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.