Familial Episodic Pain Syndrome With Predominantly Lower Limb Involvement — Comprehensive Disease Characterization

Autonomous discovery report — evidence base: human clinical case series/pedigrees, in vitro electrophysiology, and knock-in/knockout mouse models. Primary literature cited by PMID.

Summary (Answer to the Research Question)

"Familial Episodic Pain Syndrome With Predominantly Lower Limb Involvement" is the SCN11A‑related subtype of familial episodic pain syndrome (FEPS3; OMIM #615552), an autosomal‑dominant sodium channelopathy of peripheral nociceptors. It is caused by heterozygous gain‑of‑function missense variants in SCN11A, which encodes the voltage‑gated sodium channel NaV1.9 that sets the resting membrane potential (RMP) of small‑diameter dorsal‑root‑ganglion (DRG) nociceptors. Gain‑of‑function shifts NaV1.9 activation to more hyperpolarized voltages, depolarizes the RMP, and renders nociceptors hyperexcitable, producing early‑childhood‑onset, paroxysmal, cold‑/fatigue‑/weather‑triggered episodic pain predominantly in the distal lower limbs that characteristically attenuates with age. A closely related, phenotypically overlapping subtype (FEPS2, OMIM #615551) is caused by gain‑of‑function SCN10A/NaV1.8 variants; FEPS1 (TRPA1, #615040) predominantly affects the upper body.

1. Disease Information

Overview. Familial episodic pain syndrome (FEPS) is a group of rare autosomal‑dominant disorders characterized by early‑childhood onset of severe, self‑limited episodes of pain affecting mainly the distal extremities, which tend to attenuate or diminish with age (Shen 2022, 36051609: "Familial episodic pain syndromes (FEPS) are one of the distinctive syndromes characterized by early-childhood onset of severe episodic pain mainly affecting the distal extremities and tend to attenuate or diminish with age"). The subtype with predominantly lower‑limb involvement corresponds to the tetrodotoxin‑resistant sodium‑channel FEPS subtypes — chiefly FEPS3 (SCN11A/NaV1.9), with FEPS2 (SCN10A/NaV1.8) as a closely related alternative. In Japanese kindreds the syndrome was originally described as "infantile limb pain episodes" / paroxysmal limb intolerable pain, with pain most frequently in the knees and ankles (Noguchi 2017, 30549873).

Key identifiers. - OMIM: #615552 — Episodic Pain Syndrome, Familial, 3 (FEPS3; SCN11A). Related: #615551 (FEPS2; SCN10A); #615040 (FEPS1; TRPA1). - Gene OMIM: SCN11A 604385; SCN10A 604427. - MONDO (suggested): MONDO term for "familial episodic pain syndrome 3" (SCN11A‑related FEPS); parent "familial episodic pain syndrome." - ICD‑10: best fit G90.09 / R52 (pain, disorders of autonomic/peripheral nervous system) — no dedicated code. ICD‑11: 8D89 / MG30 (chronic/neuropathic pain categories) — no dedicated code. - MeSH: no dedicated descriptor; indexed under "Pain," "Sodium Channelopathies," "NAV1.9 Voltage-Gated Sodium Channel." - Orphanet: rare monogenic pain syndrome (ultra‑rare; no established ORPHA prevalence class).

Synonyms / alternative names. Familial Episodic Pain Syndrome 3; FEPS3; SCN11A‑related familial episodic pain; Nav1.9 channelopathy (episodic pain form); "infantile limb pain episodes"; paroxysmal limb intolerable pain; familial episodic limb pain. (FEPS2 synonyms: Familial Episodic Pain Syndrome 2; SCN10A/Nav1.8‑related FEPS.)

Source of information. Derived from aggregated disease‑level resources and individual pedigree/case‑series reports (multigenerational families, mostly Japanese and Chinese, plus European cases), combined with in‑vitro and animal functional studies — not from population EHR datasets.

2. Etiology

Disease causal factors — genetic. FEPS3 is a monogenic channelopathy. The primary cause is a heterozygous gain‑of‑function (GoF) missense variant in SCN11A (NaV1.9). FEPS2 is caused analogously by GoF SCN10A (NaV1.8) variants. There is no infectious or neoplastic etiology; environment acts only as a trigger of episodes, not as a cause.

