1: I have a question about the CRS staining and the results in relation to possible false negatives.  Because in most reported cases of amyloidosis are involving the kidney and liver many people only test for these two organs or they include just one other but rarely an entire necropsy I was wondering if a dog can really be considered negative if one would not perform a full necropsy at the time of death and if the numbers but more importantly the interpretation of these findings have given a wrong impression.

A1: You are correct.  I routinely submit kidney, liver, spleen and a mesenteric lymph node when possible and this is what we did in our published studies.  However, if I have a patient with a history of FSF who died in kidney failure, I might only submit a longitudinal section of a kidney because this will give me "more bang for my buck" especially when I am often paying for these out-of-pocket.  I send all of my samples to Cornell because some of the smaller laboratories don't even own Congo red stain.

Q1A: Well I do understand that for those dogs that a high suspectability especially with your experience it will not be a problem to only test these specific organs to confirm an already suspected diagnosis. It is more the dogs that do not have this particular background that in my personal opinion should be tested more in-depth before they can be declared amyloid-free. I know many people are putting very much weight on the CRS results when it comes to breeding choices but I wonder how much you can trust a negative result when you do have a full necropsy preformed. Thank you for your insite and opinion on this subject.

A1A: I agree.  Without a complete necropsy and histopathologic examination of at least kidney, spleen, liver, +/-  lymph node tissue submitted – you cannot say with certainty that the patient was truly negative.  Very likely it was negative but not with certainty.

Q2A: For instance did you know that AA Amyloidosis always start in the spleen and that dependents on the persistence and severity of the underlying inflammatory disease if this will spread out to other organs or that in cases where the underlying inflammatory disease can be sufficiently halted that already deposited fibrils can be broken down as they loose their strength over time.  I know this might be difficult to take into consideration but I do think one needs to remember this when one tests for amyloidosis also because very small deposits can be missed by CRS staining.

A2A: Yes!  So if you catch the disease early in the process and treat the underlying pro-inflammatory process, you could theoretically eliminate the disease.  There have been several reports of human FMF patients that have shown reversal of their kidney disease with colchicine and I have seen this in some Shar-Pei as well.  Also, keep in mind that the problem that is far more common is that the pathologist is complaining that my request to run congo red is unnecessary because the pink stuff is all over the place and obvious with routine stains.

Q2B: Well I have indeed also red many reports about FMF patients that have amyloid load reduction when put on colchicine but I wonder how this would be possible to measure in Shar-pei as I have not heard of a specific type of test being used to establish this load in Shar-pei. I know you have an enormous amount of experience so I think when you look at blood results in relation to family background your suspicions go up.

I want to ask you a question in relation to that. Although I am definitely not an expert in reading blood reports and I surely will not make any diagnosis as I just try to help people to understand the blood reports I did notice something that makes me suspect amyloid involvement and this was also reported in Dr. DiBartola's report in the early 90's. It seems that those dogs with elevated cholesterol or hypercholesteremia. I was wondering if you had noticed this also or if your experiences are different in this regard. I know one could probably not use this as a diagnosis element but I do wonder why there is so much consistency in what I was thinking at the time I first saw the cholesterol numbers and the later positive CRS staining.

A2B: Shar-Pei very frequently present with hypercholesterolemia and I do think it is associated with their underlying immunopathology.  This is a warning sign on blood work.  Hypothyroidism should be ruled out too.  I also typically see mild elevations in alkaline phosphatase, which I think is probably related to their low grade elevations endogenous steroids from IL-6 turning on ACTH which then stimulates the adrenal gland.  The stress and steroid release of fever event will also often cause a rise in alk phos.  (And a deflated muzzle!)

Q2C: I understand that in some cases the amyloid deposits are so severe that there are visible with the naked eye but unfortunately this will not be accepted as a definite positive diagnosis. Off course this has a more physiological effect than a real incomplete conformation.

A2C: I agree – which is why when they gripe, they get told to do it anyway.

Q3A: I really think that there is much confusion about the CRS staining and what it can say, especially because so many really believe FSF and Amyloidosis aren't related.

A3A: I thought this was a well-established fact.  Are there many in this group that believe they are not linked?

Q3B: Well I do believe they are connected because this type of amyloidosis is inflammatory related and will (according to many studies) not occur without it. Many people are not only confused by it being called familiar amyloidosis in Shar-pei but also because they find it that it is insignificantly proven this type is really AA Amyloidosis also.

