# Handbook of Genetic Counseling/Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Lobular Carcinoma In Situ (LCIS)

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Lobular Carcinoma In Situ (LCIS)

## Introduction and Contracting

* Thank you for filling out the forms that we sent you
* I reviewed the information and understand that you have some questions and concerns about breast cancer, HNPP specifically genetic testing, heart disease and allergies.
* Do you have other questions or concerns?
* Do you (B) have any questions or concerns?

## Pedigree

(already put together from intake, but ask some more questions)
* Anyone else with a diagnosis of HNPP?
* Anyone in the family have muscle weakness
* Anyone with sensory loss (i.e. insensitive to heat or cold or touch)
* Anyone with toes or feet that are mishappen or look unusual
* Anyone with difficulty walking or moving
* Anyone else with cancer in the family
* Anyone with birth defects (spina bifida, heart defects, cleft lip)
* Anyone with MR or LD
* Consanguinity and ethnicity
* Review who has allergies and heart disease (anyone else?)
* Anything that you didn't already mention in the form you filled out that you are concerned might be hereditary?

## Medical and Psychosocial History

* Could you explain how you were diagnosed with HNPP?
* When did you first notice symptoms?
* What symptoms do you have?
* Does it interfere with your daily activities?
* What have you done to help deal with the symptoms?
* What is the most difficult part of having HNPP?
* Do you have any concerns about the diagnosis?
* Has anyone explained the inheritance of HNPP?
* Do you have any other health problems?
* Assess if he works or attends school
* How is his support network
* Do friends know about diagnosis

## Lobular Carcinoma In Situ (LCIS)

* Tumor that is confined to the lobule (milk producing glands) of the breast
* Noninvasive tumor that is not believed to progress to cancer
* Behaves differently from the more common invasive cancers
* Risk is increased for breast cancer though, in women with LCIS
** Study of 211 patients followed for 30 years and only 36 developed invasive cancer (13%)
** These cancers occurred in either breast and were not confined to original LCIS location
** Some experts therefore believe that LCIS is not a true precancer
* Only 6 of the 36 died of cancer and none of those six came back for regular exams
* Other studies since show range of invasive breast cancer risk after LCIS between 16-27% over 30 years.
* Relative risk for breast cancer if diagnosed with LCIS is 7.2 (chart from Dr. Susan Love's Breast Book and calculated using the study of 211 patients)
* Prevention options include:
** Bilateral mastectomy-some choose because they want to know they have done everything they can to prevent cancer
** Follow-up exams every 6 mos and yearly mammograms.
** Take tamoxifen for less than 5 years (shown to decrease chance of breast cancer 56% in women with LCIS)
* There is no need to make an immediate decision
* Radiation and chemo are not necessary
* No reason to obtain clean margins since it doesn't become cancer itself

## Hereditary Breast Cancer

* All cancers are due to changes in the genetic material of cells
* However, most cancer is sporadic (meaning that a person does not usually inherit a genetic predisposition that makes them more susceptible to cancer)
* In about 5-10% of breast cancers, the woman has inherited a single predisposing gene for breast cancer and we call this hereditary breast cancer.
* Although LCIS increases risk for breast cancer in an individual, it is not related to hereditary breast cancer and does not increase your risk of having inherited a mutation in one of the predisposing genes
* The two known genes that account for most hereditary breast cancer are BRCA1 and BRCA2
* These genes act like brakes on a car and help tell the cell when to stop dividing
* If there are changes in these genes it is like the brakes of a car went out and the cell can continue to divide and may lead to cancer
* In families that have a mutation in one of these genes we see a number of characteristics that are clues that there is a hereditary cancer
* These include-(show visual aid)
* Based on family history we can calculate the chance of having a BRCA mutation, but we don't use LCIS in the calculation because it is not associated with an increased risk for these mutations. (We only use individuals with invasive cancer in the risk assessment)
* Even in families that have a couple of these clues their chance of having a mutation in BRCA1 or BRCA2 can still be quite low
* For instance, I saw a patient last week with breast cancer dx in her 40's and her mother and maternal grandmother had breast cancer in their 60's, but their chance of having a mutation was only around 10%
* These families, if they do not have a mutation found, are more likely to fall into a category called familial breast cancer (where we see more breast cancer than expected by chance which is probably due to a number of factors, but these factors are unknown at this time)

## Overview

* Disorder of peripheral nerves (nerves traveling to the limbs)
* Predisposes individuals to repeated pressure neuropathies (i.e. carpal tunnel syndrome and peroneal palsy with foot drop)
* Slowly progressive, hereditary, neuromuscular disorder which makes an individual susceptible to nerve injury from pressure, stretch or repetitive use.
* When injured, the nerves demyelinate or lose their insulating covering
* Pressure palsies are episodes of numbness and weakness in the injured area
* Recovery is often complete (if not the resulting disability is usually mild)
* Some have signs of mild to mod peripheral neuropathy

## Prevalence

* Uncertain, but estimated to be 2-5 cases per 100,000 (may be higher due to undiagnosed cases)

