Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant genetic disease that is clinically characterized by recurrent monoparesis and sensory loss, frequently caused by focal compression or trauma [1]. The diagnosis is confirmed by genetic testing and approximately 80% of patients show deletion of chromosome 17p11.2 of the peripheral myelin protein 22 (PMP22) gene and the remaining 20% have a pathogenic variant in PMP22 [2].

The prevalence of HNPP is known to range from 0.84 to 16 per 100,000 people, with ethnic differences [3]. Interestingly, a recent Korean study showed a significantly higher prevalence of 58.9 per 100,000 people, compared to other studies. While this higher prevalence in the Korean population needs further research, it was explained to an extent by the methodology used; the Korean study was a neonatal screening study, while other studies were performed on symptomatic patients. However, we cannot dismiss the possibility of higher frequency of HNPP in the Korean population and its under-recognition. Here, we summarize the clinical features of young male patients with HNPP who came to our emergency department, with this study aiming to improve the identification of HNPP for early and efficient diagnosis.

This study was approved by the Institutional Review Board (IRB) of the Kyungpook National University Chilgok Hospital (IRB No: KNUCH 2019-06-018). Informed and written consent was obtained from the patients for the case series.

HNPP is an autosomal dominant hereditary neuropathy caused by deletion of the PMP22 gene. The PMP22 protein is commonly found in the peripheral nerves and plays an important role in myelin compaction; its underexpression is known to cause HNPP [4]. Mild nerve injuries in a common entrapment site are known to cause demyelination and remyelination, leading to altered axonal properties and axonal degeneration in the distal segments. This phenomenon can partly explain the cause of focal entrapment neuropathies in the distal regions as the presenting symptom of HNPP. Notably, PMP22 deletion causes HNPP, while PMP22 duplication causes Charcot-Marie-Tooth disease type 1A. Simultaneous genetic testing via multiplex ligation-dependent probe amplification is possible and is covered by the national insurance system in Korea.

Clinically, a typical case of HNPP presents with a mononeuropathy and is known to involve superficial nerves instead of deep innervated nerves. A previous study showed recurrent involvement of the peroneal nerve around the fibular head, ulnar nerve at the elbow, and radial nerves with a frequency of 35%, 20%, and 8%, respectively [5]. Along with other nerves (peroneal neuropathy at the fibular head and ulnar neuropathy at wrist level), the median nerve at the wrist is one of the most common compression sites among the patients with HNPP. But an isolated idiopathic carpal tunnel syndrome is rare [2]. Typically, the first symptom occurs as a mononeuropathy in the second or third decade of life, which is consistent with our patients’ ages.

The diagnosis of HNPP can be made via electrophysiological study, along with confirmation of PMP22 deletion via genetic analysis. Studies have shown characteristic findings in the nerve conduction study suggestive of HNPP. The general electrophysiological findings of HNPP show features of polyneuropathy with demyelinating features superimposed by focal entrapment neuropathies with slow sensory conduction velocities [6-8]. A recent study that involved HNPP patients under the age of 30 years showed demyelinating features in symptomatic and asymptomatic nerves, with the highest involvement in the ulnar, peroneal, and median nerves. Moreover, there was a significant prolongation of distal motor latency in the tested nerves with slow motor velocities [9]. Another study found a significantly accentuated distal slowing in the median and peroneal nerves with less involvement of ulnar and tibial nerves [10]. These findings are consistent with our case reports, especially in those with a typical HNPP presentation.

Our case series demonstrates both typical and rare types of HNPP showing heterogeneity of clinical presentation to the emergency department (Table 1). The mean age at presentation was 26.5 years, and all patients were male. The typical cases (cases 1 and 2) presented with mononeuropathy in the common entrapment sites in the distal nerves. Therefore, the HNPP diagnosis was quick. However, cases 3 and 4 were rare HNPP cases. There have been reports on extremely rare cases, where the patient has presented with recurrent Bell’s palsy [11] and more commonly with proximal limb weakness [10]. A recent study retrospectively reviewed 51 HNPP patients under the age of 30 years and found peroneal and ulnar neuropathy in 30% of the patients and described one case of long thoracic and femoral neuropathy that is usually unaffected by compression [8]. Interestingly, in South Korea, where young males are obligated to serve the military, a different pattern of frequency was observed. A 4-year retrospective study of the medical records in the Korean army hospital showed that the most common initial presentation of HNPP was a brachial plexus lesion that showed proximal arm weakness and paresthesia [12]. The authors found brachial plexus lesions in more than 50% of HNPP patients, which is not in accordance with previous studies in other countries. Moreover, the Korean study stated that the cause of the brachial plexopathy was strenuous push-ups and exercise. This is very similar to case 3 in our study, wherein the patient first experienced symptoms during military service. In case 4, the patient had a very uncommon suprascapular neuropathy which is not usually observed in HNPP. Recent studies have reported a few cases of suprascapular neuropathy in its notch at the supraspinatus fossa caused by strenuous physical activities; this correlates with our patient who also experienced arm weakness after strenuous exercise during his military service [13].

Another report showed an interesting case of bilateral foot drop in an 83-year-old Japanese patient, who experienced symptoms after sitting with their lower legs crossed under their thighs; this presentation was indicative of bilateral common peroneal neuropathy [14]. The patient in case 3, also showed a similar history of prolonged crouching while wearing long boots that caused bilateral common peroneal neuropathy. This is an important finding because HNPP is known to present with mononeuropathy, but the Japanese case and case 3 of our study presented with symmetric bilateral compressive neuropathy.

These rare findings reflect the broad clinical spectrum of HNPP and the different environmental factors among countries that result in a variety of initial presentations in HNPP. More studies are needed to understand the Korean phenotypes in HNPP, as well as HNPP in patients over 30 years old; our case series demonstrates the need for more documented cases from different countries.

The limitation of this retrospective case series is the number of patients enrolled. This was inevitable because we only enrolled HNPP patients who primarily visited our emergency department and not our out-patient clinic. Although HNPP is still an untreatable genetic disease, environmental factors that can aggravate monoparesis and eventually lead to further deterioration should be avoided. As there is no specific clue that can lead to the diagnosis of HNPP, it is important for neurologists and emergency department doctors to be aware of these conditions to make a differential diagnosis leading to an early diagnosis and prevent further deterioration of the vulnerable peripheral nerves in patients with HNPP.