A3B: Insignificantly proven?  I didn't know there was any debate here either. This has been examined and it is AA amyloid.  What other type do people speculate it might be?

Q3C: And of course just like Denise has already stated because personal observations does not seem to agree on this specifically.  Also for what I have been reading there is also a large group that thinks that early reports say that FSF causes amyloidosis, which also does not support their observation.  Well I also do not believe FSF causes Amyloidosis so in this respect I agree but to me this doesn't mean that they aren't related just that one is not causing the other and that one still undetermined factor is causing them both. JMHO

A3C: I think our differences are of semantics here.  I normally describe them as linked disorders and I spend more time trying to convince veterinarians that FSF does NOT always equal Amyloidosis than that they ARE linked – so I can understand some people's frustration.  Their veterinarians incorrectly tell many S-P owners that their dog that just experienced a classic fever event has "amyloidosis" in the face of no evidence of the sort.  They most likely do have FSF but Amyloidosis is just a big risk at this point, not a diagnosis.  But when a S-P gets a diagnosis of Amyloidosis by biopsy or at necropsy – breeders should assume the dog had the auto-inflammatory disease of FSF even if they never had fever events.

Q4A: I think a part of this confusion besides personal observations of course is because you refer to amyloidosis in Shar-pei as being inheritable but if they are indeed related that isn't the inflammatory factor being past on from one generation to the other and not the development of amyloidosis? With this I literally mean without this inflammatory activity there will be no amyloidosis. You cannot have this type of amyloidosis without this inflammatory response. So in dogs where this inflammatory activity is not persistent or continues the risk for amyloidosis will also be reduced. I really would like you take on this.

A4A: If you eliminate the underlying auto-inflammatory disease, you should dramatically reduce the chance they will succumb to amyloidosis.  But keep in mind that we very commonly see many patients with severe chronic inflammatory processes that never develop amyloidosis.  Amyloidosis in non-Shar-Pei is a very rare disease.  So I do think that it is likely that there are two linked disorders – one in inflammation and the other in the elimination of the inflammatory waste products. It may turn out that they even lie near each other on the gene.  We'll see.

Q4B: Well I understand your view on this and although it will always be just an educated guess on my part I really believe you will never find any associated gene for amyloidosis, simply because I do not believe one exist. AA Amyloidosis can be caused by infectious diseases as well and even in dogs that do not have a high susceptibility for it so an isolated genetic suspectability to development would be highly unlikely.

A4B: Well there is likely a gene(s?) that controls the breakdown of the amyloid protein and if it exists, it could mutate.  Only further DNA research will tell (and that could be a long way off).

Q4C: Also non-Shar-pei amyloidosis isn't so rare as you might expect for instance there have been reports in families of beagles, is listed as a breed health problem in Bull-Mastiff and is also seen in Akita's. Reports have been made about amyloidosis in poodles and on more sporadic incidences in other breeds.  

A4C: Yes, I have seen other familial breed related clusters but doesn't this point to an underlying specific defect in these families in these breeds – yes, either in the increased APP etc or in the decreased elimination or both.  I'm talking about your average backyard pet who dies at age 12 – you just don't see it in the "normal" population.  And Akitas are notorious for immune dysfunction.

Q4D: Genetic linking of amyloidosis in FMF (higher incidences of amyloidosis in specific mutation sequences) has been studied but these reports are highly inconsistent due to negative post-reviews that could not support these earlier findings.

A4D: Did you see the posted request for cooperation on the new research project to validate a test for amyloidosis in S-P using radiolabeled serum amyloid-P at U of Tenn?  This would make it a lot easier to diagnose and evaluate therapies, which is the data we are lacking.

Q4E: I also understand your personal observations in seemingly severe chronic cases seem to confuse this idea but unfortunately severe symptomatic display of disease even with out of range blood results do not say much about specific inflammatory activity and how this activity motivates production of acute phase proteins.

Not every serious inflammatory disease has a high incidence of amyloidosis but they still have severe inflammatory activity also disease activity even when extremely severe can occur with a significant interval without stimulation of Serum Amyloid A protein in between these episodes. This interval could be significant enough to halt amyloid fibril formation significantly enough that it will never result into a deathly disease or even total absence.

A4E: Good point.

