Hereditary Neuropathy with liability to Pressure Palsies

Written by: Dr Jeremy Steinberg – created: 11 March 2025; last modified: 12 March 2025

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Hereditary Neuropathy with liability to Pressure Palsies
Synonym	Tomaculous neuropathy, Polyneuropathy familial recurrent
Causes	deletion of a 1.5 Mb region on chromosome 17p11.2, which includes the PMP22 gene
Inheritance	Autosomal dominant with a de novo mutation rate of approximately 20%.
Genetics	heterozygous deletion of PMP22, leading to reduced gene dosage and impaired myelin maintenance.
Pathophysiology	Reduced PMP22 protein levels result in myelin instability, making nerves susceptible to pressure-induced conduction block and damage.
Classification	HNPP is classified under hereditary demyelinating neuropathies and distinct from other polyneuropathies due to its episodic nature.
Risk Factors	Prolonged pressure on nerves, repetitive movements, trauma, rapid weight loss, and certain medications (e.g., vincristine) can exacerbate symptoms.
Clinical Features	Recurrent, transient motor and sensory deficits affecting single nerves, commonly in the peroneal and ulnar nerves, leading to weakness, numbness, and atrophy. High rates of chronic neuropathic pain, including widespread pain.
Diagnosis	Based on clinical history, electrophysiological studies, and genetic testing confirming PMP22 deletion.
DDX	Includes acquired entrapment neuropathies, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathy, and hereditary neuralgic amyotrophy.

Hereditary Neuropathy with liability to Pressure Palsies (HNPP) is an autosomal dominant disorder of myelination caused by genetic deletion of PMP22. This should not be confused with PMP22 duplication which is see in Charcot-Marie-Tooth disease type 1A. PMP22 expresses is a peripheral myelin protein. The musculoskeletal physician should be aware of the condition as it is commonly associated with neuropathic pain.

Pathophysiology

PMP22 (peripheral myelin protein 22) produces compact and stable myelin sheaths around large and small myelinated nerve fibres. There are three main types of hereditary peripheral neuropathies caused by mutation of this gene: CMT1A (duplication), CMT1E (point mutation), and HNPP (heterozygous deletion).

PMP22 deletion leads paradoxically to thickened segmental myelin sheaths, i.e. hypermyelination. These look like sausages of the myelinated fibres, and are called "tomaculae." This appearance is seen in several diseases: HNPP, CMT, CIDP, IgM paraproteinaemia, HNA, and Dejerine-Sottas.

This abnormal myelin leads to susceptibility to injury following compression. Trauma can also lead to myelin degeneration and subsequently remyelination. This can cause the nerves to look like the classic "onion-bulbs" of demyelinating diseases.

Clinical Features

History

The traditional cardinal feature is recurrent acute onset sensory and motor mononeuropathies. These are typically preceded by prolonged pressure or trauma to the peripheral nerve. Common symptoms include foot drop (peroneal nerve), carpal tunnel syndrome (median nerve), sensory loss lateral hand (ulna nerve at elbow), wrist drop (radial nerve), etc. Incomplete recovery is common (50% achieve full recovery of episodes).

The age of onset is typically in the second or third decade. But can occur earlier or later. There is a wide spectrum of severity including asymptomatic individuals. At the severe end the phenotype can mimic CMT.

Traditionally HNPP has been thought of as a "pain-free" neuropathy, however this has been shown to be manifestly incorrect. In fact, neuropathic pain is reported in a high proportion of patients with HNPP across multiple observational studies.

• A report on 19 patients, 8 had neuropathic pain (42%). 7 of these patients had neuropathic foot pain described as "burning, aching, shooting."
• A report on four HNPP patients with neuropathic pain, all with diffuse pain. Three of these four patients met the criteria for fibromyalgia.
• A report on 43 patients identified that 32 of them (74%) had persistent pain. Of the 32 with pain, 24 (55% of the total) were felt to have neuropathic pain, and 27 (62% of total) were felt to have central sensitisation.
• A report on 32 patients found that 24 (75%) had pain, with 10 (31%) having neuropathic pain, and 9 (28%) having fibromyalgia.

A family history is common, but there is a 20% de novo mutation rate.

Examination

Muscle weakness, atrophy, sensory signs, reduced or absent tendon reflexes (most commonly the ankles). Pes cavus is common.

Investigations

EMG and NCS is the first step which show diffuse prolonged conduction latencies in sensory and distal motor nerves plus conduction blocks at entrapment sites. Abnormalities are seen even in asymptomatic patients.

Ultrasound can show increased cross section of nerves at entrapment sites.

Nerve biopsy shows segmental de- and remyelination of varying large fibre loss.

Genetic testing is done to confirm the diagnosis.

Treatment

No specific treatment exists. Management of a pressure palsy attack can include transient bracing. In incomplete recovery (such as foot drop) the bracing may need to be long term.

Literature Review

Literature Review

Reviews from the last 7 years: review articles, free review articles, systematic reviews, meta-analyses, NCBI Bookshelf

Articles from all years: PubMed search, Google Scholar search.

TRIP Database: clinical publications about evidence-based medicine.

Other Wikis: Radiopaedia, Wikipedia Search, Wikipedia I Feel Lucky, Orthobullets,