Vitamin D supplements for good health

The use of vitamin D supplements is now promoted to the general population, because vitamin D deficiency is now common. For people living with Gorlin Syndrome, who need to minimise exposure to UV, vitamin D supplements are essential, unless your doctor has specifically instructed that you must not take vitamin D. This is a rare circumstance, but it can happen, in certain diseases.

General comments follow:

Everyone needs vitamin D. Recent scientific research indicated that this vitamin is vital for normal function of many body systems, and not only for maintaining our skeletons, by helping us to absorb calcium from our diets (or from calcium supplements). Vitamin D deficiency has been linked to a wide range of disease states including hypertension, depression, schizophrenia, autism, infections, cancers and autoimmune diseases such as multiple sclerosis and type 1 diabetes.

Over the years, I have found several useful sources of information about science and health, such as "Wikipedia" and the Australian ABC, which broadcasts TV shows such as “Catalyst” and radio shows such as “Health Report”, for which transcripts are available online. It is important to note the dates of these articles; this one was from 1999, and gives readers a useful introduction to the topic, but needs to be read in the context of later research:

http://www.abc.net.au/rn/talks/8.30/helthrpt/stories/s63610.htm

This discussion was about people with "normal" resistance to cancer, and not about how people with Gorlin Syndrome need to act, so they implicitly recommend more sun exposure than is advisable for people with Gorlin Syndrome.

Note especially that the expert said that our skin becomes less efficient at turning the precursor molecules into active vitamin D, as we age. No wonder that many Australians over the age of 60 are deficient in vitamin D, even though many of them would still get exposure to sunshine at a level that would suffice, if they were younger. Thus, our aging loved ones also need vitamin D supplements; see this article from ABC “Catalyst”:

http://www.abc.net.au/catalyst/stories/2514231.htm

"Vitamin D (12/03/2009)

Have we taken our fear of the sun too far? We’re told to keep out of the sun – so what are you to think when your doctor tells you that you’re not getting enough of it and as a result you now have a serious vitamin D deficiency? Dr Norman Swan soaks up some rays to find out what is really going on. …......."

Vitamin D is also vital for brain development and function, see:

http://www.abc.net.au/science/articles/2010/09/07/3005303.htm

“Low vitamin D linked to schizophrenia

Tuesday, 7 September 2010 Timothy McDonald”

See the section called “Related Stories”:

“Audio: Link between vitamin D deficiency and schizophrenia (The World Today)

Sun-shy mums may raise MS risk in babies, Science Online, 30 Apr 2010”

Note that vitamin D deficiency has also been implicated in risk of developing multiple sclerosis (MS). There has recently been a breakthrough in identification of genes that are also involved; there is an interaction between the person's genetic makeup and environmental factors including vitamin D levels. This genetic breakthrough was reported on Australian TV; see this article about it:

http://www.abc.net.au/worldtoday/content/2011/s3290760.htm

"New genes found in MS study

Liz Hobday reported this story on Thursday, August 11, 2011 12:46:00

ELEANOR HALL: One of the largest human genetic studies ever undertaken is yielding some promising results for Multiple Sclerosis sufferers.

Scientists say they've found almost 30 new genes linked to the disease and are hoping that this will lead to better treatments. ….......”

Vitamin D is also implicated in our risk of developing certain cancers; see this transcript from ABC “Catalyst”:

http://www.abc.net.au/catalyst/stories/s805444.htm

"Vitamin D and Cancer (27/03/2003)

Medical experts around the world are talking about a new epidemic, a health concern that may be dramatically increasing our risk of cancer, hypertension and even diabetes – it’s a lack of Vitamin D.

Some experts predict that up to 25 per cent of Australians could be Vitamin D deficient. The cause is something that’s been known for nearly a century, a lack of sunshine. There now seems to be a connection between breast, colon and prostate cancer and a lack of Vitamin D.

Even more amazing, one expert believes 25 per cent of breast cancer deaths could be avoided if the women had maintained adequate vitamin D levels throughout their life.

Catalyst’s Karina Kelly investigates research in Australia that appears to show that Vitamin D actually kills cancer cells while protecting healthy cells from sun damage.

Vitamin D can only be made by the body when sunlight falls on skin unprotected by sunscreen. This raises some big questions for Australians who have been living with the sun safe message for the last 20 years. … … "

“Quarterly Advocate” had this article on vitamin D:

http://www.bccns.org/news/2009Winter.pdf

"Multiple Health Concerns Surface as Winter Arrives

Source: Future Microbiology , Nov 23, 2009

CORVALLIS, Ore. – A string of recent discoveries about the multiple health benefits of vitamin D has renewed interest in this multi-purpose nutrient, increased awareness of the huge numbers of people who are deficient in it, spurred research and even led to an appreciation of it as "nature's antibiotic."

On issues ranging from the health of your immune system to prevention of heart disease and even vulnerability to influenza, vitamin D is now seen as one of the most critical nutrients for overall health. But it's also one of those most likely to be deficient – especially during winter when production of the "sunshine vitamin" almost grinds to a halt for millions of people in the USA, Europe and other northern temperate zones. Analogs of the vitamin are even being considered for use as new therapies against tuberculosis, AIDS, and other concerns. And federal experts are considering an increase in the recommended daily intake of the vitamin as more evidence of its value emerges, especially for the elderly.

"About 70% of the population of the USA has insufficient levels of vitamin D," said Adrian Gombart, principal investigator with the Linus Pauling Institute at Oregon State Univ. "This is a critical issue as we learn more about the many roles it may play in fighting infection, balancing your immune response, helping to address autoimmune problems, and even preventing heart disease." Those issues were just outlined in a new publication in Future Microbiology, a professional journal, on the latest findings on vitamin D research, at OSU and in many other programs around the world. ….........”

Note that food in Australia is not supplemented with vitamin D, as far as I know.

Immune function is important for handling infectious diseases, and also for protecting us from cancer. Our immune systems are thought to destroy most tumours, soon after they begin, leaving a minority that somehow avoid this process and grow big enough to trouble us.

__________

Among the “Educational articles” at the USA Gorlin Syndrome site was a reprint from the New England Journal of Medicine (NEJM), which is a reputable medical journal:

http://www.gorlinsyndrome.org/EduDocs/Dermatological/VitaminD/Vitamin%20D%20Deficiency.pdf

“N Engl J Med 2007;357:266-81.

Vitamin D Deficiency

Michael F. Holick, M.D., Ph.D.”

It is a very detailed review of the whole topic of vitamin D, with more information than most of us want to read, but see Table 2 on page 274 – 275, which gives examples of groups that are likely to suffer from deficiency and how to fix it. How can we swallow enough vitamin D? The richest natural sources include codliver oil or lots of "oily fish"; the same ones that are recommended as sources of "omega 3" oil or "fish oil", such as sardines or salmon. Tablets or capsules, each having 1,000 units of vitamin D3, can readily be bought at pharmacies in Australia; I now take 2 to 3 such tablets a day. Higher potency supplements require a doctor's prescription. I was reassured by the information on page 278 that explained that I was not going to “overdose” if I took up to 10,000 units / day, but that 50,000 units a day for 6 months was definitely too much vitamin D. I am obese, and obesity impairs vitamin D utilisation in the body, meaning obese people need twice as much vitamin D as most slim people. Therefore, I am taking around 3,000 units / day, taking into account the various supplements I consume. That intake is safe for me, according to the NEJM article.

Long ago, my doctor had recommended that I take a supplement of 1,000 units / day, and I did so, for a time. For some reason, I had ceased taking it, but I resumed taking vitamin D last year, at 2,000 to 3,000 IU/day, because of what I had read in NEJM. I soon felt healthier than I had felt in years!! (In those ill years, my vitamin D intake was probably 200 IU/ day, or less.) My doctor had also diagnosed me as suffering from “fibromyalgia”. I have read that chronic vitamin D deficiency is often misdiagnosed as “fibromyalgia”because its symptoms are so similar: muscle weakness, aches and pains. My “fibromyalgia”symptoms are much less troubling, now that I am not deficient in vitamin D. I have been able to resume moderate exercise at the gym. I no longer struggle to do basic daily tasks, such as walking, and my use of analgesics has decreased.