Q5A: Another question I have is about the FMF connection. Did you know that FSF is very responsive to prednisone and that this responsiveness is part of the diagnosing protocol for FMF? FMF is unresponsive to prednisone and this is the first queue for a physician to suspect FMF together with a background check on family history will in most cases confirm this diagnosis as most people are not specifically tested for genetic mutations or it couldn't be confirmed by such testing.  I really would like your take on this also.

A5A: Did you mean to type that FSF is very responsive to prednisone??

Q5B: Well, I am not sure what you are asking as I did write that indeed.  Although case reports are extremely limited as most people will never use prednisone because it has a dominant affect on the dog’s appearance.  I do know about a few cases where fever episodes are significantly suppressed by prednisone, I understand that it is not possible to make any definite conclusions based on the limited reports. Although the most dominant case I know off also includes extreme swelling as well, this dogs quality of life was extremely compromised so his owner decided to put him permanently on a low dose of prednisone. The last report I got about him he was doing very well.  I just wondered if you ever tried this for FSF. The reason I mentioned FMF in humans is very unresponsive to prednisone while it seems FSF in Shar-pei does has it could be a possible indication both disease although very similar might not have the same disease motivators.

A5B: The reason I asked you clarify this is that I do not find FSF to be steroid-responsive.  I think that there is a marked improvement in the swollen hock syndrome type signs – muzzle, hock or other joint swelling etc but I've not found that the fevers are suppressed by chronic (or even acute) corticosteroid administration.  Could you get more details about what dosages and frequency of pred were given and what the owners observed that led them to conclude it was the pred that was suppressing the fevers?  I would like to know as much as I can about all types of presentations and what seems to work.  Well thank you for your reply again. I enjoy the dialog – thank you!

Q: I have been breeding Shar Pei for just over 18 years now. I have not yet tested a positive dog but I have not lost any in the last three years.  New lines can and will bring new problems I am sure.

Previously I would have only tested a young dog that would have died suspiciously and with clinical correlations to FSF or Amlyoid. I had not had any of those. It was pointed out to me that that the dog could still harbor the problem even if dying of old age...over 14 years...... and should be tested and that the CRS test was proof positive for it. So the next dog I loose over 12 weeks will be tested.  BUT the vets I talked with disagreed with this.

I have had numerous vets tell me the CRS test is a FOOTPRINT for the pleated proteins (forgive my layman's terms) and not a diagnosis for Amlyoidosis. They have said that pleated proteins can be present without a clinical relationship to Amlyoidosis and the test is used to confirm a clinical relationship (other expressed factors)  with the disorder. Otherwise it is not a conclusive way to diagnose this problem since the proteins are a result of inflammation but not necessarily automatically Amlyoid related.  My question is: Do they have it wrong Dr. Linda?  I have heard conflicting information on this.

A: In old dogs, it makes a tough call. I'll give you an example of a Shar-Pei that I recently euthanized for cancer at > 10 yrs of age. He was tested routinely with CRS and found positive. But the amyloid was only in the medulla of the kidney - a place where it is not normally deposited except in the two animals with inherited amyloidosis (S-P and Aby cats) - so I explained to the owner that I thought it likely that he had a "mild" form of Familial Amyloidosis. But your veterinarians are right - old dogs are where it is toughest to say whether it was "regular" reactive systemic or familial amyloidosis. I would still look. You can never have too much info in a breeding program.

Q: I have had breeder friends with young dogs express fevers after being given LEPTO shots or a series of them. I have in my contracts that giving this shot under a certain age and in tandem with a grouped vaccine will void my six-year health warranty.  BUT I have had friends use Baytril on young dogs that expressed classical fevers or swollen hocks and they subsequently never again expressed. IS there some tandem play here with the nature of the modified Lepto or it is just coincidence?  OR is it possible Baytril somehow modifies the trigger reactive substance in our dogs skin and breaks a type of triggered cycle?  

