Persistent toe walking as a prominent feature in pediatric PMP22- Related neuropathies: A retrospective cohort study

David Pomarino ¹, Kevin M Rostásy ², Bastian Fregien ³

⁰Pomarino. Praxis für Ganganomalien, Hamburg, Germany.

Global Medical Genetics +

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December 30, 2025

View abstract on PubMed

Summary

Persistent toe walking in children may signal PMP22 gene-related neuropathies, not just idiopathic causes. Genetic testing like next-generation sequencing (NGS) is crucial for diagnosis and management.

Area Of Science

Genetics
Neurology
Pediatrics

Background

Persistent toe walking is often idiopathic, but PMP22 gene alterations are increasingly implicated.
PMP22 gene variants are linked to Charcot-Marie-Tooth disease type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

Purpose Of The Study

Investigate the association between PMP22 variants (duplications, deletions, point mutations) and pediatric toe walking.
Characterize the clinical and genetic features of children with PMP22 variants and toe walking.

Main Methods

Retrospective analysis of 22 pediatric patients with persistent toe walking and confirmed PMP22 variants.
Utilized a 49-gene next-generation sequencing (NGS) panel and Multiplex Ligation-dependent Probe Amplification (MLPA) for variant confirmation.
Conducted comprehensive musculoskeletal, neurological, and developmental assessments.

Main Results

Pathogenic PMP22 variants were identified in 54.5% of patients, with duplications being most common.
Lumbar hyperlordosis (90.9%) and pes cavus (90.9%) were the most consistent clinical findings.
Variants of uncertain significance (VUS) were associated with milder phenotypes.

Conclusions

Persistent toe walking can be an early indicator of PMP22-related neuropathies.
Integrating NGS and MLPA testing is vital for accurate diagnosis and management of PMP22-related disorders.
Genetic testing aids in targeted management and genetic counseling for affected families.