Genetic risk factors (causal variants). Recurrent/known pathogenic SCN11A variants include p.Arg222His (R222H), p.Arg222Ser (R222S), p.Arg225Cys (R225C), p.Phe814Cys (F814C), p.Phe1146Ser (F1146S), p.Val1184Ala (V1184A), p.Leu811Phe (L811F), and p.Asn816Lys (N816K) (Kabata 2018, 30557356; Huang 2019, 31551682; Nagao 2025, 39058404; Leipold 2015, 26645915). All are germline, heterozygous, autosomal‑dominant.

Environmental risk factors. Not causal; cold exposure, physical fatigue, and weather change precipitate attacks (Noguchi 2017, 30549873). Age is an inverse "risk factor" — episodes are most frequent in early childhood and diminish through adolescence.

Protective factors. No genetic protective alleles are established. Environmental/behavioral protection: warming the affected limb relieves pain, and avoidance of cold/fatigue reduces episode frequency (Noguchi 2017, 30549873). In animal models, transcutaneous cholesterol reversed NaV1.9‑mediated hypersensitivity (Amsalem 2018, 29459435), suggesting a candidate protective intervention.

Gene–environment interactions. The germline GoF variant lowers nociceptor threshold; environmental modulators of NaV1.9 push already‑sensitized neurons over threshold: (i) cold — GoF confers cold‑resistant hyperexcitability (Leipold 2015, 26645915); (ii) inflammation lowers membrane cholesterol, moving NaV1.9 out of lipid rafts and enhancing its activation (Amsalem 2018, 29459435); (iii) inflammatory mediators (bradykinin, ATP, PGE2, histamine, 5‑HT) directly excite NaV1.9⁺ afferents (Hockley 2014, 24972070).

3. Phenotypes

Core phenotype (symptom). Paroxysmal, severe episodic pain of the distal limbs, predominantly lower limbs (knees, ankles > wrists, elbows). Episodes last ~15–30 minutes, recur several times per day, are triggered by fatigue and precede bad weather, the affected region feels cold, and warming relieves the pain (Noguchi 2017, 30549873: "The pain typically lasts for 15-30 min and recurs several times a day. The pain is often induced by fatigue and is a prelude of bad weather. The affected regions feel cold in the patients, and warming the lesions relieves the symptoms."). - HPO: HP:0012531 (Pain); HP:0012532 (Chronic pain); HP:0025277 (Fluctuating course/episodic — episodic pain); HP:0003394 (limb pain — muscle pain proxy); HP:0002829 (Arthralgia — joint pain); HP:0001943 sensitivity.

Associated phenotypes (variant‑dependent). - Gastrointestinal: episodic abdominal pain and chronic constipation with some variants (e.g., N816K), reflecting NaV1.9 expression in myenteric neurons (Huang 2019, 31551682). HPO: HP:0002027 (Abdominal pain); HP:0002019 (Constipation). - Cold intolerance / cold‑aggravated pain (Leipold 2015, 26645915). HPO: HP:0500152 (Cold‑induced pain/temperature sensitivity). - Essential tremor co‑segregation with R225C (Leng 2017, 28298626). HPO: HP:0001337 (Tremor).

Phenotype characteristics. - Age of onset: neonatal–early childhood/infancy (HP:0011463 childhood onset; often infantile onset). - Severity: moderate–severe pain during episodes; variable expressivity between and within families. - Progression: episodic/fluctuating, characteristically spontaneously mitigating with age (adolescence). - Frequency among affected: distal‑limb pain is the defining feature (essentially 100% of affected); GI and tremor features are variant‑specific minorities.

Quality‑of‑life impact. During childhood, recurrent daily painful episodes can disrupt sleep, activity, and schooling; because episodes are self‑limited and remit with age, long‑term disability is low and life expectancy is unaffected. No disease‑specific QoL instrument (EQ‑5D/SF‑36/PROMIS) data are published.

4. Genetic / Molecular Information

Causal genes. - SCN11A — HGNC:10583; NCBI Gene 11280; Ensembl ENSG00000168356; UniProt Q9UI33 (NaV1.9/SCN11A); chromosome 3p22.2; OMIM gene 604385. Encodes the α‑subunit of the tetrodotoxin‑resistant voltage‑gated sodium channel NaV1.9. - SCN10A (FEPS2) — HGNC:10582; NCBI Gene 6336; UniProt Q9Y5Y9 (NaV1.8); 3p22.2; OMIM 604427.