A: Keep in mind that the most typical pattern for a Shar-Pei with FSF is to have a few episodes while young then not have any more (or very few) for a couple years then suddenly decompensate in kidney failure.  That is what makes it so hard to tell if you have actually helped an individual dog with your therapy.  Unless you can demonstrate that when you withdraw the drug, the signs return, you cannot be certain you've benefited your patient.  So when you have n=1 or even 6, you cannot know if what you are doing is random or not.  Let me give as an example my experience with a new drug that began to be touted as a safe and effective treatment for Cushing's disease (hyperadrenocorticism).  The "old" treatment was effective but used a drug with serious potential side effects so I was eager to try it out.  Soon, a classic case of Cushing's presented itself to me in the form of a pot-bellied Dachshund and I confirmed the disease with testing. I gave the drug and voila!  Dramatic improvement, no side effects.  I was delighted.  Next case came along, same thing.  Wonder drug VBG  Except that I didn't have another dog respond after that for years and then controlled studies came out and showed that the drug was effective – just in only 20% of the cases.  But for my first two cases, I had a 100% response rate and I couldn't understand why my colleagues were all saying the new drug didn't work.  When Dr. Vidt and I say that we see clinical improvement in our patients on colchicine – we are talking over hundreds of patients (maybe even into the thousands now) but the assessment is subjective and anecdotal.  We don't have the data for evidence-based medicine yet.  I am hoping that the results of current research will allow this soon.  But I do think our clinical impressions have the weight of much experience and I'll be shocked to my core if I was totally wrong.  You already saw another response where I talk about "Baytril responsive fever events" and yes, I have seen them and cannot explain them except as I postulated that it might be related to a low-grade infection in the kidneys or elsewhere.  Or this low-grade infection is enough of a stress to trigger FSF events in a susceptible patient.  The vaccination for Leptospirosis is a bacterin and the most likely in my opinion to induce a vaccine reaction of some sort.  I didn't use it at all for many years, deliberately removing it from my vaccination protocol for my patients.  But now we have Lepto in my area and in my clients' home territories and I have to weigh each dog's risk:benefit ratio and make a decision with the owner about giving it.  I attended a Rounds session on one of the veterinary bulletin boards I belong to and the internal medicine specialist (a specialist in renal disease) used as her case report a true story about a Shar-pei with high fever who presented in renal failure – and yeah… the dog had confirmed Leptospirosis.  So no easy answers, I'm afraid but great questions.

Q: Question & Answer co-mingled. We all know that vaccines contains several different toxins

A: What toxins are you referring to?  Remember, I am a visitor to these groups.

Q: Do you think it is possible that the toxins stay in their mucin and that is the cause for Shar Pei fever?

A: No, I don't believe there is a link between vaccination and FSF except that stressful events can act as triggers for FSF fever episodes.  I've had the following reported to me as consistent triggers for FSF events in individual dogs:  a visit to the vet with no injections or treatment given, the grandchildren visit, every Monday after a dog show weekend, a dog fight, etc., etc.

Q: I know you give your Pei vaccines, but mine will never again have one.

A: I lived through the Parvo out-break in the 1970s and I have had to treat multiple out-breaks since then of Parvo and Distemper in unvaccinated dogs including entire breeding kennels.  I'll take my chances with a cautious vaccination protocol.  Risk: Benefit.

Q:  I am also giving my fevering Pei Germanium to see if it can help against fever attacks.

A: I would be interested in hearing if it helps.

Q: I have had 4 different dogs now come down with glaucoma and unfortunately none of the sight in any of them were saved. They are all 4 from different lines and if there is common ancestors it is probably 8-10 gens back but not I can see in a 5 gen pedigree.  Could you cover Glaucoma and treatment recommendations?

A: I asked veterinary ophthalmologist Dr. John Sapienza to write an article about Glaucoma in the Shar-Pei because there are some unique aspects of their disease.  He wrote a great piece, which was published in The Barker last year.  If you would like to email me at wvc@warwick.net, I can send you a copy of that article if you don't have the old copies of The Barker.  This is the best info I've seen on the subject.

Q: I have a male intact dog, (6 1/2 years old), his mom died of confirmed A, I have 3 puppies out of him and all healthy, they are 5 years of age, is there a possibility that he is not affected with A?

A: I would say that current information would suggest that your dog is likely a carrier of the disease and may or may not manifest with fevers or go on to develop amyloidosis.  He could still have amyloid smoldering, but I think it unlikely since his offspring have been without signs at this age.  Fingers crossed.

Q: I have a 4-month-old puppy that has a skin problem going on. It started about a month ago. Since I work in a Vets office and we had had some cases of sarcoptic mange, we thought it was that. He is less itchy, but still is itches.  It mostly is his underside that is affected, black skin and smelly.  Can dogs this young have / exhibit allergies?

A: Have you done an impression smear and cytology of the affected skin?  This sounds a lot like a Malassezia yeast overgrowth, which may occur secondarily with allergies and other skin irritation.

