SEPTIN9 R106W in a Chinese family with hereditary neuralgic amyotrophy: phenotypic heterogeneity and rehabilitation in a pediatric case
Introduction Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant recurrent focal neuropathy characterized by acute episodes of severe neuropathic pain followed by muscle weakness and atrophy, most commonly affecting the brachial plexus. Pathogenic variants in SEPTIN9 with c.316C>T (p. Arg106Trp; NM_001113491.2) missense mutation corresponding to c.262C>T (p. Arg88Trp; NM_006640.4) constituting a recurrent hotspot that accounts for approximately 55% of HNA families in which a pathogenic SEPTIN9 variant can be identified. Although well documented in Caucasian and some Asian populations, reports in the Chinese population remain scarce, and the full phenotypic spectrum and optimal management strategy are incompletely defined. Methods Pathogenic variants were identified by whole-exome sequencing (WES) of the proband and confirmed by Sanger sequencing in available relatives. Results We report a three-generation Chinese pedigree harboring the SEPTIN9 R106W mutation. The proband, a 34-year-old female, experienced a painless, self-limiting left upper limb weakness at age nine that resolved spontaneously after 6 months, following a 20-year asymptomatic period. She relapsed postpartum at age 29 with bilateral upper limb pain, weakness, and atrophy, resulting in residual neurological deficits. Her 5-year-old daughter presented with infection-triggered classic childhood HNA, exhibiting distinctive facial features (hypertelorism, epicanthal folds, short palpebral fissures, microstomia, and neck webbing), scapular winging, and severe right upper-limb motor impairment. The child showed functional improvement temporally associated with treatment following corticosteroid pulse therapy, neurotrophic support, and a structured, phased rehabilitation protocol. The proband’s father had atypical hand numbness and tremor in young adulthood and later died of systemic amyloidosis at age 66, but his SEPTIN9 genotype could not be determined because genetic testing was not performed. This pedigree demonstrates marked intrafamilial variable expressivity. Discussion This report delineates the broad clinical spectrum associated with the SEPTIN9 R106W mutation in a Chinese pedigree, spanning from childhood to adulthood. Infection and childbirth were identified precipitating factors. The pronounced phenotypic variability underscores the necessity of early molecular diagnosis and cascade screening. Furthermore, prompt multidisciplinary management combining immunomodulation and structured rehabilitation achieved substantial functional recovery in the pediatric patient, highlighting the critical role of active inter vention in childhood-onset HNA.