Clinical and electrophysiologic features of the Pediatric hereditary neuropathy with liability to pressure palsies

Technical Summary: Clinical and Electrophysiologic Features of Pediatric Hereditary Neuropathy with Liability to Pressure Palsies

Problem Statement
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is a rare autosomal dominant disorder caused by a heterozygous deletion at locus 17p11.2 affecting the PMP22 gene. While characterized clinically by recurrent, non-painful peripheral nerve palsies often triggered by minor trauma or compression, the disease spectrum in children is heterogeneous and frequently underdiagnosed or misdiagnosed. Previous literature suggests onset typically occurs in the second or third decade of life, and clinical reports on pediatric HNPP in China remain scarce. The diagnostic challenge is compounded by atypical phenotypes (e.g., chronic sensorimotor polyneuropathy) and the fact that electrophysiological findings in children, particularly at the first symptom onset, may lack the classic diffuse slowing of nerve conduction velocity (NCV) seen in adults. Consequently, there is a need to clarify the specific neurophysiological features of HNPP in the pediatric population to facilitate earlier recognition and accurate diagnosis.

Methodology
The authors conducted a retrospective, single-center cohort study involving 14 pediatric patients (6 males, 8 females) diagnosed with HNPP at Beijing Children's Hospital between January 2018 and June 2026. All patients were confirmed to have a heterozygous deletion of the PMP22 gene via multiplex ligation-dependent probe amplification (MLPA) or whole exome sequencing (WES).

Data collected included age at onset, family history, clinical manifestations, provocative factors, and disease progression. The cohort was stratified into two subgroups based on the number of palsy episodes: a "single-episode" group (8 patients) and a "multiple-episode" group (6 patients).

Electrophysiological evaluation was performed using standard nerve conduction studies (NCS) on motor and sensory nerves (median, ulnar, peroneal, tibial, and sural). Parameters measured included distal motor latencies (DML), motor nerve conduction velocities (MNCV), compound muscle action potential (CMAP) amplitudes, sensory nerve conduction velocities (SNCV), and sensory nerve action potential (SNAP) amplitudes. Conduction blocks (CB) and temporal dispersion were also assessed. Reference values were based on age-matched laboratory standards.

Key Results

• Demographics and Clinical Presentation: The age at first symptom onset ranged from 6 to 12 years, with 71.4% of patients presenting in the first decade of life. The most common initial presentation was unilateral lower extremity weakness and numbness, predominantly affecting the peroneal nerve (78.5%). While 42.9% of patients experienced recurrent episodes, 50% of cases had no identifiable provocative factor, and 28.6% had a positive family history.
• Electrophysiological Findings:
  • Motor Nerves: All 14 patients exhibited abnormalities consistent with a demyelinating sensorimotor polyneuropathy. Prolonged DML was the most frequent abnormality, observed in 92.9% of cases overall, with the peroneal nerve being the most affected (93.8% in the single-episode group). Notably, some patients with normal conduction velocities still exhibited prolonged DML.
  • Sensory Nerves: Sensory abnormalities were less frequent than motor abnormalities. In the single-episode group, more than half of the patients had normal sensory conduction. The most common sensory abnormality was reduced SNCV of the sural nerve.
  • Conduction Blocks: Conduction blocks were observed in only 4.0% (4/101) of tested nerves, specifically at the ulnar nerve (elbow) and peroneal nerve (fibular head). This frequency was lower than previously reported in adult cohorts.
  • Group Comparisons: The "multiple-episode" group showed a higher prevalence of slowed MNCV and reduced CMAP amplitudes compared to the "single-episode" group.
• Genetic Confirmation: All 14 patients were confirmed to have the characteristic 17p11.2 deletion.

Key Contributions
This study provides one of the few detailed characterizations of HNPP specifically within a Chinese pediatric cohort. It highlights that:

1. Early Onset: A significant majority of pediatric patients present in the first decade of life, challenging the notion that onset is primarily in later decades.
2. Electrophysiological Heterogeneity: The study demonstrates that electrophysiological findings in children can be variable and atypical at the time of first symptom onset. Specifically, normal NCV does not exclude HNPP, and prolonged DML (particularly in the peroneal nerve) may be the sole or primary electrophysiological marker even in the absence of diffuse slowing.
3. Low Frequency of Conduction Blocks: The study reports a lower prevalence of conduction blocks (4.0%) in children compared to adult literature, suggesting that the absence of CB should not rule out the diagnosis.
4. Diagnostic Strategy: The authors propose that in cases of unexplained mononeuropathy in children, NCS should extend beyond the affected limb to include at least two other limbs to detect subclinical involvement.

Significance and Claims
The paper asserts that HNPP in children is a rare condition that is easily missed or misdiagnosed, particularly in the absence of a family history. The authors claim that their findings underscore the difficulty of diagnosing HNPP at the first symptom onset due to the variable and evolving nature of electrophysiological abnormalities.

The study concludes that genetic testing should be considered whenever HNPP is clinically suspected, even if nerve conduction study results are atypical or lack classic diffuse slowing. Early diagnosis is emphasized as essential to reduce unnecessary medical examinations and to facilitate timely prevention education, specifically advising patients to avoid activities that cause mechanical compression or subclinical trauma at vulnerable nerve sites. The authors position electrophysiological investigation as a critical tool for early diagnosis, which can guide clinical management and prevent further nerve injury, despite the lack of a curative treatment for the disease.