Pathogenic variants (SCN11A). Missense, germline, heterozygous. Representative: R222H, R222S, R225C, F814C, F1146S, V1184A, L811F, N816K. Located in functionally critical regions (e.g., L811 in the DII/S6 helix important for voltage‑sensor→pore coupling; Nagao 2025, 39058404). Classification: most reported variants are Pathogenic/Likely Pathogenic per ACMG (segregation + functional GoF evidence); novel variants may be VUS pending functional testing. Variant type/class: point missense (no frameshift/nonsense/structural variants reported for the episodic‑pain phenotype). Allele frequency: absent or ultra‑rare in gnomAD (consistent with high penetrance and dominant pathogenicity). Origin: germline (no somatic/COSMIC relevance). Functional consequence: gain of function (hyperpolarized activation, larger persistent/window current, RMP depolarization).

Genotype–phenotype / allelic spectrum. SCN11A is pleiotropic: modest GoF → FEPS3 / painful small‑fiber neuropathy; extreme GoF (sustained depolarization block) → congenital insensitivity to pain (CIP). The same residue diverges by substitution: L811Phe → FEPS, L811Pro → CIP (Nagao 2025, 39058404). R225C additionally associates with essential tremor (Leng 2017, 28298626).

Modifier genes. PRMT7 methylates NaV1.9 (Arg519) and up‑regulates NaV1.9 current and neuronal excitability — a candidate excitability modifier and drug target (Ma 2022, 34326297).

Epigenetic information. No disease‑specific DNA‑methylation/histone changes reported. (Post‑translational arginine methylation of the channel by PRMT7 is a molecular—not genomic—regulatory layer.)

Chromosomal abnormalities. None; FEPS3 is a single‑nucleotide missense disorder, not a copy‑number/structural condition.

5. Environmental Information

• Environmental factors: Cold ambient temperature and falling barometric pressure / bad weather trigger episodes (Noguchi 2017, 30549873). No toxin, radiation, or occupational exposure is implicated as a cause.
• Lifestyle factors: Physical fatigue/exertion is a major trigger; rest and warming mitigate. No association with smoking/alcohol/diet as causes.
• Infectious agents: None — not an infectious or immune‑mediated disease.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. A heterozygous germline gain‑of‑function missense variant in SCN11A alters the NaV1.9 channel protein (demonstrated: genetics + in vitro).
2. The variant shifts NaV1.9 voltage‑dependence of activation to more hyperpolarized potentials and enlarges the persistent/window current (demonstrated: voltage‑clamp; Leipold 2015; Huang 2019) → results in more channels open near rest.
3. Increased subthreshold Na⁺ influx depolarizes the resting membrane potential of small‑diameter C‑fiber DRG nociceptors (demonstrated: current‑clamp in DRG neurons).
4. RMP depolarization brings the membrane closer to firing threshold → leads to a reduced action‑potential threshold and increased firing frequency (nociceptor hyperexcitability) (demonstrated); the hyperexcitability is retained at cold temperatures ("cold‑resistant") (demonstrated: Leipold 2015).
5. Environmental modulators (cold, inflammation‑driven membrane‑cholesterol loss, inflammatory mediators, PRMT7 methylation) further potentiate NaV1.9, pushing sensitized neurons over threshold (demonstrated in models; inferred as the trigger mechanism in patients).
6. Hyperexcitable distal‑limb nociceptive afferents generate ectopic/amplified nociceptive signaling (inferred from cellular data) →
7. leads to the clinical episodic, cold‑/fatigue‑triggered distal (predominantly lower‑limb) pain (clinical).
8. Branch (variant‑dependent): NaV1.9 in myenteric/enteric neurons → episodic abdominal pain + constipation (Huang 2019). NaV1.9 effects on broader neuronal excitability → essential tremor with R225C (Leng 2017).
9. Branch (allelic): extreme GoF → sustained depolarization/inactivation block → loss of firing → congenital insensitivity to pain (opposite phenotype).
10. Age‑dependent attenuation (clinical; mechanism inferred) — episodes diminish through adolescence, possibly via developmental changes in channel expression/nociceptor maturation.

