Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[HNPP, Hereditary Pressure Sensitive Neuropathy, Tomaculous Neuropathy]
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Author:
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Thomas D Bird, MD
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Initial Posting:
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Last Update:
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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. Testing is available in clinical laboratories.
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.
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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. PMP22 is the only gene known to be associated with HNPP.
Clinical testing
Deletion testing. A 1.5-Mb deletion at 17p11.2 (including PMP22) is detected in approximately 80% of individuals with HNPP. Methods to detect the 17p11.2 deletion include the following:
Fluorescence in situ hybridization (FISH) [Mohammed & Shaffer 2003]
Long polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) [Lorentzos et al 2003 , Thiel et al 2003]
Southern blot analysis (pulse field gel electrophoresis) to detect large-scale PMP22 gene deletions
Multiplex ligation-dependent probe amplification (MLPA)
Note: In one study MPLA was used to detect smaller deletions [Sutton et al 2004].
Sequence analysis/mutation scanning. Sequence analysis of PMP22 detects point mutations and small deletions in approximately 20% of individuals with HNPP.
Table 1
summarizes molecular genetic testing for this disorder.
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirmation of the diagnosis in a proband requires detection of a PMP22 mutation using molecular genetic testing.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
The other phenotypes associated with alterations of PMP22 are Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A) and Charcot-Marie-Tooth Neuropathy Type 1E (CMT1E) (see CMT Overview).
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:
Note: Some individuals may be asymptomatic.
Other findings reported in a few individuals:
Motor brachial paralysis [Kumar et al 2002 , Makela et al 2006]
Proximal muscle atrophy and severe respiratory insufficiency [Asahina et al 2000]
CNS white matter lesions [Dackovic et al 2001 , Sanahuja et al 2005 , Tackenberg et al 2006]
Hypoglossal nerve paralysis of the tongue, including after carotid endarterectomy [Corwin & Girardet 2003 , Winter & Juel 2003]
Rapid onset and progression of neuropathy early in military physical training [Horowitz et al 2004]
Scapuloperoneal syndrome [Verma 2005]
Persons with the PMP22 frameshift mutation (p.Arg95GlyfsX128) 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 , Muglia et al 2007 , Li et al 2007].
Many individuals with the PMP22 deletion have few (or no) symptoms and go undiagnosed. The penetrance is not known.
Anticipation has not been described.
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].
The prevalence of HNPP is unknown but 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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 (1) more than one episode of compression neuropathy, (2) one episode of compression neuropathy and an unexplained polyneuropathy, or (3) 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) contrasts the clinical features of HNPP and hereditary neuralgic amyotrophy.
To establish the extent of disease in an individual diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP), the following evaluations are recommended:
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.
Protective pads at elbows or knees may prevent pressure and trauma to local nerves.
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 1997 , 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].
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, thay 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.
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.
Controversy exists as to whether surgical decompression of nerves is of benefit. Because spontaneous recovefry 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 2006].
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Hereditary neuropathy with liability to pressure palsies (HNPP) is inherited in an autosomal dominant manner.
Parents of a proband
Approximately 80% of individuals with HNPP have inherited the gene mutation from an affected parent.
Approximately 20% of affected individuals have a de novo mutation [Infante et al 2001].
It is appropriate to evaluate the parents of an individual with HNPP to determine if either parent has clinical findings of HNPP.
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 2007].
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 upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.
See Management, Testing of Relatives at Risk for information on testing 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 available 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. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 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).
Preimplantation genetic diagnosis may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see
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Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
PMP22 | 17p11.2 | Peripheral myelin protein 22 |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Gene Symbol | Entrez Gene | HGMD | GeneCards | GDB | GenAtlas |
PMP22 |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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Normal allelic variants: PMP22 spans approximately five kilobases and contains 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 the
PMP22 gene. This is the reverse of the 1.5-Mb duplication that occurs in Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A; see CMT1). This phenomenon is presumed to be the result of unequal crossing over following misalignment of flanking repeat sequences at this chromosomal location. The disease 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 in protein function [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 associatfed 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.Arg95GlyfsX128 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
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See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. Variant designation that does not conform to current naming conventions |
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, Nobbio, Caponneto et al 1997 ; Schenone, Nobbio, Mandich et al 1997].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.
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