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Hereditary Neuropathy with Liability to Pressure Palsies

Synonym: HNPP

, MD, FRCPC, CSCN.

Author Information

Initial Posting: ; Last Update: August 27, 2020.

Estimated reading time: 21 minutes

Summary

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.

Diagnosis

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).

Option 1

Single gene testing. First, perform gene-targeted deletion/duplication analysis to detect the 1.5-Mb recurrent deletion or a novel deletion involving PMP22. If no deletion is detected, perform sequence analysis.

Sequence analysis of PMP22 can detect small intragenic deletions/insertions and missense, nonsense, frameshift, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.

Option 2

A neuropathy multigene panel that includes PMP22 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in HNPP

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
PMP22Deletion/duplication analysis 3~80% 4
Sequence analysis 5~20% 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

4.
5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

Clinical Characteristics

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:

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:

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].

Differential Diagnosis

The signs and symptoms of compression neuropathy in hereditary neuropathy with liability to pressure palsies (HNPP) are the same as those of the acquired type. Thus, HNPP is part of the broad differential diagnosis of both compression neuropathies and general peripheral neuropathies, including the hereditary neuropathies and Charcot-Marie-Tooth (CMT) syndrome (see CMT Overview).

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.

Management

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.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with HNPP

System/ConcernEvaluationComment
NeurologicNeurologic evalTo evaluate for pain & determine:
  • Extent of weakness & atrophy, pes cavus, gait stability, & sensory loss
  • If there are assoc manifestations (e.g., focal atrophy or sensory loss in less common sites of entrapment)
  • If affected person &/or a family member has had episodes of acute transient nerve palsy
MusculoskeletalOrthopedics / physical medicine & rehab / PT/OT evaluationTo incl assessment of:
  • Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Feet for evidence of pes cavus & need for AFOs, specialized shoes
  • Mobility, ADLs, & need for adaptive devices
  • Need for handicapped parking
Genetic
counseling
By genetics professionals 1To inform patients & families re nature, MOI, & implications of HNPP to facilitate medical & personal decision making
Family support/
resources
Assess:

ADL = activity of daily living; AFO = ankle-foot orthosis; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

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

Table 3.

Recommended Surveillance for Individuals with HNPP

System/ConcernEvaluationFrequency
NeurologicScreening neurologic exam focused on muscle atrophy, strength, & sensory lossAnnually
Eval for neuropathic pain
MusculoskeletalPT (gross motor skills) & ADLS
OT (fine motor skills) & ADLs
Foot examinationFor pressure sores or poorly fitting footwearAnnually by physician; at more frequent intervals by affected person

ADL = activity of daily living; OT = occupational therapy; PT = physical therapy

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hereditary neuropathy with liability to pressure palsies (HNPP) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents.

Offspring of a proband. Each child of an individual with HNPP has a 50% chance of inheriting the PMP22 pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the PMP22 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and avoidance of certain agents and circumstances.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the HNPP-related pathogenic variant has been identified in an affected family member.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of HNPP, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

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 for HNPP are possible. Note: Age of onset, severity, type of manifestations, and rate of progression cannot be predicted on the basis of prenatal genetic test results.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hereditary Neuropathy Foundation
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@cmtausa.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Hereditary Neuropathy with Liability to Pressure Palsies: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Hereditary Neuropathy with Liability to Pressure Palsies (View All in OMIM)

162500NEUROPATHY, HEREDITARY, WITH LIABILITY TO PRESSURE PALSIES; HNPP
601097PERIPHERAL MYELIN PROTEIN 22; PMP22

Molecular Pathogenesis

HNPP is associated with decreased mRNA message for PMP22 and decreased peripheral myelin protein 22 in peripheral nerve. Guo et al [2014] have shown that PMP22 deficiency disrupts myelin junctions, resulting in impaired propagation of nerve action potentials.

Mechanism of disease causation. Loss of function.

The HNPP recurrent 1.5-Mb deletion is a submicroscopic DNA rearrangement. Although many genes are deleted, only PMP22, appears to be dosage sensitive, resulting in a haploinsufficiency phenotype. The proof for this concept is provided by the identification of PMP22 frameshift pathogenic variants that presumably result in null alleles in some individuals with HNPP [Stögbauer et al 2000, van de Wetering et al 2002, Kleopa et al 2004, Li et al 2013].

