小児PMP22関連ニューロパチーにおける持続的なつま先立ち歩行の顕著な特徴：後向きコホート研究

Persistent toe walking in children is often considered idiopathic; however, increasing evidence suggests that alterations in the PMP22 gene-implicated in Charcot-Marie-Tooth disease type 1 A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)-may contribute to its pathogenesis. This study investigates the association between PMP22 variants (duplications, deletions, and point mutations) and toe walking in children, aiming to delineate their clinical and genetic characteristics.

A retrospective analysis was performed on 22 pediatric patients (mean age: 7.7 years) with persistent toe walking and confirmed PMP22 variants identified through a 49-gene next-generation sequencing (NGS) panel. In selected cases, Multiplex Ligation-dependent Probe Amplification (MLPA) was applied to confirm copy number variations. Comprehensive clinical evaluations included musculoskeletal, neurological, and developmental assessments.

All identified variants demonstrated dominant inheritance. Pathogenic variants were present in 54.5 % of patients, likely pathogenic in 31.8 %, and variants of uncertain significance (VUS) in 13.6 %. Among pathogenic cases, most carried PMP22 duplications, one had a deletion, and the remainder harbored the missense variant p.(Thr118Met). The three VUS carriers exhibited comparatively milder phenotypes, such as muscle cramps, lumbar hyperlordosis, mild dorsiflexion restriction, hyporeflexia, pes cavus, and clinodactyly/brachydactyly; only one presented with tremor. Lumbar hyperlordosis (90.9 %) and pes cavus (90.9 %) were the most consistent findings.

Persistent toe walking may represent an early sign of PMP22-related neuropathies rather than a benign idiopathic gait pattern. The predominance of PMP22 duplications and characteristic neuromuscular features highlight the clinical utility of integrating NGS and MLPA testing for accurate diagnosis, targeted management, and genetic counseling.