Cancer and mutations

People with Gorlin Syndrome have only 1 working copy of a gene involved in the “Sonic Hedgehog Signalling Pathway”; generally the gene called “patched – 1” (PTCH1), but sometimes another of the relevant genes. Most people have 2 working copies of each of these genes, but Gorlin Syndrome results when one copy of a relevant gene is mutated, from conception, in all our cells. You could say that all our cells are therefore just a single - mutation - away from having NO working copy of a vital gene; a gene that can be described as a “tumour suppressor” gene, because it acts to prevent our cells becoming malignant or forming tumours.

Genes occasionally mutate. This is directly relevant to cancer.

In basic biology courses, genetic mutations are generally discussed in the context of inheritance, where the mutation may be passed to descendants. In humans and many other species, only the cells in specialised parts of the organism will pass their genes to descendants. In humans, the ovaries of women and the testes of men contain cells that produce “gametes”: ova from women, and spermatozoa from men. Mutations in ova or spermatozoa are called “germ-line” mutations, because they may be passed to descendants (“germ” is old scientific jargon related to seeds and reproduction). Cells in the rest of our body also accumulate genetic mutations over our lifetime, when the DNA in those cells is damaged, but those are genetic mutations which are not passed to descendants; they will affect only a part of that person's body. Such mutations are called “somatic mutations”, because “somatikos” is Greek for “of the body”. Wikipedia has a brief article about this scientific term.

http://en.wikipedia.org/wiki/Somatic

Many cancers are thought to result from somatic mutations. Therefore, I want to help people living with Gorlin Syndrome to understand what somatic mutations are, and know how they can minimise the rate of somatic mutations in their own bodies and minimise the rate at which tumours begin.

How can we minimise genetic mutations?

Some of the factors causing genetic mutations are not able to be controlled by us. We can (and should) choose to minimise our exposure to UV and to “ionising radiation” such as X-rays, but all of our bodies naturally contain some radioactive atoms and we are exposed to radiation from rocks, bricks and cement, and from outer space (“cosmic rays”), so we cannot avoid all radiation – induced genetic mutations.

In addition, the cellular mechanisms that copy DNA during cell division are not 100% perfect, so occasional mistakes are made in copying genes. There are repair mechanisms operating to fix these errors in DNA replication, but sometimes they fail to correct all the errors, and the alteration in DNA is then copied as the cell multiplies. The mutation is perpetuated in cells derived from the original altered cell.

Since every cell in people living with GS already carries a mutation in a relevant gene, our risk (or rate) of tumour formation is higher than in most people. It is important that we do what we can to avoid a mutation in our single copy of the relevant gene, because loss of that sole copy will cause severe damage to the cell involved, and will generally lead to initiation of a tumour as the cell multiplies.

I will explain what I think we can do about this. What we eat and drink is worth considering.

First, do NOT smoke. Smoke contains carcinogenic molecules; molecules that promote cancer formation. Many increase the rate of genetic mutations. Secondly, diet is worth considering. In my opinion, it is common sense to do what we can to stay well.

Public health experts recommend that everyone should eat certain foods, to minimise risk of cancers. People living with Gorlin Syndrome especially need to do this; I am convinced that it is important and worthwhile. Diet is known to influence rates of tumour formation, and I think this effect will probably be more – obvious in Gorlin Syndrome than in the absence of Gorlin Syndrome, because we are so sensitive to carcinogenic agents. Eating plenty of antioxidant – rich foods will help our bodies prevent or repair the inevitable DNA damage that occurs as we age, even in areas of our bodies that are not exposed to extra radiation.

Green tea is sometimes promoted as a source of antioxidants. It was investigated years ago in the UK as an agent to slow down the rate of BCC formation in people with GS. It seems that "black" tea (that is, Ceylon / Indian style tea) also help to prevent BCCs; I am glad about this, because I drink a lot of “black tea” (with milk).

See this article from "Quarterly Advocate":

http://www.bccns.org/news/2007Summer.pdf

"As Published in Journal of the American Academy of Dermatology, May 2007

Tea Drinkers May Have Lower Skin Cancer Risk

People who unwind with a cup of tea every night may have a lower risk of two common forms of skin cancer, new research suggests. In a study of nearly 2,200 adults, researchers found that tea drinkers had a lower risk of developing squamous cell or basal cell carcinoma, the two most common forms of skin cancer. Men and women who had ever been regular tea drinkers -- having one or more cups a day -- were 20 percent to 30 percent less likely to develop the cancers than those who didn't drink tea. … … …"

It is good to know that tea has many good effects on my body, as well as being a refreshing daytime drink.

Red wine is another source of dietary antioxidants, but there are plenty of non-alcoholic choices; apparently, fruits and vegetables that are naturally coloured red, orange, yellow, purple or green are good sources, too.

I will discuss vitamin D in another post. In brief: take vitamin D, in a supplement!

Australian Gorlin Syndrome Mutual Support Group website

The Australian Gorlin Syndrome Mutual Support Group (AGSMSG) now has its own website:

http://home.vicnet.net.au/~gorlinsyndromesupport/LightNEasy.php?page=Home

The home page features photos taken at some of the lunch meetings of the group, in Adelaide, South Australia.

An introduction to the Sonic Hedgehog Signalling Pathway

As an undergraduate, I did not study the topic "embryology"; how a single fertlised egg grows into an organised animal body, so I am just beginning to grasp the relevant science now, by reading online.  Biological science has progressed fast over recent decades.  Fortunately, the internet can bring resources from afar, for little effort.  The difficulty lies in interpreting what we read.

Do we GS people need to understand anything about the basic science related to this topic?  I think we need to try to grasp it to some extent, especially if we are thinking of taking part in trials of new drug therapies which manipulate the "Sonic Hedgehog" function in our cells, to attempt to reduce the symptoms of GS.  After all, to give "informed consent", a patient needs to know something about what is involved and what is being attempted.  If we are planning to use experimental drugs to alter the function of this pathway, I think it wise to understand something about what is already known about its function.

Some basics:

The Sonic Hedgehog Signalling Pathway is a set of protein molecules in the cell, all of which need to work well, in order to get normal operation of this pathway.  Sometimes, people talk as if the gene is the protein.  This is not quite correct, and may lead to confusion for those who are trying to understand what is involved.  A gene is made of a string of "bases" (these are often written as A, T, C and G) joined together to make DNA, which is found on a chromosome, and a gene can be inherited.  A protein is made of a string of amino acids joined together by the cell, using instructions encoded in the gene.  The protein does the "job" in the cell.  It may help if I use an analogy:

I have recently taken up knitting again.  The gene is quite like the knitting pattern; it is a series of instructions that tells the cell how to knit together amino acids (that come from our diet) to make a protein that can become part of the cell; there are instructions very like those in knitting, such as: when to change to a different colour, knit, purl, add stitches, cast off stitches, slip stitches, repeat a sequence etc.  The protein is the product of genetic instructions in the cell; in knitting, the product of all those crafty instructions is a scarf or a beanie etc.  The knitting pattern can be written on paper, but the knitted product is made of yarn, and can be worn.  I hope that helps readers to picture these minuscule complex things in our cells.

Gorlin Syndrome is caused by a mutation of genes involved the the Sonic Hedgehog Signalling Pathway.  It is a "dominant" characteristic, therefore you see effects of  such a mutation in single dose; where there is one chromosome carrying a relevant mutated gene, while the other chromosome of that pair carries a normal copy of the same gene.