PMP22-specific laboratory technical considerations. The most common pathogenic variant, present in 80% of affected individuals, is the recurrent 1.5-Mb submicroscopic DNA deletion at 17p11.2 that includes PMP22. This is the reciprocal of the 1.5-Mb duplication that occurs in Charcot-Marie-Tooth neuropathy type 1A (see CMT Overview); both of these rearrangements result from unequal crossing over following misalignment of flanking repeat sequences at this chromosomal location.

Table 4.

Notable PMP22 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000304​.4NP_000295​.1c.281dupGp.Arg95Glnfs128Recurrent variant; possible genotype-phenotype correlation [Lenssen et al 1998]
c.289delTp.Tyr97ThrfsTer14See footnote 1 [Yurrebaso et al 2014].
c.353C>Tp.Thr118MetConflicting interpretations of pathogenicity [van Paassen et al 20142

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Associated with painful neuropathy without recurrent nerve palsies in one family [Yurrebaso et al 2014]

2.

Reported as a benign polymorphism, as an autosomal recessive inherited variant, or as an autosomal dominant variant with the HNPP phenotype. Detailed in National Center for Biotechnology Information, ClinVar (VCV000008431​.12) (accessed 8-18-20).

Chapter Notes

Author Notes

Dr Nicolas Chrestian is a pediatric neurologist specializing in neuromuscular disorders and neurogenetics. He is currently chief of service at Centre mère-enfant CHU de Québec in Quebec City, as well as professor clinician at Laval University. He has an interest in rare neuromuscular disorders including spastic paraparesis, congenital myopathies, and hereditary neuropathies.

Nicolas Chrestian, MD FRCPC
Chief of service, Child Neurology
CME-CHUL, CHU de Québec
Université Laval
2705 Boulevard Laurier
Québec, QC Canada G1V 4G2
Tel: 418-654-2787 #3
Fax: 418-654-2710
Nicolas.Chrestian@chudequebec.ca

Author History

Thomas D Bird, MD; University of Washington (1998-2020)
Nicolas Chrestian, MD, FRCPC, CSCN (2020-present)

Revision History

  • 27 August 2020 (bp) Comprehensive update posted live
  • 25 September 2014 (me) Comprehensive update posted live
  • 11 May 2010 (me) Comprehensive update posted live
  • 14 January 2008 (me) Comprehensive update posted live
  • 28 September 2005 (me) Comprehensive update posted live
  • 27 August 2003 (me) Comprehensive update posted live
  • 7 April 2003 (tb) Author revisions
  • 20 June 2001 (me) Comprehensive update posted live
  • 28 September 1998 (tb) Review posted live
  • 6 January 1998 (tb) Original submission

References

Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 8-18-20.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 8-18-20.

