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Hereditary Neuropathy with Liability to Pressure Palsies

Synonyms: HNPP, Hereditary Pressure Sensitive Neuropathy, Tomaculous Neuropathy
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: May 11, 2010.

Summary

Disease characteristics. Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by repeated focal pressure neuropathies such as carpal tunnel syndrome and peroneal palsy with foot drop. The first attack usually occurs in the second or third decade. Recovery from acute neuropathy is often complete; when recovery is not complete, the resulting disability is usually mild. Some affected individuals also have signs of a mild to moderate peripheral neuropathy.

Diagnosis/testing. The diagnosis of HNPP is established in an adult with recurrent focal compression neuropathies who has a family history consistent with autosomal dominant inheritance. PMP22 is the only gene known to be associated with HNPP. A contiguous gene deletion of chromosome 17p11.2 that includes PMP22 is present in approximately 80% of affected individuals; the remaining 20% have a mutation in PMP22.

Management. Treatment of manifestations: A wrist splint may alleviate carpal tunnel syndrome; ankle-foot orthoses (AFOs) may alleviate foot drop.

Prevention of primary manifestations: Protective pads at elbows or knees may prevent pressure and trauma to local nerves.

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

Other: Surgical decompression of nerves is not beneficial and may cause harm.

Genetic counseling. HNPP is inherited in an autosomal dominant manner. Each child of an affected individual is at a 50% risk of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family; however, requests for prenatal testing for typically adult-onset conditions such as HNPP are not common.

Diagnosis

Clinical Diagnosis

The diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP) is established in an adult with (1) recurrent focal compression neuropathies and (2) family history consistent with autosomal dominant inheritance.

Findings that support the diagnosis include the following:

  • Mild polyneuropathy, with or without symptoms
  • Evidence on physical examination of previous nerve palsy such as focal weakness, atrophy, or sensory loss
  • Absent ankle reflexes (50%-80%)
  • Diffusely reduced tendon reflexes (15%-30%)
  • Mild to moderate pes cavus foot deformity (20%)

Electrophysiologic studies are usually abnormal:

  • Prolongation of distal nerve conduction latencies (e.g., of the median nerve at the wrist) occurs in essentially all individuals whether symptomatic or asymptomatic.
  • According to Mouton et al [1999], the key electrophysiologic diagnostic features are bilateral slowing of sensory and motor nerve conduction at the carpal tunnel with at least one additional abnormal finding for motor conduction in one peroneal nerve. Infante et al [2001] emphasize the need to evaluate sensory conduction in the sural nerve and motor conduction in at least two nerves across usual entrapment sites, especially the ulnar nerve at the elbow. Li et al [2002] found evidence for prolonged distal motor latencies in the median and peroneal nerves but not ulnar or tibial nerves.
  • Nerve conduction velocity (NCV) may be delayed at the site of compression.
  • General motor NCVs are usually normal (>40 m/s); a few individuals have electrical evidence of a mild diffuse polyneuropathy.

Sural nerve biopsy often shows evidence of demyelination and "tomaculous" (focal, sausage-like enlargement of the nerve) change. Tomaculous change is not specific and has been noted occasionally in other neuropathies.

Molecular Genetic Testing

Gene. PMP22 is the only gene in which mutation is known to cause HNPP.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in HNPP

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
PMP22Deletion / duplication analysis 21.5-Mb deletion including PMP22~80%
Sequence analysis 3Point mutations and small deletions~20%

1. The ability of the test method used to detect a mutation that is present in the indicated gene.

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

3. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband requires detection of a PMP22 mutation using molecular genetic testing. If the PMP22 deletion test is normal in a person with the typical HNPP phenotype, the next step is PMP22 sequence analysis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in a single nerve beginning in adolescence or young adulthood. The most common presenting symptom of HNPP is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy) [Pareyson et al 1996, Kumar et al 2002, Li et al 2004]. Some individuals experience transient sensory phenomena without weakness. History of actual physical compression of the nerve may or may not be present.

Occasional episodes have been reported during pregnancy, perhaps related to physiologic changes such as soft tissue swelling and edema. The nerve palsies often recur over a period of many years, but some individuals have a single episode and some individuals who have a disease-causing mutation are asymptomatic.