In our BCCs, the mutated gene is not making its "gene product" (which is a protein, like many other gene products), so the rest of the Sonic Hedgehog Signalling Pathway cannot work properly, and so cells grow out of control; a tumour begins.  If it stops working in a few cells while our bodies are still small and just - forming before birth, we develop with a a malformation.

In our other cells, the Sonic Hedgehog Signalling Pathway (SHH) is operating slower than in normal cells, due to the cell having one copy of one of the genes instead of 2 copies; this causes the various malformations found in many people with GS, such as bifid ribs, anomalies of vertebrae, incomplete dentition, extra fingers, missing fingers or a large cranium.  However, most cells in our bodies behave almost normally, unless they lose the remaining copy of the gene; this transforms them into a malignant cell.  Will the body kill that cell, or will the cell multiply and form a significant tumour? What happens next depends on various factors, including the presence of other genes.

An article in the US group's "Quarterly Advocate", explained something about the genetics and mutations which lead directly to tumour formation:

http://www.bccns.org/news/2007Fall.pdf

"Basal cell nevus syndrome is caused by a tumor suppressor gene, called PTCH, located on chromosome 9. Mutations in this gene may increase the risk of ovarian cancer.

Tumor suppressor genes usually control cell growth and cell death. Both copies of a tumor suppressor gene must be altered, or mutated, before a person will develop cancer. With basal cell nevus syndrome, the first mutation is inherited from either the mother or the father in 60 percent to 80 percent of cases. In 20 percent to 40 percent of cases, the first mutation is not inherited and arises de novo (for the first time) in the fertilized egg from which the person with symptoms was conceived. Whether de novo or inherited, this first mutation is present in all of the cells of the body and, as such, is called a germline mutation.

Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. For example, if the second mutation is in the skin, then skin cancer may develop. If it is in the ovary, then ovarian cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of PTCH is just the first step in the process. What causes of these additional mutations to be acquired is unknown. Possible causes include chemical, physical, or biological environmental exposures (such as sunlight) or chance errors in cell replication.

Some individuals who have inherited a germline tumor suppressor gene mutation may never develop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family, when, in reality the mutation is present. Persons with a mutation, regardless of whether they develop cancer, however, have a 50/50 chance to pass the mutation on to the next generation.

It is also important to remember that the gene responsible for basal cell nevus syndrome is not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father's side of the family."

Why does the PTCH1 gene sometimes completely stop working in a cell?  See my blog on “Genetics and Lifestyle”.


This recent article in "DermNet NZ", published by the New Zealand Dermatological Society Incorporated, is a good brief summary of the genetics involved, including Gorlin Syndrome:

http://dermnetnz.org/pathology/bcc-genetics.html

It was published 13 July 2011, and mentions several several genes:

"There is evidence that mutations in the PTCH1, PTCH2, SMO and SUFU genes predispose patients to BCC."

although later, it still attributed (all) GS to heritable mutations in PTCH1.  In the Orphanet paper, in the "Etiology" section:

http://www.ojrd.com/content/3/1/32

"The PTCH1 gene has recently been mapped to the long arm of chromosome 9 (q22.3-q31) with no apparent heterogeneity [8,96]. Approximately 50% of NBCCS patients have allelic losses including this site..."

Some other scientific resources say that around 80% of us have a mutated PTCH1 gene.  Anyhow,  the remainder have mutations in other genes that are involved in the Sonic Hedgehog Signalling Pathway; genes other than PTCH1, which is short for "patched homolog 1".  So far, there is a generally - available DNA test only for PTCH1, so genetic testing is of limited benefit in families affected by GS.  It may be worth testing the children, if testing of the adults in the family has already shown that family's GS problem is due to PTCH1 mutation.  Otherwise, the diagnosis still depends on detection of symptoms and signs.  After all, this is a "syndrome"; it is not defined by the presence or absence of a certain gene.

That paper says a few things about another "Patched" gene in humans; PTCH2.  It seems that losing one of your copies of PTCH2 does not cause GS on its own, but having a mutation in PTCH1 as well as a mutation in PTCH2 leads to the symptoms of GS being worse than when it was only PTCH1 that had mutated.  This is how I understand the paragraph where they say:

"In striking contrast to PTCH1-/- mice, PTCH2-/- animals were born alive and showed no obvious defects and were not cancer prone [135]. However, loss of PTCH2 markedly affected tumor formation in combination with PTCH1 haploinsufficiency. PTCH1+/-PTCH2-/- and PTCH1+/-PTCH2+/- animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with PTCH1+/- animals [135]. Therefore, PTCH2 modulates tumorigenesis associated with PTCH1 haploinsufficiency [135]."

I think it can be "translated" like this:

- you can build a normal body without any functioning PTCH2 genes, but not without any functioning PTCH1 genes

- having only 1 normal copy of PTCH1 gave symptoms of GS, when there were 2 copies of the normal PTCH1 gene present

- in animals with only 1 normal copy of PTCH1, there were more symptoms of GS, when there was only one copy of the normal PTCH2 gene present; when there was a mutation in both PTCH1 and PTCH2

See also the section "Other genes of importance in BCC risk", as having fair skin is known to make BCCs a major feature of GS, while GS people with very dark skin have few BCCs.  Only sophisticated genetic tests (not yet widely available) can determine whether we have any mutations in the other relevant genes which will increase the risk of us developing tumours.

The drugs mentioned in the section "Experimental therapies based on BCC genetics" are giving hope to families affected by GS that the children might access effective therapies that will effectively neutralise the symptoms of GS, but it is important to be aware that these drugs are still experimental, and that altering the function of SHH can have very unpleasant, even catastrophic, side effects.
The Wikipedia article explains it in some detail, but you need a science education to follow it all.

http://en.wikipedia.org/wiki/Hedgehog_signaling_pathway

I will "translate" a few bits:

It says: "Mammals have three Hedgehog homologues, of which Sonic hedgehog is the best studied".

We have 3 versions of these sets of genes, in contrast to a single set of these genes in fruitflies, and each version might have its special role, but researchers so far have focussed on the set called "Sonic Hedgehog".   (The other sets in humans are called "Desert Hedgehog" and "Indian Hedgehog".)

"The pathway is equally important during vertebrate embryonic development."

These SHH pathways need to operate normally during the formation of our organs, before we are born, in order that the body will have the correct components in the correct places.

"In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract and lungs fail to develop correctly."

These are mice in which scientists have destroyed these genes, while the mouse babies are tiny embryos, to see what would happen to the mouse foetuses as they develop.  They do not form organs correctly.

"Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues."

These genes also need to operate sometimes after we are born, but just when and where they are needed, eg to repair damage to body parts; to make the nearby cells multiply in order to rebuild damaged bits.

"The pathway has also been implicated in the development of some cancers."

If they operate at the wrong times, it results in cancer.

"Drugs that specifically target hedgehog signaling to fight this disease are being actively developed by a number of pharmaceutical companies."

These drugs turn off the "hedgehog" genes, which offers hope to those people with Gorlin Syndrome in whom the tumours are really badly out of control ..... but there are going to be side effects to turning off this important "repair" pathway.

Once we have grown, it is involved in repair of damaged body areas, according to Wikipedia: see the parts on "Role" and "Human disease" eg:

"Hedgehog signaling remains important in the adult. Sonic hedgehog has been shown to promote the proliferation of adult stem cells from various tissues, including primitive hematopoietic cells[25], mammary[26] and neural[27] stem cells. Activation of the hedgehog pathway is required for transition of the hair follicle from the resting to the growth phase.[28] Curis Inc. together with Procter & Gamble are developing a hedgehog agonist to be used as a drug for treatment of hair growth disorders.[29] This failed due to toxicities found in animal models.[30]"

NB: Oxford Dictionary:

http://oxforddictionaries.com/view/entry/m_en_gb0013990#m_en_gb0013990
"agonist

noun
1 Biochemistry; a substance which initiates a physiological response when combined with a receptor.  Compare with antagonist"
(I think that makes the "hedgehog agonist" something that turned the hedgehog gene ON.)
Scientists need to know more about these matters, if they are ever to manipulate stem cells to fulfil their theoretical potential that receives so much "hype" in the media.  Meanwhile, they aim at simpler goals eg:

"Biotech companies are also attempting to turn this pathway on after a patient has a stroke or heart attack."