Literature Cited

  • Abe A, Nakamura K, Kato M, Numakura C, Honma T, Seiwa C, Shirahata E, Itoh A, Kishikawa Y, Hayasaka K. Compound heterozygous PMP22 deletion mutations causing severe Charcot-Marie-Tooth disease type 1. J Hum Genet. 2010;55:771–3. [PubMed: 20739940]
  • Al-Thihli K, Rudkin T, Carson N, Poulin C, Melançon S, Der Kaloustian VM. Compound heterozygous deletions of PMP22 causing severe Charcot-Marie-Tooth disease of the Dejerine-Sottas disease phenotype. Am J Med Genet A. 2008;146A:2412–6. [PubMed: 18698610]
  • Barroso FA, Leiguarda R, Nogués MA. Hereditary neuropathy with liability to pressure palsies manifesting by recurrent neuropathic pain. J Clin Neuromuscul Dis. 2006;8:26–30.
  • Bayrak AO, Bayrak IK, Battaloglu E, Ozes B, Yildiz O, Onar MK. Ultrasonographic findings in hereditary neuropathy with liability to pressure palsies. Neurol Res. 2015;37:106–11. [PubMed: 25005138]
  • Beales D, Fary R, Little C, Nambiar S, Sveinall H, Leng Y, Tampin B, Mitchell T. Characterisation of pain in people with hereditary neuropathy with liability to pressure palsy. J Neurol. 2017;264:2464–71. [PubMed: 29079893]
  • Bellone E, Balestra P, Ribizzi G, Schenone A, Zocchi G, Di Maria E, Ajmar F, Mandich P. An abnormal mRNA produced by a novel PMP22 splice site mutation associated with HNPP. J Neurol Neurosurg Psychiatry. 2006;77:538–40. [PMC free article: PMC2077485] [PubMed: 16199442]
  • Chanson JB, Echaniz-Laguna A, Blanc F, Lacour A, Ballonzoli L, Kremer S, Namer IJ, Lannes B, Tranchant C, Vermersch P, de Seze J. Central nervous system abnormalities in patients with PMP22 gene mutations: a prospective study. J Neurol Neurosurg Psychiatry. 2013;84:392–7. [PubMed: 23243264]
  • Chrestian N, McMillan H, Poulin C, Campbell C, Vajsar J. hereditary neuropathy with liability to pressure palsy in childhood: case series and literature update. Neuromusc Disord. 2015;25:693–8. [PubMed: 26189194]
  • Cortese A, Piccolo G, Lozza A, Schreiber A, Callegari I, Moglia A, Alfonsi E, Pareyson D. Laryngeal and phrenic nerve involvement in a patient with hereditary neuropathy with liability to pressure palsies (HNPP). Neuromuscul Disord. 2016;26:455–8. [PubMed: 27241821]
  • Corwin HM, Girardet RE. Hereditary neuropathy with liability to pressure palsies mimicking hypoglossal nerve injuries. Neurology. 2003;61:1457–8. [PubMed: 14638986]
  • Cruz-Martinez A, Arpa J, Palau F. Peroneal neuropathy after weight loss. J Peripher Nerv Syst. 2000;5:101–5. [PubMed: 10905469]
  • Del Colle R, Fabrizi GM, Turazzini M, Cavallaro T, Silvestri M, Rizzuto N. Hereditary neuropathy with liability to pressure palsies: electrophysiological and genetic study of a family with carpal tunnel syndrome as only clinical manifestation. Neurol Sci. 2003;24:57–60. [PubMed: 12827539]
  • Dubourg O, Mouton P, Brice A, Leguern E, Bouche P. Guidelines for diagnosis of hereditary neuropathy with liability to pressure palsies. Neuromuscul Disord. 2000;10:206–8. [PubMed: 10734269]
  • Gouider R, LeGuern E, Gugenheim M, Tardieu S, Maisonobe T, Léger JM, Vallat JM, Agid Y, Bouche P, Brice A. Clinical, electrophysiologic, and molecular correlations in 13 families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion. Neurology. 1995;45:2018–23. [PubMed: 7501152]
  • Guo J, Wang L, Zhang Y, Wu J, Arpag S, Hu B, Imhof BA, Tian X, Carter BD, Suter U, Li J. Abnormal junctions and permeability of myelin in PMP22-deficient nerves. Ann Neurol. 2014;75:255–65. [PMC free article: PMC4206215] [PubMed: 24339129]
  • Horowitz SH, Spollen LE, Yu W. Hereditary neuropathy with liability to pressure palsy: fulminant development with axonal loss during military training. J Neurol Neurosurg Psychiatry. 2004;75:1629–31. [PMC free article: PMC1738805] [PubMed: 15489403]
  • Infante J, Garcia A, Combarros O, Mateo JI, Berciano J, Sedano MJ, Gutierrez-Rivas EJ, Palau F. Diagnostic strategy for familial and sporadic cases of neuropathy associated with 17p11.2 deletion. Muscle Nerve. 2001;24:1149–55. [PubMed: 11494267]
