Hereditary Neuropathy With Liability To Pressure Palsies

Clinical characteristics.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy). The first attack usually occurs in the second or third decade but earlier onset is possible. Neuropathic pain is increasingly recognized as a common manifestation. Recovery from acute neuropathy is usually complete; when recovery is not complete, the resulting disability is mild. Some affected individuals also demonstrate a mild-to-moderate peripheral neuropathy.

Diagnosis/testing.

The diagnosis of HNPP is established in a proband with suggestive clinical and electrophysiologic findings and either the 1.5-Mb recurrent deletion or a novel deletion involving PMP22 (in 80%), or a PMP22 sequence variant (in 20%) identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and involves occupational therapy and physical therapy as needed to address issues with fine motor and gross motor skills, including activities of daily living. Bracing, such as with a wrist splint or ankle-foot orthosis, may be useful transiently or in some instances permanently. Special shoes, including those with good ankle support, may be needed. Neuropathic pain can be treated with analgesic medications. Protective pads at elbows or knees may prevent pressure and trauma to local nerves.

Surveillance: Routine screening neurologic examination focused on muscle atrophy, strength, sensory loss, and neuropathic pain; physical and occupational therapy assessments of gross motor and fine motor skills and activities of daily living; foot examinations for pressure sores or poorly fitting footwear.

Agents/circumstances to avoid: Prolonged sitting with legs crossed; prolonged leaning on elbows; occupations requiring repetitive movements of the wrist; rapid weight loss; vincristine.

Evaluation of relatives at risk: Asymptomatic relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing for the PMP22 pathogenic variant identified in an affected family member in order to be advised about agents and circumstances to avoid.

Genetic counseling.

HNPP is inherited in an autosomal dominant manner. Approximately 20% of individuals with HNPP have the disorder as the result of a de novo PMP22 pathogenic variant. Each child of an affected individual is at a 50% risk of inheriting the PMP22 pathogenic variant. Once the PMP22 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary neuropathy with liability to pressure palsies (HNPP) should be suspected in individuals with the following clinical findings, electrophysiologic studies, imaging studies, and family history.

Typical clinical findings

• Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites
• Painless nerve palsy after minor trauma or compression
• Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss
• Complete spontaneous recovery from neuropathies (in 50% of occurrences) within weeks
• Mild-to-moderate pes cavus foot deformity (in 4%-40% of individuals)

Electrophysiologic studies

• Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist and of common peroneal nerve at fibular head) is observed in most individuals, whether symptomatic or asymptomatic.
• Electrophysiologic criteria to consider in the diagnosis of HNPP include bilateral increase in median nerve motor and distal sensory latencies with at least one additional abnormal motor conduction finding in one peroneal nerve (89%) [Dubourg et al 2000].
• Absent or reduced sural responses are observed in one third of affected individuals [Robert-Varvat et al 2018].
• Nerve conduction velocity may be delayed at the site of compression even with conduction block [Robert-Varvat et al 2018].

Imaging studies

• Ultrasonography shows multifocal increase in nerve cross-sectional area at and outside entrapment sites [Bayrak et al 2015, Padua et al 2018].
• MRI may show increased nerve caliber and asymmetric swelling and hyperintensities of fascicules at entrapment sites [Yurrebaso et al 2014].

Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of HNPP is established in a proband with suggestive findings by identification of either the 1.5-megabase (Mb) recurrent deletion or a novel deletion involving PMP22 (in 80%), or a PMP22 sequence variant (in 20%) by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous PMP22 variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of single-gene testing and a multigene panel or comprehensive genomic testing. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of HNPP has not been considered are more likely to be diagnosed using a multigene panel or genomic testing (see Option 2).

Clinical Description

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [Kumar et al 2002, Li et al 2004]. Some individuals experience transient sensory phenomena without weakness. A history of actual physical minor compression of the nerve may or may not be present.

The first attack generally occurs in the second or third decade (age range: 2-70 years; mean 37 years) but could be at any age. With the widespread availability of molecular genetic testing, reports of early onset have become increasingly common [Chrestian et al 2015].