Q:  My Pei has FSF and has recently started colchicine.  She had three fever episodes right a month part. The last one was very serious. She ran a 106 plus degree off and on for two days.  She was very sick. Previous to this she had been taking 1500 mg MSM, 1000 mg Vitamin C and Vitamin E. She also has mucinosis, which does not seem to bother her.  And, in the past she has had reoccurring ear infections that seem to be under control right now.  I am concerned about the frequency of her episode and the fact that they have changed so much. She previous to last had one about once a year.  Her first occurred when she was about two and half.

A: 106 plus degrees is the point at which you need to seek veterinary intervention IMO.  If this were my patient, I would instruct you on giving 50% Dipyrone injectable anytime the fever went over 103.5 or so because of her history of life-threatening fever spikes and give you some to administer at home.  What dose of colchicine is she on now and how often (how much does she weigh too)?  It is rare but S-P can and do die during fever events if the inflammatory cascade gets out of control.  If you have not already done so, get a urinalysis done and possibly a urine culture.  I am assuming your veterinarian checked her blood work and there were no significant abnormalities. FSF episodes can be completely random – which means they can occur in clusters or not at all for years.  What you need to determine is if there are any stressful triggers that are new that might be setting off these events.

Q: What lab work do you recommend for a S-P that occasionally has fevers?

A: This depends on whether we are talking about the initial fever event or routine follow-up exams.  The initial lab tests depend on the findings on physical exam and the history of the event.  With the first attack, I may just run a CBC, blood chemistry screen and urinalysis (UA) or I may run a gazillion tests because something seems "off".  In my area, tick borne diseases are common and easily confused with FSF so I often run these tests.  After the initial work-up and a diagnosis of FSF, I recommend at least annual physical exams, CBC, Chem screen and UA.  I tell the owners if he isn't right, I want the dog back ASAP for exam and possible tests.  If they are vomiting, have diarrhea, wt. loss, change in thirst or patterns of urination or just "ain't doing right", I want to see them (and bring urine!).  Monitoring can be expensive and I find this recommendation gives a balance between cost and caution.  I would say the best test you could run (every 3-6 months?) in an at-risk Shar-Pei is a first morning urinalysis after they have not drank any water during the night.  A dilute urine concentration is usually the earliest warning sign that the dog is losing kidney function – this will occur long before it shows up on blood work.  Proteinuria occurs when there is damage to the glomerular portion of the kidney cortex and since S-P amyloid is laid down there erratically, this is often only a very late finding in advanced kidney disease and can't be relied upon to be a warning sign of amyloidosis.  (If the urine protein to creatinine ratio is elevated in a patient without lower urinary tract disease, this is significant anytime.)  If I get a low urine specific gravity, I advise the owner to repeat it to see if the abnormality is consistent and if it is, we start taking steps to slow the progression of kidney disease to a near stall.  (Kidney disease is progressive no matter what you do but this is one place colchicine may help if it is amyloidosis).  I would start the dog on Eukanuba's Early Stage Kidney Veterinary Prescription Diet at this point (or the owner could cook an equivalent if so inclined).

Q: I am wondering what you recommend for pain?  My boy Mojo was on prednisone for 6 years for itchy inflamed skin until I took him off in 2004 when he began limping and was diagnosed with mild arthritis in his left knee.  Since being off pred his hocks are constantly swollen (huge) and he has difficulty walking and seems to be in a lot of pain. You can see pictures of his hocks under thyroid in the forum.  He turned 7 in October. He was recently diagnosed hypo thyroid and is on medication for this and is also on homeopathic remedies for the pain in his back legs.  His legs seem to be draining constantly lately and the swelling is reduced somewhat from the remedies but I am just wondering what you recommend for pain.