  • Kalfakis N, Panas M, Karadima G, Floroskufi P, Kokolakis N, Vassilopoulos D. Hereditary neuropathy with liability to pressure palsies emerging during vincristine treatment. Neurology. 2002;59:1470–1. [PubMed: 12427913]
  • Karadima G, Koutsis G, Raftopoulou M, Karletidi KM, Zmbelis T, Karandreas N, Panas M. Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15-year experience. J Peripher Nerv Syst. 2015;20:79–85. [PubMed: 26110377]
  • Kim K-E. Characteristic features of hereditary neuropathy with liability to pressure palsy (HNPP) presenting with brachial plexopathy in soldiers. J Neurol Sci. 2014;346:174–7. [PubMed: 25175852]
  • Kleopa KA, Georgiou DM, Nicolaou P, Koutsou P, Papathanasiou E, Kyriakides T, Christodoulou K. A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes. Neurogenetics. 2004;5:171–5. [PubMed: 15205993]
  • Koehler PJ. Hereditary neuropathy with liability to pressure palsies: the first publication (1947). Neurology. 2003;60:1211–3. [PubMed: 12682341]
  • Koehler PJ, Baas F. Hereditary neuropathy with liability to pressure palsies. Diagnosis in the first family (1947) confirmed. J Peripher Nerv Syst. 2012;17:412–3. [PubMed: 23279343]
  • Koike H, Hirayama M, Yamamoto M, Ito H, Hattori N, Umehara F, Arimura K, Ikeda S, Ando Y, Nakazato M, Kaji R, Hayasaka K, Nakagawa M, Sakoda S, Matsumura K, Onodera O, Baba M, Yasuda H, Saito T, Kira J, Nakashima K, Oka N, Sobue G. Age associated axonal features in HNPP with 17p11.2 deletion in Japan. J Neurol Neurosurg Psychiatry. 2005;76:1109–14. [PMC free article: PMC1739771] [PubMed: 16024889]
  • Kramer M, Ly A, Li J. Phenotype HNPP (hereditary neuropathy with liability to pressure palsies) induced by medical procedures. Am J Orthop (Belle Mead NJ). 2016;45:E27–8. [PMC free article: PMC4876709] [PubMed: 26761923]
  • Kumar N, Muley S, Pakiam A, Parry GJ. Phenotypic variability leads to under-recognition of HNPP. J Clin Neuromuscul Dis. 2002;3:106–12. [PubMed: 19078663]
  • Lenssen PP, Gabreels-Festen AA, Valentijn LJ, Jongen PJ, van Beersum SE, van Engelen BG, van Wensen PJ, Bolhuis PA, Gabreels FJ, Mariman EC. Hereditary neuropathy with liability to pressure palsies. Phenotypic differences between patients with the common deletion and a PMP22 frame shift mutation. Brain. 1998;121:1451–8. [PubMed: 9712007]
  • Li J, Ghandour K, Radovanovic D, Shy RR, Krajewski KM, Shy ME, Nicholson GA. Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies. Arch Neurol. 2007;64:974–8. [PubMed: 17620487]
  • Li J, Krajewski K, Lewis RA, Shy ME. Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies. Muscle Nerve. 2004;29:205–10. [PubMed: 14755484]
  • Li J, Parker B, Martyn C, Natarajan C, Guo J. The PMP22 gene and its related diseases. Mol Neurobiol. 2013;47:673–98. [PMC free article: PMC3594637] [PubMed: 23224996]
  • Manganelli F, Pisciotta C, Dubbioso R, et al. Electrophysiological comparison between males and females in HNPP. Neurol Sci. 2013;34:1429–32. [PubMed: 23207550]
  • Marriott M, Macdonell R, McCrory P. Flail arms in a parachutist: an unusual presentation of hereditary neuropathy with liability to pressure palsies. Br J Sports Med. 2002;36:465–6. [PMC free article: PMC1724562] [PubMed: 12453844]
  • Moszyńska I, Kabzińska D, Sinkiewicz-Darol E, Kochański A. A newly identified Thr99fsX110 mutation in the PMP22 gene associated with an atypical phenotype of the hereditary neuropathy with liability to pressure palsies. Acta Biochim Pol. 2009;56:627–30. [PubMed: 19830275]
  • Muglia M, Patitucci A, Rizzi R, Ungaro C, Conforti FL, Gabriele AL, Magariello A, Mazzei R, Motti L, Sabadini R, Sprovieri T, Marcello N, Quattrone A. A novel point mutation in PMP22 gene in an Italian family with hereditary neuropathy with liability to pressure palsies. J Neurol Sci. 2007;263:194–7. [PubMed: 17707409]
  • Novakova L. Sussova J. Unusual form of hereditary neuropathy with liability to pressure palsies. Clin Neurophysiol. 2012;123:e41.