While the nerve palsies often recur over a period of many years, some individuals have a single episode and some individuals with molecularly confirmed HNPP remain asymptomatic. Even within the same family extreme variability is seen. Nerve palsies and electrophysiologic abnormalities are more frequent in men than women [Manganelli et al 2013].

The most common sites of focal neuropathy (in decreasing order of frequency) are the following:

• Peroneal nerve at the fibular head causing foot drop
• Ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand
• Median nerve at the wrist causing carpal tunnel syndrome with thenar muscle weakness and atrophy and sensory loss over the thumb and index finger [Del Colle et al 2003]
• Brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [Marriott et al 2002]

Involvement of other less commonly affected nerves includes the following:

• Motor brachial plexopathy [Kim 2014]
• Hypoglossal nerve paralysis affecting the tongue, including after carotid endarterectomy [Corwin & Girardet 2003, Winter & Juel 2003]
• Scapuloperoneal syndrome [Barroso et al 2006]
• Sciatic neuropathy [Topakian et al 2014]
• Laryngeal and phrenic nerve involvement [Cortese et al 2016]
• Facial nerve involvement [Poloni et al 1998]

Pain is increasingly recognized as a common manifestation. In one study, 74% individuals had persistent pain lasting more than a week; of these, three quarters developed neuropathic pain and almost 90% were likely to have central sensitization (i.e., development and maintenance of chronic pain) [Beales et al 2017].

Other manifestations can include:

• Rapid onset and progression of neuropathy early in military physical training [Horowitz et al 2004]
• Multifocal presentation
  • Progressive muscular atrophy [Tohge et al 2016]
  • Charcot-Marie-Tooth hereditary neuropathy-like pattern [Gouider et al 1995]
• Chronic inflammatory demyelinating polyneuropathy-like disorders [Rajabally et al 2016]
• Central nervous system white matter lesions compatible with demyelination (usually asymptomatic) [Novakova & Sussova 2012, Chanson et al 2013]

Prognosis. Full recovery over a period of days to months occurs in approximately 50% of episodes. While incomplete recovery is common and often associated with frustration and disability associated with recurrent pressure palsies, the degree of disability in performing activities of daily living is usually not severe. Poor recovery correlates with a history of prolonged focal compression of the nerve [Koike et al 2005]. Chronic neuropathic pain appears as a sequel to post-entrapment in 50% to 75% of affected individuals.

Genotype-Phenotype Correlations

More than 26 single PMP22 nucleotide variants have been reported to cause HNPP. It is not clear if there are genotype-phenotype correlations with these variants since each is limited to a few families [Li et al 2013].

Of note, six families with the PMP22 frameshift variant p.Arg95Glnfs128 have a typical HNPP phenotype and are also more likely to have an associated clinically evident motor/sensory neuropathy mimicking Charcot-Marie-Tooth neuropathy type 1 (CMT1; see CMT Overview) [Lenssen et al 1998]. A similar phenotype has been described in individuals with other single-nucleotide variants in PMP22 [Bellone et al 2006, Li et al 2007, Muglia et al 2007, Moszyńska et al 2009, Taioli et al 2011].

Penetrance

Penetrance is 100% but expressivity is highly variable even within the same family.

For an unknown reason men typically have more severe clinical nerve palsies and electrophysiologic studies.

Nomenclature

Hereditary neuropathy with liability to pressure palsies was previously referred to as hereditary pressure-sensitive neuropathy, tomaculous neuropathy,* recurrent pressure-sensitive neuropathy, and "tulip-bulb digger's palsy" or "potato-grubbing palsy" [Koehler 2003]. Of note, a PMP22 deletion was identified in the original Dutch family reported by De Jong in 1947 as having potato-grubbing palsy [Koehler & Baas 2012].

* Sural nerve biopsy often shows evidence of demyelination and "tomaculous" change (focal, sausage-like enlargement of the nerve), a nonspecific finding noted occasionally in other neuropathies.