Safety first:

There has been a "real life" example of the unfortunate effects, on unborn animals, of cyclopamine; a drug that affects the SHH pathway.   An article about this can be read online in the "Quarterly Advocate":

http://www.bccns.org/news/2006Spring.pdf

"The Curious Case of The One Eyed Sheep
Matthew Herper. Forbes. New York: Nov 28

How a freakish birth defect among Idaho lambs 50 years ago has led to a powerful new cancer treatment.

Idaho sheep ranchers couldn't figure out why, in the decade after World War II, a random batch of their lambs were being born with strange birth defects.  The creatures had underdeveloped brains and a single eye planted, cyclopslike, in the middle of their foreheads. In 1957 they called in scientists from the U.S. Department of Agriculture to investigate.

The scientists worked for 11 years to solve the mystery. One of them, Lynn James, lived with the sheep for three summers before discovering the culprit: corn lilies. When the animals moved to higher ground during droughts, they snacked on the flowers. The lilies, it turned out, contained a poison, later dubbed cyclopamine, that stunted developing lamb embryos. The mothers remained unharmed. The case of the cyclopamine and the one-eyed Idaho lambs remained a freakish chemistry footnote for the next 25 years; researchers never could uncover why cyclopamine caused birth defects...."


See the article for the rest of the story.  It will become clear why drugs affecting the SHH pathway may never be safe in pregnancy.  In the present experimental trials of other drugs affecting the SHH pathway, children are not allowed to participate.  I assume this is normal in trials where the effects might be seen in adults, but there would also be some concern that such drugs, known to be able to disrupt normal body construction, might permanently harm children.  Among adult volunteers, there are reports of severe side effects such as loss of hair and sense of taste.  On the other hand, some GS people taking the SHH inhibitors in trials are thrilled with the good effects; see:

http://www.skinandallergynews.com/resources/rss-feeds/single-article/aad-oral-vismodegib-promising-for-basal-cell-nevus-syndrome/545d88a3f3.html


In this article about Vismodegib (formerly known as GDC-0449), they mentioned something that has been said at a few of our GS group's lunches: "These patients have terrible phobias after undergoing tons and tons of biopsies and surgeries, so they're really incredibly grateful for this drug."  I can understand why!  I have come to dread having more surgery, but I had more excisions in recent months.  I will put up with a lot of trouble from Aldara side effects, if it keeps me away from the scalpel, and I hope to try PDT one day, but I am nervous of these new drugs; they are powerful and may upset various body systems.

Meanwhile, we can try to minimise our numbers of cancers, by other means such as sunscreen.  Diet is probably important, too.  I will write more about that later.

Sensory effects of Gorlin Syndrome

See the US group's newsletter "Quarterly Advocate":

http://www.bccns.org/news/2006Fall.pdf

"Update on St. Louis BCCNS Symposium Written by: Dr. Maulik Shah

On May 2nd and 3rd of 2005, the BCCNS Life Support Network in conjunction with the Departments of Dermatology and Pediatrics at Saint Louis University held a very unique conference in St. Louis, MO. This conference was one of the first of its kind where the participants were medical professionals, research scientists and persons with BCNS as well as their family members. This colloquium was an incredible success. As part of this conference, persons with BCNS were asked to fill out a number of surveys to document their medical history and information. In addition, BCNS members underwent clinical evaluations including eye exams, orthopedic exams, hearing exams and skin exams. For many people, we also managed to collect tissue samples, serum and DNA for research purposes. As you can see, the scope of this conference was quite far-reaching but everything went well thanks to the participants and the many people who helped organize the meeting. ..."


A few of their findings relevant to function of the nervous system and senses:


"36% of BCNS persons had strabismus, an eye condition where one or both eyes do not align properly. ...

Chalazion, an abnormal nodule of the eyelid, often associated with the glands of the eye, was found in 29% ...

Nystagmus ...in 12% of BCNS persons. Nystagmus is an involuntary movement of the eye or when an eye twitches without a purpose.

5% of BCNS persons had a coloboma or a gap in the nerve going to the eye. ...

A large number of BCNS persons (approximately 36%) had some degree of hearing loss. If hearing loss was present, it was more likely to affect both ears rather than just a single ear. ...

22%, had mild hearing loss. About 12% had moderate hearing loss; 5% had hearing loss that would be qualified as profound. ...

Overall, BCNS does play an important role in quality of life. We are currently trying to further analyze this data to understand what aspects of the medical condition or treatment have the greatest effect on quality of life. In addition to the SkinDex, we analyzed the CES-D information. The CES-D is a depression scale used to identify persons that may be at risk for developing clinical depression. Interestingly, about 50% or half of those filling out the survey would be categorized at risk for clinical depression and in need of further assessment. ..."


See the article; it is quite readable.  I found it encouraging to read about what a group of GS people can achieve in furthering knowledge about the syndrome, with the help of interested experts.


My personal observations:

I have suffered from clinical depression.  The antidepressant “mirtazapine” has helped me greatly.

My hearing is considered normal in tests, but I have long experienced trouble when trying to converse where there is a lot of background noise.

High glare overloads my eyes and brain badly.... really, a lot of any kind of stimulation is unpleasant to me!  (I am blue eyed and introverted, so these observations might have little to do with GS.)

My physical coordination is imperfect; if I try to run, I soon trip.  A few years ago, a neurologist told me that my right leg is "partially denervated".  The right foot often twitches, and there is decreased sensation; I can develop blisters without feeling the injury.  When I am unwell, my gait can become unsteady, and my right leg is more wobbly than the left; giving less support as I walk.  (Use of Aldara on my BCCs has this effect on me, sometimes.)

My hand : eye coordination is not good "at speed"; even when young, I could not SEE a moving squash ball, much less hit it!  When I was young, I could see larger balls, eg tennis balls and hockey balls at school, but the last time I attempted to play tennis (age about 45), I was completely unable to tell where the ball was, once it began to move and was airborne.

I was very interested to read about the vision defects which they found in participants with GS, because my eyes flick a lot; this has become more of a problem as I aged and when I have been more stressed.  They also like to diverge; my eyes can jump around between 14 to 18 units of divergence when they are unfocussed.  My optometrist tells me that normal eyes range from 0 (both eyes aiming in the same direction, when completely relaxed) to 2 (the eyes aiming slightly outwards, when completely relaxed).  One optometrist told me, several years ago, that my eyes actually take it in turns throughout the day to "run" my vision, for walking around etc.  If I exert some concious effort, I can make them aim at the same target for normal binocular vision to do fine work, but if I am tired / stressed/ unwell, those times are brief; soon, one eye soon wanders off.  If I look in a mirror, and relax, I can use one eye to see the other one flick away and aim outwards; alternating as I choose.

Have you had regular eye checks, including measuring divergence?  I had a severe problem when severely - stressed several years ago (age around 30).  I suffered severe chronic eye pain, due (the optometrist told me then) to the eye muscles being overworked, as they tried to tug my eyes together numerous times each day, forcing them to act as a team, to do a certain task in that job, while they soon diverged again, requiring another effort to make them operate as a team.  I was prescribed eye exercises as are generally used for small children, which helped me a bit.  Changing jobs was a more potent fix, for me.

