FEPS3) caused by SCN11A gene mutations, within a single pedigree.

A proband who presented to the outpatient clinic of Capital Center for Children′s Health, Capital Medical University in July 2017 and was molecularly confirmed to carry an SCN11A gene mutation, along with seven affected family members (the father and grandmother of the proband, the maternal cousin of the proband′s father, the two sisters and brother of the proband′s grandmother, and the grandmother′s deceased mother), were enrolled in this study. A retrospective analysis was performed to evaluate clinical manifestations, genetic test results, therapeutic interventions, and outcomes of all eight patients. Concurrently, a literature review of FEPS3 related pedigrees was conducted using domestic and international databases to summarize the disease profile. This study was approved by the Institutional Ethics Committee of the Capital Center for Children′s Health, Capital Medical University (Approval No. SHERLL2020012).

① The proband was a male outpatient, evaluated at 2 years and 3 months of age, presented with over 1-year history of paroxysmal crying and limbs pain. His prior medical history was unremarkable. Physical examination and routine laboratory tests revealed no notable abnormalities. Genetic analysis identified a pathogenic missense variant in SCN11A gene, namely c. 665G>A(p.R222H). A confirmed diagnosis of FEPS3 was established based on the combined clinical and genetic findings. The proband was advised to avoid identifiable triggers, including cold exposure and strenuous physical activity, and received oral ibuprofen for symptomatic relief during painful episodes. At the most recent follow up, at over 10 years of age, he still experience intermittent limbs pain predominantly involving the distal portions of the elbows and knees following vigorous exercise. ② Among the four generations of affected family members of proband, seven individuals-including the proband′s father, the maternal cousin of the proband′s father, four members of the grandmother′s generation, and the grandmother′s mother-exhibited pain episodes analogous to those of the proband. Both the father and the grandmother tested positive for the identical SCN11A gene pathogenic variant c. 665G>A(p.R222H), confirming FEPS3 in these two cases. The remaining five affected members were clinically diagnosed as FEPS3 patients based on their clinical presentation and the genetic characteristics of the disease. All seven family members avoided cold and other known triggers, and administered oral ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAID) to relief pain during pain attacks. Notably, limbs pain began to abate between 18 and 30 years of age and resolved completely by the age of 40 in all affected individuals. ③ Literature search results: a total of six FEPS3 relevant literature describing 15 FEPS3 pedigrees confirmed by genetic testing were retrieved. Pooled analysis of these 16 FEPS3 families (including this study) indicated that most patients experienced disease onset during infancy, with episodic limbs pain as the cardinal feature. Pain was frequently exacerbated by cold, fatigue, and illnesses, and was often accompanied by hyperhidrosis, constipation, diarrhea, and abdominal pain. All 16 pedigrees harbored heterozygous missense mutations in SCN11A gene, encompassing 9 distinct variant sites. NSAID provided transient but effective pain control, and the majority of patients exhibited marked symptomatic amelioration or even complete resolution with advancing age.

Patients with FEPS3 caused by SCN11A gene mutations presents as recurrent episodic limbs pain with an early life onset. Early and definite diagnosis can be achieved through molecular genetic testing. FEPS3 has familial inheritance patterns. NSAID offer effective symptomatic management, and pain symptoms tend to significantly diminish or disappear with advancing age.