The first attack is usually in the second or third decade (mean age: 37 years), although the age range extends from two to 70 years. Radial nerve palsy has been reported in a two-year-old with HNPP [Hardon et al 2002] and peroneal nerve palsies have been reported shortly after birth [Goikhman et al 2003].

Males and females are equally affected.

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

  • The peroneal nerve at the fibular head causing foot drop
  • The ulnar nerve at the elbow, causing hypothenar and interossei muscle weakness and atrophy with sensory loss over the lateral aspect of the hand
  • The 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]
  • The brachial plexus and radial nerve, causing transient sensory symptoms and hand pain [Marriott et al 2002].

Full recovery over a period of days to months occurs in approximately 50% of episodes. Incomplete recovery is fairly common, but the remaining symptoms are rarely severe. Poor recovery correlates with a history of prolonged focal compression of the nerve [Koike et al 2005].

Symptomatic individuals have the frustration and disability associated with recurrent pressure palsies, although the degree of handicap in performing activities of daily living is usually not severe.

In addition to the typical presentation of HNPP, Mouton et al [1999] described five other phenotypes:

  • Recurrent positional short-term sensory symptoms
  • Progressive mononeuropathy
  • CMT-like polyneuropathy
  • Chronic sensory polyneuropathy
  • Chronic inflammatory demyelinating polyneuropathy-like disorder [Korn-Lubetzki et al 2002]

Note: Some individuals may be asymptomatic.

Other findings reported in a few individuals:

Genotype-Phenotype Correlations

Persons with the PMP22 frameshift mutation (p.Arg95Glyfs*128) have a typical HNPP phenotype but are also more likely to have an associated clinically evident motor/sensory neuropathy mimicking Charcot-Marie-Tooth Neuropathy Type 1 (CMT1) [Lenssen et al 1998]. Other point mutations in PMP22 with a similar phenotype have been described [Bellone et al 2006, Li et al 2007, Muglia et al 2007, Moszyńska et al 2009].

Shy et al [2006] described an HNPP phenotype associated with the p.Thr118Met mutation in PMP22.

Al-Thihli et al [2008] reported a severely affected child with a two abnormal PMP22 alleles: a PMP22 deletion inherited from the mother and deletion of exons 2 and 3 of PMP22 inherited from the father.

Penetrance

Many individuals with the PMP22 1.5-Mb deletion have few (or no) symptoms and go undiagnosed. The penetrance is not known.

Anticipation

Anticipation has not been described.

Nomenclature

Hereditary neuropathy with liability to pressure palsies was previously referred to as tomaculous neuropathy, recurrent pressure-sensitive neuropathy, and tulip-bulb digger's palsy or potato-grubbing palsy [Koehler 2003].

Prevalence

The prevalence of HNPP is unknown; it is estimated at two to five cases per 100,000 population. The actual prevalence may be higher because of under-diagnosis.

Meretoja et al [1997] found the prevalence in Finland to be 16:100,000.

Differential Diagnosis

Pressure palsies are most commonly the result of environmentally acquired physical compression of peripheral nerves. The most common are the 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. 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).

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

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

The proportion of individuals with a single episode of compression neuropathy who have a 17p11 deletion or PMP22 point mutation is not known. However, because some individuals with HNPP may have no family history of neuropathy, a single episode of nerve compression, or a de novo mutation, some authors have advocated molecular genetic testing of individuals with a negative family history who have compression neuropathy. A more selective approach is to test only those individuals with either:

  • More than one episode of compression neuropathy,
  • One episode of compression neuropathy and an unexplained polyneuropathy, or
  • One episode of compression neuropathy and a family history of neuropathy.

HNPP sometimes involves the brachial plexus, thus overlapping with hereditary neuralgic amyotrophy, a distinct disorder that maps to 17q. Stogbauer et al [2000] contrast the clinical features of HNPP and hereditary neuralgic amyotrophy.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the following evaluations are recommended:

  • History of focal nerve symptoms
  • Family history
  • Neurologic examination
  • Electromyography / nerve conduction velocity (EMG/NCV)

Treatment of Manifestations

Transient bracing, such as with a wrist splint or ankle-foot orthosis (AFO), may be useful. Some individuals with residual foot drop may permanently use an AFO.