A: This is a good time to talk about chronically swollen hocks.  I think this is where we may be seeing some of the "bad side" of mucin or hyaluranon (I also think there may be a good side).  When mucin/hyaluranon (HA) is damaged, its breakdown products are highly inflammatory.  The breakdown products are removed from the damaged area primarily by the lymphatics and also some through the blood vessels.  I have seen many Shar-Pei present to me over the years with severely swollen hock areas – some so severe that they were continuously weeping a thin mucoid serum into large pools on the exam table.  I believe now that this occurs when the lymphatics and blood vessels draining the hock area (an area where there is heavy mucin accumulation in most S-P) are damaged by the breakdown products of HA.  I think this can occur after an FSF event and sometimes trauma (visualize: two young S-P hauling each other around by their back legs in play VBG)  My treatment for this is two-fold:  low dose alternate morning prednisone at the lowest dose needed to control signs (pred shuts down the production of HA by the fibroblasts and acts as an anti-inflammatory) and pentoxifylline (treats vasculitis).  When I say low dose pred - 5 mg Pred will usually do it but I've used dosages from 2.5-10 mg every other morning only until signs are resolved then only as needed.  This is something you need to discuss with your veterinarian and they can contact me if they have questions (most vets will have never seen a case of this).  It is NOT swollen hock syndrome.  You should never mix NSAIDS with pred.  If I had to control the arthritis pain in a dog on low dose pred, I would use tramadol, which is a very good analagesic with a very wide safety margin.  It is a prescription drug available through your vet or by Rx at human pharmacies.

Q: I have had CSP for 22 years and experienced most of the problems at some time or another.  I have had 3 dogs in these years that would fever and would also get the swollen hocks.  A Vet in Minnesota who has taken care of a large volume of CSP over the past 20 years has through trial and error become the "go to guy" for the CSP people.  For years he has recommended ibuprofen at the first signs of a fever and SHS.  I know this makes some vets/owners shudder.  But...I have always used it when I had these dogs that fevered and it worked amazingly well.  The fever would be gone in roughly 30 minutes and the dogs seemed to feel fine in an hour.  The swelling would be gone by the next day.  It worked every time.  What are your thoughts on the use of ibuprofen during the onset?  I know it works but is it safe to use on a very limited basis.

A: I know the vet you are referring to – he cooperated in some of our early studies.  I've never tried ibuprofen – have seen too many cases of toxicity when the owners give it over-the-counter and frequently overdose them or give it too long.  BUT I have to admit on reflection, that it probably is not a bad choice of NSAID when used once or twice at the correct dose and just not chronically.  I've sat down and figured out the toxicity range when trying to figure out if a dog that has been given ibuprofen by the owners then shows up at my office for whatever the original inciting reason for drugging the dog is at risk for complications and there is a window where it would be safe.  Frankly, I would prefer it to aspirin.  (Aspirin tabs, not willow bark … )  The dose should be determined by a veterinarian and the dog should be getting regular routine blood work and urinalysis done.  Most of the toxicities I've seen are when the dog was given human dosages for days (or ate the whole freaking bottle like one S-P patient of mine - and lived BTW).

Q: Because of dealing in many, many different lines over the years, and never completely getting away from this, I just can't escape the feeling that they are all capable of producing it, given the right circumstances of what mate they are bred to, and how the genes fall into place.

A: I do think there are multiple factors coming into play including environment, penetrance and expression of the genes, which they inherit among other things.  I am hoping that there are "normal" Shar-Pei out there.  I remember the days before I saw my first case of FSF and I do think some dogs are "clear".  The problem is that we don't know who they are and how to identify them.  There were so few dogs back then and all of us were eager to breed to the stud of the month – who inevitably seemed to die young of amyloidosis.  If a breeder didn't have it to start with, they usually saw it within 5 yrs of getting into Shar-Pei actively.  I do think there are "hot" lines – they get it early and they get it bad and they die young and when bred to asymptomatic dogs they stamp their imprint fiercely.  We are all just speculating until we get a test but it is possible your stud dog was `normal" or possibly at worst a carrier.  Without a way to test your dog's potential breeding partners – it's Russian roulette for all breeders.  It is heartbreaking and frustrating.

PS - a definition of Gene Penetrance that I think is important here:

Individuals who have inherited a heterozygous gene mutation, i.e., a mutation inherited only from one parent, may or may not develop a disease resultant from such mutation. The rate of occurrence of a genetic disease among individuals carrying the same gene mutation is known as gene penetrance. Differences in gene penetrance may occur even among individuals with identical genotypes due to several external factors, such as environmental exposure to genotoxic pollutants, inappropriate diet, life style, or drug abuse. The accumulative DNA damage caused by these factors may lead to the damaging of other genes, such as modifier genes, that modulate the mutated gene and its other normal copy, thus contributing to the manifestation of disease, or cause mutation in the other copy (allele) of the gene that was normal at birth. The latter case is known as loss of heterozygosis (LOH), and will induce diseases that require a second mutation, or LOH, such as cancers. Gene penetrance in hereditary cancers is highly variable because it depends on several other factors, including those above described.