To characterize presentation of small-fiber neuropathy (SFN) in children using adult-standardized symptoms, signs, diagnostics, and blood tests.

SFN presentations reflect abnormal firing and degeneration of the unmyelinated and thinly myelinated sensory/autonomic/homeostatic neurons. Characteristic external symptoms include chronic pain/paresthesias and reduced sensations. Internally, premature fatigue, postural orthostasis/tachycardia, and gastrointestinal dysfunction are common.

This single-center, case-control series analyzed records from consecutive children referred for SFN evaluation. Inclusion required initial age <18y plus ≥1 clinimetric and objective baseline neuropathy test (lower-leg skin biopsy, autonomic function testing (AFT), electrodiagnostics). 49 population-recruited, screened, healthy children provided controls. Metrics included child/parent-completed Small-fiber Symptom Surveys, standardized neuropathy exams, blood tests for common causes of adult neuropathy, and available genetic results.

Among 422 patients screened, 218 were included. Initial ages averaged 14.4±3.4y (2.7-17.9y); 67.9% were female. 60.1% had test-confirmed neuropathy. Among 214 initial biopsies, 40.2% were diagnostic (≤5^th centile). Among 103 AFTs, 40.8% reported neuropathy (≥2 abnormal domains), including sweating (55.1% abnormal), tilt-tables (50.4%), Valsalva (7.9%), and heart-rate variability (7.1%). Electrodiagnostics were normal in 91.3% (21/23); two HSAN1 siblings had abnormal or borderline results. Blood tests for adult metabolic/toxic/nutritional causes were noncontributory. High prevalences of ANA titers ≥1:160, SSA/SSB, and selective immunoglobulin deficiencies implicated dysimmunity. Among 43 exome/panel gene-tests, 3 identified pathogenic/likely pathogenic neuropathy-gene variants (2 SCN9A, 1 multiple immunodeficiency variants), with 12 uncertain/benign variants. In test-confirmed vs. possible patients, unusual/changing skin color, then burning skin were the symptoms most over-represented. Exams identified lower leg/foot hyperemia and sensory reductions at the great toes as the most prevalent signs.

This large survey of children referred for SFN objectively confirmed it in 60%. Skin symptoms, female prevalence, and scarce electrodiagnostic abnormalities mirrored adult SFN. However, most adult causes, including diabetes, were noncontributory and exams were less often abnormal. Deterministic gene variants were rare, but essential to detect for targeted therapy.