Detail by category

• Molecular pathways / biochemical abnormality: primary defect is an ion‑channel (voltage‑gated Na⁺ channel) dysfunction; NaV1.9 is the threshold channel with the most hyperpolarized activation among VGSCs and sets RMP (Köster 2025, 39836077). Downstream: action‑potential electrogenesis and neurotransmitter release from nociceptor terminals. Modulation by inflammatory mediator signaling (bradykinin/ATP/PGE2), lipid‑raft/cholesterol biology, and PRMT7 arginine‑methylation.
• Cellular processes: neuronal membrane depolarization, action‑potential generation, nociceptor sensitization/hyperexcitability (not apoptosis/inflammation‑driven tissue destruction).
• Protein dysfunction: gain of function via altered gating (not misfolding/aggregation); molecular‑dynamics work suggests some variants (L811F) increase structural stability and impede necessary conformational changes (Nagao 2025, 39058404).
• Immune involvement: none primary; inflammation is a modulatory trigger, not an autoimmune mechanism.
• Tissue damage: none — pain is due to aberrant neuronal signaling, not tissue injury; no fibrosis/necrosis/ischemia.
• Suggested ontology terms: GO:0086010 (membrane depolarization during action potential); GO:0019228 (neuronal action potential); GO:0035725 (sodium ion transmembrane transport); GO:0005248 (voltage‑gated sodium channel activity, MF); GO:0050966 (detection of noxious stimulus). Cell types: CL:0000198 (nociceptor), CL:0002249 / CL:0000101 (sensory/DRG neuron), CL:0011103 (enteric neuron). Subcellular: GO:0005886 (plasma membrane), GO:0045211 (axon/terminal), GO:0045121 (membrane raft).

7. Anatomical Structures Affected

• Organ/system level: peripheral nervous system (somatosensory), specifically primary sensory neurons; secondary involvement of the enteric nervous system (GI symptoms with some variants). Body system: nervous (sensory) and digestive (variant‑dependent).
• Tissue/cell level: nervous tissue — small‑diameter C‑fiber nociceptors and Aδ nociceptors of the dorsal root ganglia and trigeminal ganglia; myenteric neurons for GI features (Huang 2019, 31551682). CL:0000198 (nociceptor); CL:0000101 (sensory neuron).
• Subcellular level: neuronal plasma membrane, including cholesterol‑rich lipid rafts from which NaV1.9 redistributes upon sensitization (Amsalem 2018, 29459435). GO CC: GO:0005886, GO:0045121 (membrane raft).
• Localization (UBERON): UBERON:0000044 (dorsal root ganglion); UBERON:0001132 (trigeminal ganglion); UBERON:0002240 (spinal cord dorsal horn, downstream); distal limb targets — UBERON:0002103 (hindlimb)/UBERON:0003823 (leg), knees/ankles. Lateralization: bilateral (both legs) and typically symmetric/migratory.

8. Temporal Development

• Onset: congenital/infantile to early childhood; onset pattern is recurrent‑paroxysmal (acute episodes on a chronic predisposition).
• Progression: episodic/fluctuating, not progressive; individual episodes are self‑limited (~15–30 min). Over years the disorder spontaneously attenuates, typically remitting or markedly improving around adolescence (Noguchi 2017, 30549873; Shen 2022, 36051609).
• Disease duration: symptomatic phase is childhood‑limited in most; the underlying genotype is lifelong and can manifest as milder adult sensitivity.
• Remission: predominantly spontaneous/age‑dependent; treatment‑induced relief is symptomatic.
• Critical periods: childhood (peak symptom burden and the window for supportive management and trigger avoidance).

9. Inheritance and Population

• Inheritance: Autosomal dominant (heterozygous). 50% offspring recurrence risk.
• Penetrance / expressivity: high but variable penetrance; variable expressivity in age of remission, episode frequency, and presence of GI/tremor features. No confirmed anticipation, mosaicism, or consanguinity requirement (dominant, not recessive).
• Founder effect: p.R222H is a founder mutation in the Tohoku region of Japan (7 of 48 families) (Kabata 2018, 30557356: "A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan").
• Carrier frequency: not established; pathogenic alleles are ultra‑rare/absent in gnomAD.
• Epidemiology: ultra‑rare; no reliable prevalence/incidence per 100,000 is published. Reported cohorts are largely Japanese (≥48 families) and Chinese, with additional European cases.
• Geographic distribution of variants: R222H enriched in Tohoku, Japan; R225C reported in Chinese kindreds; V1184A (cold‑aggravated) in European cases.
• Sex ratio / age distribution: autosomal dominant → no strong sex bias (≈1:1); affected individuals are predominantly children/adolescents.