Prevalence

The prevalence of HNPP is unknown; it is estimated at 7:100,000-16:100,000 population. The actual prevalence may be higher because of under-diagnosis.

The types of pathogenic variants and phenotypic spectrum are quite homogenous across different populations [van Paassen et al 2014, Karadima et al 2015].

Acquired Disorders

Compression neuropathies. Pressure palsies are most commonly the result of environmentally acquired physical compression of peripheral nerves. The most common are carpal tunnel syndrome with compression of the median nerve at the wrist,* peroneal pressure palsy with compression of the superficial peroneal nerve at the fibular head, and ulnar nerve compression at the elbow.

* HNPP is not a common cause of isolated idiopathic carpal tunnel syndrome [Stockton et al 2001, Sander et al 2005].

Diabetes mellitus. Persons with an underlying polyneuropathy, such as those with diabetes mellitus, are at increased risk for compression neuropathies.

Vasculitic neuropathy. Although affected persons present with acute and multifocal onset that may mimic HNPP, progression of the findings and lack of recovery without treatment suggest this diagnosis.

Chronic inflammatory demyelinating polyneuropathy (CIDP). Multifocal neuropathies such as multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy or Lewis and Sumner syndrome should be considered in the differential diagnosis, as these entities are treatable [Shah et al 2015]. Moreover, individuals whose findings overlap both CIDP and HNPP have been reported, suggesting that recurrent demyelination could be a trigger for an autoimmune reaction [Vrinten et al 2016].

Hereditary Disorders

Hereditary peripheral neuropathies should be considered in the differential diagnosis of HNPP, including CMT hereditary neuropathy and multisystem disorders in which peripheral motor neuropathy may be a presenting feature (i.e., before multisystem involvement is appreciated) and/or one manifestation in a complex neurologic disorder (see CMT Overview, Table 1. Other Hereditary Neuropathies).

Hereditary neuralgic amyotrophy (OMIM 162100). HNPP sometimes involves the brachial plexus, thus overlapping with hereditary neuralgic amyotrophy, a distinct disorder associated with heterozygous pathogenic variants in SEPT9. Stögbauer et al [2000] compare the clinical features of this disorder and HNPP.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No specific treatment for the underlying genetic or biochemical defect exists, and no special diet or vitamin regimen is known to alter the natural course of HNPP.

Treatment is symptomatic and involves the following.

Neuropathy

• Occupational therapy and physical therapy may be needed to address issues with fine motor and gross motor skills, including activities of daily living.
• Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Special shoes, including those with good ankle support, may be needed.
• Some individuals with residual foot drop may permanently use an AFO.
• Protective pads at elbows or knees may prevent pressure and trauma to local nerves.

Pain. Since pain is known as a common complication, clinicians should assess for pain and treat with analgesic medications according to the level of neuropathic pain. Medications could range from common topical analgesics to more systemic neuropathic treatment (including pregabalin, carbamazepine, and duloxetine). Orthosis (e.g., a foot pad or heel insert or an AFO) could help to improve pain during the recovery phase.

Other. Because spontaneous recovery is common and because there is no systematic controlled study of surgical intervention, the benefits of a surgical approach are controversial.

Surveillance

Agents/Circumstances to Avoid

Activities that are risk factors for pressure palsies include the following [Cruz-Martinez et al 2000, Marriott et al 2002]:

• Prolonged sitting with legs crossed
• Prolonged leaning on elbows
• Occupations requiring repetitive movements of the wrist
• Rapid weight loss
• Wearing a heavy backpack on shoulders

Particular care must be taken in positioning during surgery (particularly knee surgery) to avoid nerve compression [Kramer et al 2016].

Vincristine, commonly used in the chemotherapy of lymphoma, has been reported to exacerbate HNPP, as other potential neurotoxic chemotherapy or agents [Kalfakis et al 2002].

Medications that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.

Evaluation of Relatives at Risk

Asymptomatic relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing for the PMP22 pathogenic variant identified in an affected family member in order to be advised about agents and circumstances to avoid.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.