  • Padua L, Coraci D, Lucchetta M, Paolasso I, Pazzaglia C, Granata G, Cacciavillani M, Luigetti M, Manganelli F, Pisciotta C, Piscosquito G, Pareyson D, Briani C. Different nerve ultrasound patterns in Charcot-Marie-Tooth and hereditary neuropathy with liability to pressure palsies. Muscle Nerve. 2018;57:E18–23. [PubMed: 28802056]
  • Poloni TE, Merlo IM, Alfonsi E, Marinou-Aktipi K, Botti S, Arrigo A, Taroni F, Ceroni M. Facial nerve is liable to pressure palsy. Neurology. 1998;51:320–2. [PubMed: 9674839]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Rajabally YA, Adams D, Latour P, Attarian S. Hereditary and inflammatory neuropathies: a review of reported associations, mimics and misdiagnoses. J Neurol Neurosurg Psychiatry. 2016;87:1051–60. [PubMed: 27010614]
  • Robert-Varvat F, Jousserand G, Bouhour F, Vial C, Cintas P, Echaniz-Laguna A, Delmont E, Clavelou P, Chauplannaz G, Jomir L, Pereon Y, Leonard-Louis S, Manel V, Antoine JC, Lacour A, Camdessanche JP. Hereditary neuropathy with liability to pressure palsy in patients under 30 years old: neurophysiological data and proposed electrodiagnostic criteria. Muscle Nerve. 2018;57:217–21. [PubMed: 28407266]
  • Sander MD, Abbasi D, Ferguson AL, Steyers CM, Wang K, Morcuende JA. The prevalence of hereditary neuropathy with liability to pressure palsies in patients with multiple surgically treated entrapment neuropathies. J Hand Surg Am. 2005;30:1236–41. [PubMed: 16344182]
  • Shah A, Rison RA, Beydoun SR. Chronic inflammatory demyelinating polyneuropathy manifesting as neuropathy with liability to pressure palsies: a case report. J Clin Neuromuscul Dis. 2015;17:78–83. [PubMed: 26583495]
  • Stockton DW, Meade RA, Netscher DT, Epstein MJ, Shenaq SM, Shaffer LG, Lupski JR. Hereditary neuropathy with liability to pressure palsies is not a major cause of idiopathic carpal tunnel syndrome. Arch Neurol. 2001;58:1635–7. [PubMed: 11594922]
  • Stögbauer F, Young P, Kuhlenbäumer G, De Jonghe P, Timmerman V. Hereditary recurrent focal neuropathies: clinical and molecular features. Neurology. 2000;54:546–51. [PubMed: 10680781]
  • Taioli F, Cabrini I, Cavallaro T, Acler M, Fabrizi GM. Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene. Brain. 2011;134:608–17. [PubMed: 21252112]
  • Tohge R, Shinoto Y, Takahashi M. Case of hereditary neuropathy with liability to pressure palsies presenting progressive muscular atrophy with lower motor neuron degeneration in the spinal cord and the brainstem. Neurol Clin Neurosci. 2016;4:19–21.
  • Topakian R, Wimmer S, Pischinger B, Pichler R. Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy. BMJ Case Rep. 2014;2014:bcr2014206883. [PMC free article: PMC4202070] [PubMed: 25326571]
  • van de Wetering RA, Gabreels-Festen AA, Timmerman V, Padberg GM, Gabreels FJ, Mariman EC. Hereditary neuropathy with liability to pressure palsies with a small deletion interrupting the PMP22 gene. Neuromuscul Disord. 2002;12:651–5. [PubMed: 12207933]
  • van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, Verhamme C, Baas F, de Visser M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and hereditary neuropathy with liability to pressure palsies. Orphanet J Rare Dis. 2014;9:38. [PMC free article: PMC3994927] [PubMed: 24646194]
  • Vrinten C, Gu X, Weinreich SS, Schipper MH, Wessels J, Ferrari M, Hoijtink H, Verschuuren J. An n-of-one RCT for intravenous immunoglobulin G for inflammation in hereditary neuropathy with liability to pressure palsy (HNPP). J Neurol Neurosurg Psychiatry. 2016;87:790–1. [PMC free article: PMC4941134] [PubMed: 26187721]
  • Winter WC. Juel VC. Hypoglossal neuropathy in hereditary neuropathy with liability to pressure palsy. Neurology. 2003;61:1154–5. [PubMed: 14581692]
  • Yurrebaso I, Casado OL, Barcena J, Perez de Nanclares G, Aguirre U. Clinical, electrophysiological and magnetic resonance findings in a family with hereditary neuropathy with liability to pressure palsies caused by a novel PMP22 mutation. Neuromuscul Disord. 2014;24:56–62. [PubMed: 24239057]
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