These days, I let my eyes "do their own thing" most of the time; most of the time, I am using vision out of one eye at a time ("alternating monocular vision").  Sometimes, I notice the eyes change over as I am walking or doing other simple tasks.  Mostly, I have my attention on other things, so I do not pay the changeover much attention.  For many tasks in the lab now, I consciously use input from one eye only; I look over my specs for very fine work, and let the eyes diverge, and just use monocular vision, then force binocular vision for a moment, and back to monocular.  This strategy helps me detect tiny details that are important in my work.  Age 56, I have very little accommodation in my lenses now, but as I am very myopic, I can still see very small things with unaided vision, if they are close enough.  I have read online, where other folk with alternating monocular vision have posted on internet forums, that they feel their eyes regularly swap tasks as they read; eg one eye reads the left side of the page of text, and the other eye takes over to read the right side of the page.

How is your eyesight and hearing?  Like me, were you unaware that some of those oddities can be part of GS?

As for other sensory losses, how is your sense of smell?  When Dr Georgia Trench confirmed to me that I have GS, she specially asked about smell, and about no other senses.  I was astonished that this oddity was also part of GS!  Before that day, I had often noticed there was something odd about my sense of smell.  It is not complete anosmia (lack of a sense of smell) but I often have great difficulty in detecting odours that seemed powerful to other people.  Georgia told me it is transient; that my sense of smell will come and go.  And I found that is true!  Working in a clinical microbiology laboratory, we use our sense of smell to help us work out what a certain bacterial culture may be, and to detect certain organisms such as yeasts.  Some bacteria generate odoriferous molecules that are offensive or “eye watering”, yet on some days, I am almost "blind" to those really pungent pongs... while I can smell all sorts of subtle odours, on another occasion.  Occasionally, I wonder how transient partial anosmia can occur; what physiological changes underly these transient changes.

Have you noticed similar sensory impairment?

Indoors sources of UV

These should be shielded by material that absorbs UV,. Otherwise, replace them, or at least keep them at a distance from your skin.

I do not wear sunscreen every day. I apply it only when I plan to be out of doors for a significant amount of time, without other means of shading my skin, such as an umbrella or long sleeves. I use Hamilton's “Quadblock”, on days when I apply sunscreen. I like it for holidays, when I am hiking and sightseeing, but it is tedious to apply sunscreen properly on all skin, and leaves me feeling “greasy”, so it is not a daily routine for me. I also worry a little about the safety aspect of applying such chemical agents to skin; I wonder how safe the substances are. I will use them, when necessary, but not every day if there is little UV risk.

When I am indoors, I expect to encounter no UV sources, but we may have such indoors exposure, without realising it. Did you know that some lamps can emit significant levels of UV, and should not be used indoors near people with Gorlin Syndrome? Any light source that emits a bright – white light may emit UV; you need to be careful when buying lamps, and investigate the properties of the radiation emitted by the apparatus.

This is why you need to be careful about choosing light sources for the home:

Modern lighting is generally designed to deliver light of a type similar to sunlight. Candles, and other fires, deliver red to yellow light, but modern people desire brighter and “whiter” light than that; even old incandescent globes delivered a yellowish light, that is seldom desired for work and study, now. This brings the risk of UV exposure, indoors.

Visible light is part of the “electromagnetic spectrum”. Red light has the longest wavelength, and blue / violet light has the shortest. The range of energy is the reverse: blue / violet light has photons of higher energy than red light. Just outside the ranges of wavelength and energy are infra – red radiation (heat energy, that is longer wavelength and lower energy than red light) and, at the other end of the spectrum of visible light, is ultra - violet light (shorter wavelength and higher energy than violet light).

You can view diagrams of these relationships here:

http://en.wikipedia.org/wiki/File:Electromagnetic-Spectrum.png

http://en.wikipedia.org/wiki/File:EM_spectrum.svg

Much background information on the nature of light, and other electromagnetic radiation, can be read in the source pages at Wikipedia (it might be too much information!):

http://en.wikipedia.org/wiki/Light

http://en.wikipedia.org/wiki/Electromagnetic_spectrum

has a table of wavelength, frequency and energy of photons of the different types of EM radiation.

Why do sources of visible light emit UV? It depends on details of the physics involved. I am not a physicist, but I will attempt to explain some of the principles involved.

Heat an object (that does not burn or evaporate) and it will glow dull red. Heat it more, and it glows yellow. Hotter still, it will emit light that is more white. Heat it more, and it will emit some UV as well. To generate very high energy radiation, such as X rays, the temperature must be very high, and special apparatus is required.

The change in colour results from more high energy photons being emitted, as well as the lower energy photons; as the temperature rises, first yellow and then blue parts of the spectrum are being emitted, and as they mix with the red, the overall colour is white light …. eventually …. if you achieve a high enough temperature. This is the principle of an “incandescent” light globe. See Wikipedia, if you want more info on the physical principles:

http://en.wikipedia.org/wiki/Incandescent_light_bulb

I note the experts are warning that some people need to be careful near these globes, but the warnings are possibly being inadequately - disseminated to those who most need to know, such as people with Gorlin syndrome. See this section:

" Health issues

Although some sources claim fluorescent lighting causes more health problems than incandescent lighting (see Light sensitivity and Over-illumination for discussion), more research needs to be done in this field. According to the European Commission Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) in 2008, the only property of compact fluorescent lamps that could pose an added health risk is the ultraviolet and blue light emitted by such devices. The worst that can happen is that this radiation could aggravate symptoms in people who already suffer rare skin conditions that make them exceptionally sensitive to light. They also stated that more research is needed to establish whether compact fluorescent lamps constitute any higher risk than incandescent lamps.[74] "

As I read this next quote, I realised I need to discuss this matter with my workplace, as we have begun using poorly – shielded compact fluorescent lamps in the desk – lamp fittings with which we illuminate our personal workspaces, so there is excessive exposure to UV, during the work day. See:

http://en.wikipedia.org/wiki/Fluorescent_lamps_and_health

“Ultraviolet radiation risk

Some fluorescent lamps emit ultraviolet radiation that in some circumstances can exceed safe levels. The Health Protection Agency of the United Kingdom has conducted research that concluded exposure to some compact fluorescent lamps (CFLs) for 1 hour per day at a distance of less than 30 cm can exceed safe levels. Touching the exposed bulb results in equivalent exposure to ultraviolet radiation as that of being in direct sunlight.[13]

In 2009, Natural Resources Canada released a report [14] describing the UV exposure due to lamps of several types. The report states that at 3 cm distance, the recommended daily exposure to ultraviolet radiation for skin and eye damage was attained between 50 minutes and 5 hours depending on the type of lamp; the report observes that such a close distance is unlikely in actual use. The report states that most bare spiral lamps tested gave off more UV than the 60 watt incandescent lamp tested, but that the double-envelope CFLs emitted less UV. At 30 cm distance, the recommended maximum daily exposure was attained between 3 hours and 6 hours, with little difference between the studied 60 Watt incandescent lamp and any bare-spiral CFL. The report states that the Threshold limit values used represent otherwise healthy individuals who are not experiencing any hypersensitivity conditions or exposed to substances that increase UV sensitivity. Outdoor sunlight can supply the maximum recommended daily UV exposure in 20 to 100 minutes.”

The first sort of lamp that alarmed me was the “Halogen” lamp; an incandescent lamp that runs at much higher temperature than the old – style incandescent lamps which emitted a yellow light, with less of the high energy radiation that is greater risk to us. Unfortunately, these old style lamps are being phased out, as experts consider they use too much electricity for the amount of light emitted. Such globes can still be purchased in odd sizes and fancy shapes. I have several stored; I hope that stock suffices until better choices are available. I hope that LED lights may provide us with better choices, once they are available in shops.

