Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: PMP22
Condition: Hereditary Neuropathy with Liability to Pressure Palsies
GENEDISEASE PAIRS: PMP22162500
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
The prevalence of hereditary neuropathy with liability to pressure palsies (HNPP) is not well known, though it has been estimated between 1/50,000 and 1/14,000. The actual prevalence may be higher because of under diagnosis. A study of the Finnish population found that prevalence may be as high as 1/6,250.
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Clinical Features
(Signs / symptoms)
HNPP is characterized by episodic focal motor and sensory peripheral neuropathies in the hands and feet. These attacks are typically painless. The nerve palsies often recur over a period of many years, but some individuals have a single episode and others with a pathogenic variant remain asymptomatic. In many cases these symptoms are triggered by mechanical stresses to the nerve, such as compression, repetitive movement and/or stretching of the affected limbs. Common clinical manifestations include carpal tunnel syndrome and peroneal palsy with foot drop. In 50% of cases, recovery from the acute neuropathy is complete within a few days to months. Incomplete recovery is common, though the resulting disability rarely severe. Chronic motor deficits after nerve palsies are noted in 10-15%. In rare cases, strenuous activities can lead to severe and prolonged limb paralysis.
 
Atypical presentations of HNPP are common and can include: recurrent positional short-term sensory symptoms, progressive mononeuropathy, Charcot-Marie-Tooth like polyneuropathy, chronic sensory polyneuropathy, and chronic inflammatory demyelinating polyneuropathy-like disorder.
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Natural History
(Important subgroups & survival / recovery)
Most individuals with HNPP typically experience their first episode in the second or third decade at a mean age of 37 years, but with a large range from birth through the eighth decade. The most common presenting symptom is acute onset of a focal neuropathy of a single nerve (mononeuropathy). Males and females are equally affected. Occasional episodes have been reported during pregnancy, likely related to physiological changes. Older patients often develop a symmetric sensory motor polyneuropathy. HNPP is not life threatening, and patients have a normal life expectancy.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease following diagnosis the following evaluations are recommended:
 
• History of focal nerve symptoms
 
• Family history
 
• Neurologic examination
 
• Electromyography/nerve conduction velocity
 
• Clinical genetics consultation. (Tier 4)
1
Protective pads at the elbows or knees may prevent pressure and trauma to local nerves. (Tier 4)
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Surveillance
No surveillance recommendations have been provided.
 
Family Management
No family management recommendations have been provided.
 
Circumstances to Avoid
Patients are advised to avoid prolonged sitting with legs crossed, prolonged leaning on the elbows, occupations requiring repetitive movements of the wrist, and rapid weight loss as these have been reported in case reports as being associated with the onset of HNPP symptoms. (Tier 3)
1 3
Vincristine, used in chemotherapy, has been reported to exacerbate HNPP. A single case report related to this exposure was identified. No studies were identified reporting the rate of developing HNPP symptoms following vincristine exposure (Tier 3)
1 3
An overview of case reports addressing Charcot Marie Tooth (CMT) and toxic medication effects identified 22 reports (30 patients) addressing vincristine toxicity; however it is unclear whether this evidence may apply to HNPP. 18 of 30 patients developed marked sensory symptoms or new onset weakness, with some developing dysarthria and dysphagia. Nearly all reports describe eventual improvement, but frequently not to baseline levels. These cases occurred in both adults (15) and children (15). Most individuals having a reaction were previously unsuspected or undiagnosed with CMT (26 of 30) and were only recognized following administration of vincristine; however, 10 cases, in retrospect, had overt clinical signs or a close relative with known CMT. (Tier 5)
4
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
 
Prevalence of Genetic Mutations
The prevalence of pathogenic variants in PMP22 associated with HNPP was unavailable. However, PMP22 accounts for an estimated 100% of HNPP cases and thus the prevalence of pathogenic variants in PMP22 is expected to be similar to the prevalence of HNPP, or between 1/50,000 and 1/20,000. (Tier 4)
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Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
Studies screening relatives of index patients have identified that 6-23% of family members may be asymptomatic. These rates are not reported within the context of the exposure to potential triggers. (Tier 3)
3
 
Information regarding relative risk was unavailable.
 
 
Expressivity
Large intrafamilial clinical variability has been noted. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
The interventions identified in this report include wearing protective pads and avoidance of potential triggers including vincristine.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Individuals with HNPP are typically identified after their first episode and diagnosed via genetic testing and/or electrophysiological studies. Thus, patients are likely to escape detection prior to their first episode. Given pain is often a presenting symptom, individuals with HNPP are often clinically misdiagnosed with fibromyalgia upon presentation. (Tier 4)
1 3

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Neuropathy / Avoidance of triggers
1
3C
0C
3
7CC
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. TD Bird. Hereditary neuropathy with liability to pressure palsies. 1998 Sep 28 [Updated 2014 Sep 25]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1392
2. Hereditary neuropathy with liability to pressure palsies. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=640
3. 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.
4. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in charcot marie tooth disease. J Neurol Sci. (2006) 242(1-2):47-54.
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