10. Diagnostics

• Clinical diagnosis rests on the characteristic history: autosomal‑dominant family history + early‑childhood recurrent, self‑limited, cold/fatigue‑triggered distal (lower‑limb) pain relieved by warmth. No specific routine laboratory abnormality or biomarker; inflammatory markers, imaging (X‑ray/MRI), and standard nerve conduction studies are typically normal (large myelinated fibers spared) — useful mainly to exclude alternatives.
• Electrophysiology: conventional NCS usually normal; research‑level microneurography/skin biopsy for small‑fiber assessment may be considered (small‑fiber pathology overlaps the SCN11A spectrum).
• Genetic testing (definitive): single‑gene sequencing or a hereditary‑pain/sodium‑channelopathy gene panel including SCN11A, SCN10A, SCN9A, *TRPA1; WES/WGS for atypical/panel‑negative cases. CMA, karyotyping, FISH, mtDNA, and repeat‑expansion testing are not indicated (point‑mutation disorder). Variant interpretation benefits from functional (electrophysiology) confirmation* given the GoF/LoF‑to‑phenotype divergence.
• Diagnostic criteria: no formal society criteria; diagnosis is molecular + clinical.
• Differential diagnosis: growing pains (benign, no family‑segregating molecular cause), erythromelalgia / inherited erythromelalgia (SCN9A) — but erythromelalgia features red, hot, hyperperfused extremities (opposite of the cold sensation here) (Klein‑Weigel 2018, 29299961), paroxysmal extreme pain disorder (SCN9A), Fabry disease, small‑fiber neuropathy, juvenile idiopathic arthritis, and autoinflammatory periodic syndromes.
• Screening: cascade genetic testing of at‑risk relatives once a familial variant is identified. No newborn/population screening.

11. Outcome / Prognosis

• Survival/mortality: normal life expectancy; no disease‑specific mortality. Not a life‑threatening condition.
• Morbidity/function: morbidity is episodic childhood pain with possible sleep/activity disruption; long‑term disability is minimal because episodes remit with age.
• Disease course/complications: benign natural history with spontaneous mitigation around adolescence; complications limited to variant‑specific GI symptoms (constipation) or comorbid essential tremor (R225C).
• Recovery potential: high — most patients improve substantially without disease‑modifying therapy.
• Prognostic factors: specific variant (biophysical severity), presence of GI/tremor features; age is the dominant prognostic factor (improvement over time). No validated prognostic biomarker.

12. Treatment

No disease‑specific approved therapy; management is symptomatic and the condition is largely self‑limiting.

• Supportive care (first‑line): warming affected limbs (relieves pain), avoidance of cold and fatigue (Noguchi 2017, 30549873). NCIT: Supportive Care (C15272).
• Pharmacotherapy (off‑label, symptomatic): simple analgesics/NSAIDs; state‑dependent sodium‑channel blockers — carbamazepine, lidocaine, mexiletine. Carbamazepine can act as an activation modulator that partially normalizes gain‑of‑function sodium‑channel gating (Han 2018, 30135145). NCIT: Carbamazepine (C376), Lidocaine, Mexiletine, NSAID (C198).
• Pharmacogenomics / precision medicine: genotype‑guided rationale — GoF NaV1.9 is the direct target; NaV1.9‑selective blockers are investigational (preclinical/early development), highlighted for cold pain and small‑fiber neuropathy (Chen 2025, 40206072). PRMT7 inhibition (e.g., DS‑437) reduces NaV1.9 currents and pain hypersensitivity in mice — a candidate strategy (Ma 2022, 34326297). Transcutaneous cholesterol reversed NaV1.9‑mediated hypersensitivity in models (Amsalem 2018, 29459435).
• Advanced therapeutics (gene/cell/RNA): none in clinical use; conceptually amenable to allele‑selective ASO/gene‑editing given the dominant GoF mechanism (future direction).
• Surgical/interventional: not applicable.
• Treatment outcomes/adverse events: no controlled trial data; management guided by general neuropathic‑pain practice and drug‑specific safety profiles.

13. Prevention

• Primary prevention: not possible (germline genetic cause); preconception/prenatal genetic counseling and options (PGT/prenatal testing) can prevent transmission where desired.
• Secondary prevention: cascade genetic testing of relatives for early recognition; early trigger‑avoidance counseling.
• Tertiary prevention: minimize episode burden via avoidance of cold/fatigue and prompt warming; manage variant‑specific complications (e.g., constipation).
• Immunization / public‑health / environmental interventions: not applicable.
• Counseling: genetic counseling for autosomal‑dominant 50% recurrence risk and variable expressivity is central. NCIT: Genetic Counseling (C15311).
• Prophylaxis: no established prophylactic drug; behavioral trigger avoidance is the mainstay.