See:

http://en.wikipedia.org/wiki/Halogen_lamp

Some halogen lamps do emit UV, or "near UV" radiation, able to cause sunburn. In a modified halogen lamp, the tungsten filament emits UV but the glass, and maybe other layers of filters, block UV from reaching users. You need to find out if these safety filters are in place. I have long considered halogen lamps unsafe for use near the skin, after I read a warning about them, many years ago; before I knew I had Gorlin Syndrome. See:

"High temperature filaments emit some energy in the UV region. Small amounts of other elements can be mixed into the quartz, so that the doped quartz (or selective optical coating) blocks harmful UV radiation. Hard glass blocks UV and has been used extensively for the bulbs of car headlights.[12] Alternatively, the halogen lamp can be mounted inside an outer bulb, similar to an ordinary incandescent lamp, which also reduces the risks from the high bulb temperature. Undoped quartz halogen lamps are used in some scientific, medical and dental instruments as a UV-B source."

and:

"Spectrum

Like all incandescent light bulbs, a halogen lamp produces a continuous spectrum of light, from near ultraviolet to deep into the infrared. Since the lamp filament can operate at a higher temperature than a non-halogen lamp, the spectrum is shifted toward blue, producing light with a higher effective color temperature."

and

"Additionally, it is possible to get a sunburn from excess exposure to the UV emitted by an undoped quartz halogen lamp. To reduce unintentional UV exposure, and to contain hot bulb fragments in the event of explosive bulb failure, general-purpose lamps usually have a UV-absorbing glass filter over or around the bulb. Alternatively, lamp bulbs may be doped or coated to filter out the UV radiation. When this is done correctly, a halogen lamp with UV inhibitors will produce less UV than its standard incandescent counterpart."

The next type of lamp I expect to see sold widely is based on light-emitting diodes (“LED”). The physics involved in generating the photons (light energy) is harder to understand, so just focus on the safety statements, unless you are a physicist; see the last 2 sentences here:

http://en.wikipedia.org/wiki/LED

"White LEDs can also be made by coating near ultraviolet (NUV) emitting LEDs with a mixture of high efficiency europium-based red and blue emitting phosphors plus green emitting copper and aluminium doped zinc sulfide (ZnS:Cu, Al). This is a method analogous to the way fluorescent lamps work. This method is less efficient than the blue LED with YAG:Ce phosphor, as the Stokes shift is larger, so more energy is converted to heat, but yields light with better spectral characteristics, which render color better. Due to the higher radiative output of the ultraviolet LEDs than of the blue ones, both methods offer comparable brightness. A concern is that UV light may leak from a malfunctioning light source and cause harm to human eyes or skin."

So, if you want a LED - based lamp for "white light" as in lighting a room, or for reading, you may be offered a lamp that emits UV ... or you may not; we still need to be careful, when buying "white" LED lamps. They will need UV – absorbing filters.

It is hard to keep up with all the issues.

Genetics and lifestyle

I recommend the material, available for all to read, at the American group's site. They have numerous excellent "Educational articles" and a newsletter called the "Quarterly Advocate".  I intend to refer to these materials in many of my posts, but I will analyse them and comment.
The "fall 2006" issue can be read here:

http://www.bccns.org/news/2006Fall.pdf

It included an article called "The Genetics of Gorlin Syndrome: A Primer”
Written by: Sherri J. Bale, Ph.D., FACMG, Clinical Director, GeneDx, Inc.

Readers of this blog may find it a useful way to begin to understand how this syndrome can be inherited.  In my comments on this article, I mean no disrespect to the author; it is just that there are some other things which I consider worthy of mention.

(1) This syndrome results from a malfunction in the "Sonic Hedgehog Signalling Pathway", which has more than the single component controlled by the PTCH1 gene, also called "Patched 1".  That is why it is described as a pathway.  Some cases of Gorlin Syndrome result from a mutation in one of the other steps of the pathway, such as the gene called "Smoothened" ("SMO").  At present, patients can access a genetic test for PTCH1 mutations, but not for changes in other parts of the pathway.

The severity of symptoms varies between people with GS.  Much of this variation must depend on the person's environment, especially their exposure to carcinogens, such as UV and Xrays; see point (3).  One genetic factor influencing severity of GS has been identified; some people carry a mutated PTCH2 gene, as well as a mutated PTCH1 gene, according to the section on "Etiology" in this scientific review of relevant research:

1. Nevoid basal cell carcinoma syndrome (Gorlin syndrome)
Lorenzo Lo Muzio
Orphanet Journal of Rare Diseases 2008, 3:32doi:10.1186/1750-1172-3-32
The electronic version of this article is the complete one and can be found online at: http://www.ojrd.com/content/3/1/32

It is in technical language for scientists and doctors, but it explains that carrying a mutation in one of our copies of both PTCH2 and PTCH1 leads to greater severity of GS symptoms than when only PTCH1 is mutated.  A mutation only in PTCH2 seems to have no effect in people who have 2 working copies of PTCH1.


(2) The author described the GS as: " 'inherited', or passed from one generation to another."

This is not quite accurate; see later where she refers to those of us with GS who have 2 unaffected parents.  We are "new mutants" or as she termed it, we "resulted from de novo mutation, meaning that they represent the first occurrence of a mutation of the PTCH gene in their family".  A better term for the situation is to describe GS as "heritable" = "able to be inherited".  If _you_ have GS, there is a 50% chance, each conception, that your baby will have GS..... if you choose to have children (I chose to remain childless).  If you want children, there are ways to avoid passing on GS; see a genetic counsellor.  Science IS advancing, especially in genetics, so maybe they will develop a way to screen your embryos for the GS mutation (if you are using IVF).  A man with GS might simply choose to use donor sperm to inseminate his wife.

For a list of Australian Genetic Counsellors, see my post"Brochure for patients and carers". The url:

http://gorlinsyndromeaustralia.blogspot.com/2011/08/brochure-for-patients-and-carers.html

(3) My understanding is that having a "mutated PTCH gene" is not quite like having a gene "for" GS, like having a gene "for" red hair or "for" any of the simple single - gene disorders; in GS, we have only a single copy of a very vital gene (PTCH1) which keeps a cell doing what it is supposed to do as a normal part of the body, that lives only to serve other cells of the body.  Anything that causes that single copy of the PTCH1 to stop working is likely to lead to trouble for the body.  And bad things do happen to genes, all the time; they can be broken or lost from cells as the cells multiply ... just by chance ("bad luck", you might say).  Sometimes, when all chromosomes are copied as part of cell division, the 2 copies of exactly the same chromosome end up in the same daughter cell, instead of each daughter cell getting a copy of each separate chromosome; if the 2 "dud" copies end up in one daughter cell, that cell goes on a wrong path from then on, multiplying to form a tumour, and the 2 good copies in the other daughter cell keep it acting normal, as before.  The scientific term for this is "loss of heterozygosity":

http://en.wikipedia.org/wiki/Loss_of_heterozygosity

These little errors happen all the time, as cells copy their DNA and divide; no process is perfect.  Next division, there could be the "dud" section of DNA on both chromosomes in the same cell.  That cell can no longer carry out the normal function of PTCH1, and a tumour may develop from it, as it divides.

If such a mutation happens in a cell in the testis or ovary, in cells that form gametes for the next generation, then the change might be passed to the next generation if ... a BIG "if"  ... if the altered ova or sperm happens to combine with the other partner's gamete, to form an offspring.  This is a "germline mutation" since it occurred in the cells that will form the "germ" of the next generation.

If such a mutation happens in the cells of other organs, it is called a "somatic mutation", and these cannot be passed to the next generation.  I think that the significance of "somatic mutations" is not taught about to students in schools as often as it should be, because it DOES still matter; it is thought to be a major factor in formation of tumours such as cancers. According to the "multi - hit hypothesis" of how cancers start, a cell only turns into a cancer cell after 2 or more changes in it have occurred, and we who have GS are already 1 significant step along the path that converts a normal cell into a tumour cell .... in ALL .... yes, all .... of the cells in our bodies.  But we can still slow down the rate of the other changes that occur to cells as they travel towards the state we call "malignant".  It is vital that we do so.  We have much less "leeway" to be careless with our DNA, compared to "normal" people.