Prevention of Primary Manifestations

Protective pads at elbows or knees may prevent pressure and trauma to local nerves.

Prevention of Secondary Complications

Bracing of weak muscles, such as ankle-foot-orthosis for foot drop, may prevent injury.

Agents/Circumstances to Avoid

Risk factors for pressure palsies (and thus activities to avoid) include prolonged sitting with legs crossed, occupations requiring repetitive movements of the wrist, prolonged leaning on elbows, and rapid weight loss [Cruz-Martinez et al 2000, Marriott et al 2002].

Vincristine, commonly used in the chemotherapy of lymphoma, has been reported to exacerbate HNPP [Kalfakis et al 2002].

Evaluation of Relatives at Risk

Relatives at risk may wish to clarify their genetic status by undergoing molecular genetic testing; if found to have the PMP22 mutation identified in an affected family member, they can choose to avoid the aforementioned agents and circumstances.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

Controversy exists as to whether surgical decompression of nerves is of benefit. Because spontaneous recovery is common and because no systematic controlled study of surgical intervention has been done, this decision must be made on an individual basis, taking into consideration knowledge of the natural history of the disease. There is a developing consensus that surgical repair of carpal tunnel syndrome is of little benefit to individuals with HNPP and that transposition of the ulnar nerve at the elbow may actually produce poor results [Lazar et al 2007].

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face 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

Note: Although 80% of individuals diagnosed with HNPP have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members [Beydoun et al 2008].

Sibs of a proband

  • The risk depends on the genetic status of the proband's parents.
  • If a parent is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

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

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are 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 treatment.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for HNPP is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for HNPP, an affected family member should be tested first to confirm the diagnosis in the family and identify the mutation.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of HNPP, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing of asymptomatic at-risk individuals during childhood. Consensus holds that individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing in the absence of symptoms. The principal arguments against such testing are that it removes the individual's choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as HNPP are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

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, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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

Normal allelic variants. PMP22 spans approximately 5 kb and has four exons.

Pathologic allelic variants. The molecular defect present in 80% of affected individuals is a 1.5-Mb 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 CMT1). These rearrangements are the result of unequal crossing over following misalignment of flanking repeat sequences at this chromosomal location. HNPP is likely to be the result of a gene dosage effect.

Approximately 20% of families with HNPP have a variety of PMP22 point mutations that produce frameshifts, premature termination of translation, or other abnormalities [Young et al 1997, Lenssen et al 1998, Stogbauer et al 2000, van de Wetering et al 2002, Kleopa et al 2004]. The clinical and molecular aspects of other point mutations associated with the HNPP phenotype are reviewed by Stogbauer et al [2000] and van de Wetering et al [2002]. These include mutations resulting in frameshifts, premature termination translation, 5' splice-site mutation, and a mutation affecting the junction of the extracellular loop and the first transmembrane domain of PMP22. Additionally, Meuleman et al [2001] have reported a 3' splice-site mutation, preceding coding exon 3, resulting in a mild HNPP phenotype. The p.Arg95Glyfs*128 mutation not only results in a frameshift at residue 95 but also creates a new translation termination site, thereby adding 61 more amino acids to the length of the protein. See Table 2.

Table 2. Selected PMP22 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.281_282insGp.Arg95Glyfs*128 2
(Gly94fs)
NM_000304​.2
NP_000295​.1
c.353C>Tp.Thr118Met 2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

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

1. Variant designation that does not conform to current naming conventions

2. See Genotype-Phenotype Correlations.

Normal gene product. Peripheral myelin protein 22 is a 160-amino acid protein that is present in compact myelin and has four transmembrane domains.

Abnormal gene product. HNPP is associated with decreased mRNA message for PMP22 and decreased peripheral myelin protein 22 in peripheral nerve [Gabriel et al 1997, Schenone et al 1997a, Schenone et al 1997b].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Policy Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 10-8-12. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 10-8-12.

Literature Cited

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Suggested Reading

  1. Chance PF. Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy. Neuromolecular Med. 2006;8:159–74. [PubMed: 16775374]
  2. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 227. Available online. Accessed 10-08-12.

Chapter Notes

Revision History

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