To characterize skin-biopsy-confirmed pediatric small-fiber neuropathy (pSFN) presentations to inform care and research.

Ectopic firing and degeneration of small-diameter sensory/autonomic/trophic peripheral axons can cause widespread chronic pain/paresthesias/itch, exertional intolerance, orthostatic hypotension, and gastrointestinal distress. Adult SFN was characterized in the mid-90’s as lower-leg PGP9.5-immunolabeled skin-biopsy testing developed. Pediatric cases emerged 1-2 decades later, and today, most pediatric SFN remains undiagnosed/untreated. Childhood SFN can cause life-long socio-economic harm. Causal associations are strongest for dysimmunity, with ~10% genetic. We recently reported SFN-diagnostic skin biopsies in 53% of juvenile fibromyalgia. With 2-6% fibromyalgia prevalence in U.S. schoolchildren (thus potentially ≥1% pSFN prevalence) characterization becomes a priority.

We analyzed data from all Massachusetts General Hospital patients <18y at time of SFN-confirming skin-biopsy (neurite density <5th centile) or neuropathogenic variants, comparing data to >47 age-matched healthy controls. Children/parents completed on-line adult-validated Small-fiber Symptom Surveys (SSS) and neurologists administered the Mass. General Neuropathy Exam Tool (MAGNET). Causality (medical diagnoses, blood tests, genomics), other neuropathy testing (composite autonomic function (AFT)), and tracking/outcomes data were co-analyzed.

Among 143 participants (mean age 14.4±3.4y; range 1.4-17.9y), 76% are female, 2.8% Hispanic, 90.8% Caucasian, 1.4% Asian, 2.1% Black, and 5.6% multiracial/other/unknown. Age at symptom onset averaged 9.7±5.2y. SSS scores (n=75; full scale=136) averaged 44.1±25.9 (moderate). The most reported symptoms (frequency “sometimes/often/always”) were physical and/or mental fatigue, sleep difficulties, headaches, orthostatic dizziness/faintness, and restless legs. 61% (14/23) MAGNETs were in the normal range. Blood tests predominantly identified markers of dysimmunity. Pathogenic/likely pathogenic variants were prevalent and almost exclusively in neuropathy-related and other neurologic-associated genes. No patients had diabetic/nutritional/metabolic causes.

Most children with confirmed-SFN present with normal neurologic exams, suggesting symptoms and objective tests are most important for diagnosis. Blood testing, including genomics, should guide treatment. These data identify need for pediatric age-specific case definitions, SSS, MAGNET, AFT and screening recommendations, including genomics.