What can we do to make our personal health outcome the best possible?  Try to minimise things in our environment that make these errors more likely to happen or harder for cells to repair before the next cell division happens; as far as I know, from then on, the error in part of the DNA cannot be repaired; it is copied.  Minimise exposure to carcinogens such as UV radiation and Xrays.  I reckon it is best to give up smoking, or never ever start smoking, and as far as I know, eating a diet rich in antioxidants helps our cells reduce or repair the occasional DNA damage, before it leads to longterm trouble.

To put it another way, health authorities advise everyone to minimise their risk of cancers by doing these things.  For GS people, it is very important that we take these precautions.  We still need regular checkups and must treat some tumours, but by being careful, we can minimise the number of tumours, and have a good life.

My journey with Gorlin Syndrome (part 1)

I met Dr Georgia Chevenix- Trench, in the 1990s, when she came to Adelaide. In collaboration with research groups around the world, the research group at the Queensland Institute of Medical Research was hoping to find and study "the gene for Gorlin Syndrome". An initial step in this kind of research involved taking samples from people with GS and from their close relatives, and comparing their chromosomes, to discover which chromosome was physically altered to cause GS. Georgia examined me and took blood, confirming that I do indeed have GS, but she told me that nobody would use my case to represent GS in a medical text book, as I was so mildly affected. She examined my parents, and took blood from them as well. In those days, they occasionally mailed a "BCNS Newsletter" to update the participants, and Georgia also contacted me a few more times, after our meeting. Georgia asked me to write something about the effects of GS on my life, as they were relatively mild; she hoped it would encourage those who were frightened by the medical literature, which generally emphasise the severe effects of GS. She mentioned how worried they were about a certain 18yo girl who had become depressed on learning she had GS. I wrote my article, and Georgia said it had helped the girl, and she also published it in the "BCNS Newsletter".

I just found the issue in which my story appeared, in February 1994. It was in my shed, in a folder full of the medical papers I copied and read soon after diagnosis; as a scientist, it was how I coped at the time. I felt that knowledge was power, and it enabled me to think of ways to keep the impact of GS on my life as mild as possible. Later, for several years, I seldom thought of GS: I just took care of my skin, and had checkups and excisions when necessary, but in between I tried to "think normal". There are other issues in life, after all.

I will tell my recent story at another time, but note a few updates for now:

I wrote this article in 1994; since then, Dad had his third melanoma; a “Hutchinson's Freckle”; it came back, years after excision, and killed him in 2007 at 90 years. Mum died at 89 years, in 2010. She was always well, until she developed bowel cancer at 86 years (newly widowed) then myeloma at 87 years; that killed her.

I now call GS“ Gorlin syndrome” ; omitting the “'s”.

My BCC tally is now around 75, counting those that were excised and tested. I have used Aldara cream many times, seeing hundreds of spots reacting, most of which were probably tiny (“sub –clinical”) BCCs; the early stage is called “naevoid” --- or“nevoid”, in American spelling.

Age 56 now, new oral cysts are unlikely, but others in the Adelaide group have had oral cysts in midlife, so I should organise a check for that, one of these days. Kristi Schmitt Burr, Executive Director BCCNS Life Support Network, recently wrote to me: “World Health Organization determined that our oral cysts should be called Keratocystic Odontogenic Tumors (KCOT or KOT) and that oral cysts is too wide an identifier. If we are educating our members about the presence of these invasive growths, and the nature of their rapid advancement, I suggest using the new global term.” The people I met who had “incomplete dentition” (missing teeth) did not have GS; this sign can occur in other situations.

Dad's brother is still alive, and doing OK for a man in his late eighties.

Once the PTCH1 gene was found, its function was soon understood, as similar genes had been extensively studied in Drosophila fruit flies and in mice.

Georgia told me that about 30% of GS people in her lists are "new mutants" and she commented that is a high % for a condition that does not prevent people having children. I never wanted to have kids, so all is well; my little deletion ends with me. BTW, she let me know that mine was small, as that fact had saved them a huge amount of work, in locating the gene "for" GS, back then. Great timing! I had only realised that I had GS a few days before Georgia was due in Adelaide, on that last trawl for blood etc before the big "push" to track down the DNA sequence. I am a scientist, so I was thrilled that my appearance on the GS scene (so to speak) saved them a lot of lab work; that GS gene had to be somewhere in the small bit of DNA missing in one of my chromosome, and they found what was necessary.

Being a carer for my elderly parents, plus working, plus my chronic fatigue + pain (fibromyalgia) kept me ..... busy / stressed / stretched, in recent years. Now, I have time to take care of myself.

From "BCNS Newsletter" February 1994:

In June 1993, at the age of 39, I discovered that I have Gorlin's syndrome. I had wondered why I had undergone so many operations, especially that I had already had 11 basal cell carcinomas removed. The doctors had been nagging me about staying out of the sun, apparently assuming that I had incurred the cancers by excessive sun - worship usual among Australians, but I have very fair skin, begin to feel the "bite" in ten minutes, and after several sun burns in childhood, I have tried to avoid the full force of the sun. I knew that sunshine caused wrinkles and cancer by observing the older generation. My father has spent a lot of time in the sun and has had all three types of skin cancer - two melanomas and uncounted BCCs and SCCs - and my mother has had a few SCCs. This is not unusual for such blue - eyed, fair - skinned people after 70 - odd years enjoying farming, fishing and bowls in our climate. I burn much more quickly than they, so my participation in outdoor activities was limited and painful in the years before effective sunscreens. If I had known about Gorlin's syndrome then I would have been even more sun - conscious!

There were other signs that I had Gorlin's syndrome but no one thought anything of it. As a kid I thought my big head showed extra brains, to pick a silly example! The first real problems manifested in my 20s as four operations for keratocysts in the maxilla (upper jaw). A few teeth had failed to develop anyhow, and I lost more in the operations to remove the cysts. Recurrence of cysts within a year of the previous operation was particularly hard to take, as I assumed the operations and tooth loss would go on forever, but the last cysts were removed 14 years ago.

During my Science degree, I had read a lot about Genetics, and tried to deduce what genes were in my family tree, as of course all families have some odd genes. I had often wondered if the cysts and missing teeth were associated with an underlying developmental error, and was fascinated to learn that some of my relatives had the same teeth missing. While working in '81 / '82 (on bacterial genetics) in the Genetics department at Monash University, I found a book on Human Genetics and, looking up "keratocysts", found a reference to Basal Cell Naevus Syndrome. I did not understand the jargon, and all I recall is that it was inherited (as a dominant gene so would be evident in carriers) and caused cancers and other terrible sounding disorders. I thought that all cases had affected relatives and all of the symptoms, and so concluded that I did not have BCNS. I did not ask advice. Since then, when occasionally I searched for references to keratocysts (to see what the risk of recurrence is after 10 - 15 years) I always rejected the papers that mentioned BCNS, being so sure that they had no relevance to my situation.

Dad's brother had a melanoma successfully removed 40 - 50 years ago and Dad had his first melanoma in 1982, so I began to have check - ups for skin cancer in 1983, but the dermatologist found nothing significant. The numerous little lumps in my skin, and the few suspicious moles he removed, were benign. This lulled me into a false sense of security, until a little lump on my nose began to expand more and more rapidly (my first BCC). I left it a little longer than I should because I could not believe that it was malignant. The repair work went well, and although I have had two other BCCs on my face, other people find it hard to trace the scars. Unfortunately, I have scarred more on my back.

