Hereditary neuropathy with liability to pressure palsy

HNPP is generally considered a relatively mild, pressure-sensitive peripheral neuropathy characterised by recurrent focal mononeuropathies, predominantly affecting nerves vulnerable to compression. The peroneal, ulnar, median, and radial nerves, as well as the brachial plexus, are most commonly involved. Clinical manifestations typically include recurrent episodes of numbness, paraesthesia, muscle weakness, and occasionally muscle atrophy. Although symptoms are often mild or localised, electrophysiological studies frequently reveal more widespread peripheral nerve involvement. Together with the marked phenotypic heterogeneity, this can contribute to delayed, missed, or incorrect diagnoses, particularly in sporadic cases. Disease onset most commonly occurs during the second or third decade of life but may range from early childhood to adulthood. Clinical severity is highly variable, extending from asymptomatic individuals to patients experiencing recurrent focal neuropathies. Overall, HNPP has a favourable prognosis. Most neuropathic episodes resolve completely within days to months, and although some patients may experience residual deficits, persistent symptoms are usually mild and rarely lead to significant long-term disability.

The prevalence of HNPP is approximately 16/100,000. Because of its variable clinical presentation and phenotypic overlap with other peripheral neuropathies, HNPP is frequently underdiagnosed. Consequently, the true prevalence may be higher than currently reported, with genetic screening studies estimating a prevalence of approximately 58.9 cases per 100,000 individuals.

The majority of patients with HNPP – approximately 80 % of affected individuals – carry a recurrent 1.5-Mb heterozygous 17p11.2 deletion at 17p11.2 encompassing PMP22, a gene essential for normal peripheral myelin function. Loss-of-function point mutations in the PMP22 gene are found more seldom. Penetrance is considered complete; however, clinical expressivity is highly variable, even among affected individuals within the same family.

HNPP is inherited in an autosomal dominant manner, and approximately 20% of affected individuals have the disorder as the result of a de novo PMP22 variant. Each child of an affected individual has a 50% chance of inheriting the variant. Relatives can carry the variant and remain free of symptoms, so an unremarkable family history does not exclude the diagnosis.

HNPP should be suspected in individuals with recurrent focal compression neuropathies, particularly in the presence of a family history consistent with autosomal dominant inheritance. Additional findings may include residual weakness, muscle atrophy, sensory deficits, reduced deep tendon reflexes, and pes cavus. Electrophysiological abnormalities can support the diagnosis, but definitive confirmation requires molecular genetic testing.

The differential diagnosis of neuropathies in paediatric populations presents unique challenges. While the common acquired neuropathies seen in adults are largely absent in childhood, clinicians must consider numerous hereditary and metabolic conditions with diverse clinical presentations.

The differential diagnosis in adults:

Acquired disorders:

• Compression (entrapment) neuropathies, e.g., carpal tunnel syndrome
• Chronic inflammatory demyelinating polyneuropathy (CIDP), e.g., Lewis and Sumner syndrome
• Vasculitic neuropathy

Hereditary disorders:

• Hereditary neuralgic amyotrophy

• Establishing the diagnosis: identifying the causative germline pathogenic variant confirms the clinical diagnosis at the molecular level.
• Condition-specific management: knowing the diagnosis allows the circumstances that provoke nerve palsies to be avoided, among them prolonged sitting with the legs crossed, prolonged leaning on the elbows, occupations requiring repetitive movements of the wrist, and rapid weight loss.
• Testing of family members: once the familial pathogenic variant is known, at-risk relatives can be offered predictive testing to clarify their variant status.

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