## Description

* Recurrent sensory and motor neuropathy in a single nerve beginning in adolescence or young adulthood
* Most common symptom is acute onset of non-painful mononeuropathy
* History of physical compression of nerve may or may not be present
* Usually starts in 20's to 30's but range is 10-70's
* Some asymptomatic and some may have just one episode
* Most common sites
** Peroneal nerve causing foot drop
** Ulnar nerve causing weakness, atrophy and sensory loss over hand
** Median nerve at wrist causing carpal tunnel syndrome and sensory loss over thumb and index finger
* Full recovery in days to months occurs in ½ of episodes
* Remaining symptoms rarely severe
* Some develop diffuse polyneuropathy (% unknown)
* Absent ankle reflexes (50-80%)
* Diffusely reduced tendon reflexes (15-30%)
* Mild to moderate pes cavus foot deformity (20% of symptomatic individuals)
* One case reported with severe respiratory insufficiency (gene deletion and proximal muscle atrophy)

## Diagnosis

* Established in adults who have recurrent focal compression neuropathies and a family history consistent with AD inheritance
* Presence of underlying neuropathy further supports dx
* Other phenotypes besides typical presentation
** Recurrent positional short-term sensory symptoms
** Progressive mononeuropathy
** CMT-like polyneuropathy
** Chronic sensory polyneuropathy
** Chronic inflammatory demyelinating polyneuropathy-like
* Some patients can be asymptomatic
* Delayed nerve conduction may be present
* Prolongation of distal nerve conduction latencies (found in virtually all patients even if no symptoms)
* General nerve speed is normal, but some have diffuse polyneuropathy
* Key diagnostic features (Mouton 1999)
** Bilateral slowing of sensory and motor nerve conduction at carpal tunnel with at least one abnormal finding for motor conduction in one peroneal nerve
* Sural nerve biopsy often shows demyelination and focal enlargement of nerve (tomaculous change) but this is not specific for HNPP

## Genetics

* Due to changes or deletion of PMP22 gene (peripheral myelin protein 22) located at 17p11.2
* Gene is similar to growth arrest specific gene in mouse and rat
* There are flanking repeat sequences at the locus which may be mechanism for deletion
* Likely that there is gene dosage effect because mutations are not gain of function
* Normal gene product present in compact myelin and this PMP22 protein decreased in peripheral nerve of those affected

## Inheritance and Risks

* Autosomal Dominant (AD) inheritance with most individuals inheriting it
* Parents may serve as carriers without showing signs or symptoms
* Child has a sporadic mutation
* Parent is asymptomatic or mildly affected and was not diagnosed
* 50% risk to sibling if parent affected
* No instances of germline mosaicism, but theoretically possible
* 50% risk to children of affected

## Genetic testing

* DNA testing for deletion that includes PMP22 gene
* Detects 80% of patients and available clinically
* Remaining 20% have a point mutation producing frameshifts, premature termination or other abnormalities of protein (a number of which can be tested for clinically)
* There are some geneotype phenotype correlations for frameshift and point mutations
* Can test at risk adults who are asymptomatic
** Should discuss motivation for testing (Why would it be helpful to them to be tested)
** Discuss life, health, disability insurance coverage and employment discrimination
* Do not test asymptomatic children due to it being adult onset
** Removes their choice to not know
** Possibility of stigmatization

## Prenatal testing

not offered because not clinically available

## Related disorders and Differential Diagnosis

* (Charcot Marie Tooth) CMT1A and some patients with CMT4 also have mutations in the gene PMP22
* pressure palsies most commonly result of environmentally acquired compression
* those with underlying neuropathy (i.e. if have diabetes mellitus), increased risk of compression neuropathies
* acquired type of pressure palsies same as those in HNPP
* Charcot Marie Tooth
* Sometimes HNPP involves brachial plexus and can overlap symptoms of hereditary neuralgic amyotrophy (distinct disorder maps to 17q)

## Management

* No treatment for biochemical defect or special diet or vitamins alter HNPP
* Risk factors for PP's
** Sitting with legs crossed
** Occupations with repetitive wrist motions
** Leaning on elbows prolonged period
** Rapid weight loss
* Bracing may be useful (wrist splint or ankle-foot-orthosis (AFO) for foot drop)
* Controversial whether surgical decompression of nerve is beneficial

## References

* Dr. Susan Love's breast book. Perseus Publishing. 2000. Love.
* What you really need to know about Cancer. Johns Hopkins University Press. 1997. Buckman.

## Web references

* Geneclinics (www.geneclinics.com) HNPP
* http://www.hnpp.org/welcome.htm
* http://www.charcot-marie-tooth.org
* What is Neuropathy

## Patient resources and references

* http://www.hnpp.org/welcome.htm (website to learn about HNPP)
* Charcot-Marie-Tooth Association
    2700 Chestnut street
    Chester, PA 19013-4867
    Phone: 1-800-606-CMTA
    Fax: 610-499-9267
    Email: CMTAssoc@aol.com
    http://www.charcot-marie-tooth.org

## Notes

The information in this outline was last updated in 2002.