While working at the Adelaide Children's Hospital last year, I had an informal chat to a dermatologist about my tendency to develop BCCs and she surprised me by looking at the palms of my hands and correctly guessing a bit of my medical history. I inferred from her line of questions that she suspected an inherited cause of these conditions, that it was rare and interesting, because she asked me if some of her colleagues could look at me. It was weird, being "Exhibit A", while three doctors talked at once, debating the diagnosis. Apparently they were not sure someone so mildly affected could have so - and - so's syndrome (I couldn't catch the name). None of us had time that day to sort out the situation. We were all supposed to be elsewhere doing our work! As a scientist, I was curious, and I was excited to think that there was a coherent explanation for so many coincidental ailments.

A couple of days later I looked up hereditary causes of basal cell carcinomas in the hospital library and was shocked to realise I had BCNS - the doctors had called it "Gorlin's Syndrome". The pictures in the textbooks frightened me. The prognosis seemed gloomy. I felt a terrible tension, not knowing if it was true or not. Two days later, by coincidence, I was able to meet Georgia Trench on a visit to Adelaide, and she gave me the first BCNS Newsletter and a lot of information which settled the matter for me. It was a relief to have my self - diagnosis confirmed so soon because the uncertainty was very wearing. A few months later it was confirmed in an official consultation in the hospital Genetics Department.

It was interesting to learn so much about the condition, for example that many cases have no affected relatives. One important aspect is the unpredictability of the effect of this gene in a person. I am so mildly affected that my condition was unnoticed by oral surgeons in Adelaide, Sydney and Melbourne whom I had consulted about keratocysts, by my dermatologist and plastic surgeon, and by all the other medical staff who have seen me. The medical literature emphasises the most severely affected cases, and this needs to change. For one thing, if the textbooks accurately reflected the wide range of effects of this gene in various people, doctors may correctly diagnose Gorlin's syndrome early in life so we can be given regular check - ups for tumours and could make appropriate choices of occupation and sports to minimise sun exposure. The texts that I found presented the extreme situation as typical, along with pictures of untreated cancers. First I felt the road went down, down all the way, then I remembered they are pictures of other people, not me, and I would not suffer like that if I continue my strategy of regular skin checks, begun years before hearing of Gorlin's syndrome. I stopped feeling sorry for myself as I realised how much worse it could have been. I also stopped feeling guilty, as this is not my fault. I now plan to educate my doctors about my underlying condition, and it is vital that they address my health needs sensibly. For example, my plastic surgeon had become irritable about my recurrent tumours, but has an improved attitude now he knows that BCNS, not sunbaking, is the problem.

Well, I am glad to know the truth, and to hear about others coping with this condition. That is why I wrote. I found the newsletter that Georgia gave me encouraging, and I hope my story will encourage others. At first I thought about BCNS a lot, but then I just got on with life, as before, finding work to do and focussing on more important things. Since 1975, when I decided to serve Jesus Christ in any way I could, I began to consider eternity more than the present, and my quality of life has been determined more by my spiritual health than by my bodily health. I am sure that none of my relatives have Gorlin's syndrome, which is good news personally, but from the research angle, I know it is important to follow this gene within families to learn more about what the normal gene does. That is, I assume the genetic material responsible for the trouble must be a defective version of a proper gene, unable to do its proper job on cellular metabolism correctly. What job would it normally do? One of these days I plan to check the literature for the answer, just for interest.

Dr. Robert J Gorlin

Dr Gorlin was involved in describing many syndromes for the first time, but BCNS may be the best known among those bearing his name.  He encouraged the use of other names for BCNS, but "Gorlin Syndrome" is its usual name.

"The Quarterly Advocate" is a publication of the BCCNS Life Support Network in the US. In the issue of March 2005, I found a short biography of Robert Gorlin (now deceased), which fills in more about his early life (he certainly "did it tough" as a young person!). I retyped it for the Australian Gorlin Syndrome Mutual Support Group email, and post it here:

...............

"ROBERT JAMES GORLIN, D.D.S., M.S., D.Sc. (Athens) (Thessalonika) (Maryland) (Copenhagen).

Born in Hudson, New York, in 1932, Bob Gorlin was the only child of James Alter Gorlin and Gladys Gretchen Hallenbeck. Abandoned by his biological mother and raised by his great aunt, until at age 11, young Bob rejoined his father and stepmother. His father was a small businessman, with little formal education. The family moved often to towns throughout New Jersey. At age 14, they moved into a two bedroom apt, with grandparents, uncles, aunts, cousins and 2 borders). During high school, a general science teacher recognized some hidden talents in him and requested he take a college prep. course. He received a scholarship to attend Columbia College in New York City. Through his ingenuity creating income earners, such as: a "corsage agency" for fraternity dances; a "personal stationery agency"; and a "personal laundry service", he managed to float an education and received his BA in 3 years. He honorably served his country in the Army from 1943 to 1944; and again in the Naval Reserve, Active Duty at Great Lakes USNTC, Illinois, from 1953 - 56.

Dr. Gorlin earned his doctorate of Dentistry from Washington Univ. School of Dentistry 1944 - 47. He was Dental Dir. & Pathologist for Operation Blue Jay, in Thule, Greenland, in '51 &'52; later attended State Univ. of Iowa, as an instructor for Oral Pathology and Chemistry. He held joint appointments as the Professor of Pathology, Dept. of Laboratory Medicine and Pathology; Professor of Pediatrics, Dept, of Pediatrics; Professor of Obstetrics and Gynecology, Dept. of Obstetrics and Gynecology; and Professor of Otolaryngology; all at the School of Medicine, Univ. of Minnesota from 1971 - 1993. Dr. Gorlin found his life's partner and spouse, in the remarkable gentlewoman, Marilyn Alpern, marrying in 1952. Marilyn and Bob are the proud parents of Cathy and Jed, and love to spend time with their 5 grandchildren."

http://www.bccns.org/news/2005Spring.pdf

Following it was a Chronology of Publications by Dr Gorlin.

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I recently found a page dedicated to the memory of Dr. Robert J Gorlin, in the newsletter of the Minnesota Dental Association; it was a pleasure to read more about this excellent man.   The url:

http://www.mndental.org/features/2008/09/16/48/as_we_knew_him

"As We Knew Him

Introduction: Nelson L. Rhodus, D.M.D., M.P.H., F.A.C.D.*:

“Well of course I know who Dr. Gorlin is. He’s one of the main reasons I am going to Minnesota!” This is what I said to one of my colleagues more than 25 years ago when I made the decision to join the faculty of the University of Minnesota.

It was such a distinct pleasure to know and work with Bob Gorlin over the years. No, it was much more than that: it was a pure joy. He was a person you really looked forward to seeing. Whistling down the hallway, waving to me in the cafeteria, or bursting into my office announcing some discovery, it was pure pleasure. You always had time or made time to visit with Bob Gorlin. My perception of Bob can be summed up in three categories: genius, generous, and genuine.

If Bob Gorlin wasn’t a genius, I don’t know who could be defined as one. He knew and could remember so many facts, speak so many languages. The breadth of his knowledge was incredible: art, history, architecture, anthropology, linguistics; even more amazingly within medicine itself: genetics, pediatrics, dermatology, otolaryngology, oncology. An expert who held academic appointments in so many disciplines, he was actually a dentist. By an amazing stroke of fate, the US Army randomly assigned him to enter dental school at Washington University in St. Louis. Anyone who has heard his lectures on the “Evil Eye”, the Hapsburg Jaw, or “About Face” needs no convincing of his genius. His more than 600 scientific publications and numerous international academic awards and accolades leave little doubt. Inquisitive and drawn to the unusual, Bob investigated, named, and consulted on literally hundreds of rare and challenging syndromes. He enjoyed the odd and eccentric. ... ."

See the page for much more.  By all accounts, he was a wonderful clinician, mentor, and human being.  Some of the anecdotes about him, by people who knew him, had me chuckling but with growing admiration for this remarkable man.