14. Other Species / Natural Disease

• Taxonomy / orthologs: human SCN11A (NaV1.9). Mouse Scn11a — NCBI Gene 24046; MGI:1345149 (Chr 9). Rat Scn11a ortholog exists. NaV1.9 (originally NaN/SNS2) is evolutionarily conserved across mammals with conserved nociceptor‑restricted expression.
• Natural disease in other species: no naturally occurring animal disease cataloged in OMIA for SCN11A episodic pain; disease knowledge in animals comes from engineered models, not spontaneous veterinary cases.
• Comparative biology: mouse NaV1.9 gating and DRG expression closely parallel human, enabling faithful modeling; conservation of the RMP‑setting/threshold role underlies the translational validity.
• Transmission: not applicable (non‑infectious, non‑zoonotic).

15. Model Organisms

• Model type: mammalian — mouse (Mus musculus, NCBI Taxon 10090); plus in‑vitro heterologous expression (HEK293, DRG electroporation) and patient‑derived DRG‑neuron electrophysiology.
• Genetic models:
• Knock‑in (disease‑variant) mice: Scn11a‑R222S — hypersensitive to hot and cold stimuli, increased DRG input impedance and evoked AP firing (Noguchi 2017, 30549873). F802C and F1125S (orthologues of human F814C/F1146S) — elevated RMP and increased AP firing to high input current; F1125S also increases firing probability at low input (Kabata 2018, 30557356). A796G knock‑in used in modifier studies (Ma 2022, 34326297).
• Knockout (loss‑of‑function) mice: NaV1.9‑null — reduced nociceptor excitability, +55% C‑fiber electrical threshold, higher mechanical thresholds, impaired noxious heat sensing (Hoffmann 2017, 27780178); attenuated visceral afferent activation (Hockley 2014, 24972070); NaV1.8/NaV1.9 double‑KO mildly affects acute pain and deregulates C‑LTMR/neuropeptide genes (Alves‑Simões 2025, 39382328).
• Phenotype recapitulation: strong — GoF knock‑ins reproduce the cardinal DRG hyperexcitability and thermal/cold hypersensitivity; reciprocal KO produces the opposite (hyposensitivity), establishing causality bidirectionally.
• Limitations: mice model peripheral electrophysiology and behavioral proxies, not the subjective, episodic, weather‑triggered nature of human pain or its spontaneous adolescent remission; genetic background and orthologue‑residue differences require care.
• Applications: target validation, variant functional classification, and testing of NaV1.9‑directed and modifier (PRMT7, cholesterol) therapeutics.
• Resources: MGI/IMPC/IMSR for Scn11a alleles.

Supported and Refuted Hypotheses

Supported: 1. The lower‑limb‑predominant FEPS is a NaV1.9 (SCN11A) gain‑of‑function channelopathy (multiple kindreds + electrophysiology + mouse models). 2. Nociceptor RMP depolarization → hyperexcitability is the mechanistic core (in vitro + KI/KO). 3. Autosomal‑dominant inheritance with a Japanese R222H founder effect. 4. Cold/fatigue trigger episodes via physiological modulation of NaV1.9. 5. Benign, age‑attenuating natural history.

Refuted / excluded: - Not caused by tissue damage, inflammation‑as‑primary, infection, or structural/chromosomal abnormality. - Not an erythromelalgia phenotype (patients feel cold, relieved by warmth — the inverse of erythromelalgia).

Limitations & Future Directions

• No population‑level prevalence, sex‑ratio, or QoL‑instrument data; cohorts are small and geographically skewed (Japan/China).
• Ambiguity in whether the exact source label ("predominantly lower limb") intends FEPS3 (SCN11A) vs FEPS2 (SCN10A) — both cause distal, predominantly lower‑limb episodic pain; FEPS3 is the best‑characterized match and the primary focus here, with FEPS2 covered as the close alternative.
• No controlled treatment trials; NaV1.9‑selective analgesics and allele‑selective genetic therapies are the key future opportunities.

Evidence source key: human clinical (pedigrees/case series) — PMIDs 30549873, 30557356, 31551682, 28298626, 39058404, 26645915; in vitro/electrophysiology — 39836077, 30135145, 34326297, 29459435; mouse models — 30549873, 30557356, 27780178, 24972070, 39382328; reviews — 36051609, 29299961, 40206072.