Not a lot, really.
- We know that it’s complicated
- we know that there are several genes involved – at least nine but probably (very?) many more
- we know that you don’t have to have all of them (or perhaps this might be better expressed as "you don't need many of them") to develop the disease
- we know that the genes are on different chromosomes
- we have not found a single one, so far, that is on a chromosome that determines your morphological gender (X or Y chromosomes)
- we know that many of the genes are located near the place in their chromosome where genes are found that control a certain set of processes involved in signaling things to start or stopping cells from producing certain chemicals or doing other things.
The bare bones of the story so far are in a photo thread linked at the bottom of this post.
But first, a little analogy for those who don’t know much about genes, chromosomes and alleles.
Imagine a library that houses the complete set of instruction manuals that set out all the processes involved in building an Airbus A350XWB.
First off, it’s huge – there are a very large number of processes involved – so think of the warehouse in the final scene of “Raiders of the Lost Ark.”
Second, it’s organised by shelves, great long shelves, 44 of them, arranged in pairs back-to-back, together with one odd pair of shelves. In the analogy, each shelf is a chromosome, and the strange pair are the X and Y chromosomes that determine morphological gender. Each shelf is jam-packed with manuals – some 30 000 in all.
The manuals are lever-arch files cleverly organised so that each (loose-leaf) page is limited to instructions for a single element of one process – say, making a rivet.
In this analogy, each page is a gene, and each gene codes for – that is, it provides instructions for – one particular protein (often an enzyme) or part of a protein.
Here and there on the shelves are manuals that contain special pages that explain when to start obeying instructions from this or that page in some other manual. These are “genetic switches” and are obviously a key to how the entire library – or genome – functions.
Next door is another library, organised in an identical way, except that a tiny proportion of the pages are different from the ones in the first library. Perhaps one-page codes for blue seats instead of cream, or hemstitches rather than blanket stitches in the carpeting. Almost none of these variant pages have to do with fundamental things like rivets or altimeter dials or the twist in the gas turbine fan blades.
In the analogy, the pages are genes and the variant pages are alleles of those genes.
Many of these variant pages contain just a single difference – perhaps the only change in the entire page is that the word “sink” is changed to “sunk” somewhere, or “homely” is changed to “comely”, or something is missing from, or added to, one variant, so perhaps “appeal” in one library might be “appal” in the other; and it’s a fairly safe bet that a page giving instructions involving “stamped” is likely to lead to a different process than one that involves “stampede”.
Thus, by analogy, alleles often code for slightly different enzymes whose behaviour may make the difference between having blue or green eyes or getting and not getting Dupuytren's or Ledderhose disease.
The reason that there are two libraries in this analogy is that every now and then Airbus Industrie decides to take entire sections out of one library and exchange them for an identical section from the other. Identical, that is, except for any alleles that happen to be different in the two libraries.
At this important and ceremonial event, workers are told to grab huge batches of manuals in a vast armload and swap them with the same manuals in the other library, in order, as a coherent whole. Each manual in the analogy is a group of genes or “recombination block” that tends to stay together whenever anyone reorganises the library – which is to say, when mum and dad’s genes are passed on to their child. (It’s rare that the reorganisation will involve splitting a manual in two but it does sometimes happen. Genes tend to travel down the generations in great clusters, not individually.)
You’ll have heard that we humans share 99% of our genes with chimps and bonobos.
You’ll also have heard that your child shares half of your genes.
It’s more accurate to say that your child gets half of her genes from you and half from her other parent. Almost all of her genes are identical not only to yours and her other parent, but also to any random human or bonobo – and half of them are identical with those in a banana.
These shared genes typically code for fundamental things - in the analogy, you don't want variants in the pistons that actuate the flaps or the frequencies used by the nose cone radar - and mammals don't need a range of variants in the way neurons signal across synapses.
This means that all humans are 99.9% genetically identical.
Roughly half of the remaining 0.1% of your daughter’s genes consists of genes that you share with her, but not with her other parent. That half of 0.1% of her genome (the sum total of her genes) codes for enzymes that will tend to make her resemble you – perhaps in her body shape, her colouration, her aptitude for sport, her susceptibility to dental caries, the shape of her hands and fingers, and whether she might develop Dupuytren's and Ledderhose disease later in her life.
How many genes are involved in Dupuytren's and Ledderhose diseases? And are they the same for both diseases?
Nobody really knows. One study identified 9 "Dupuytren's" genes on chromosomes 7, 20 and 22; another study suggests that genes on chromosomes 1, 2, 3, 4, 5, 6, 8, 11, 16, 17, 20 and 23 may be associated with Dupuytren’s disease, and chromosomes 6, 11 and 16 “may contain the genes for DD”. Disturbingly, only chromosome 20 is implicated in both studies, which invites the question of how reliable such studies are, and how many other, so far unknown, genes there may be.
Together these studies suggest that “Dupuytren’s genes” are located on chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 16, 17, 20, 22 and 23 - that is to say on 14 of the 22 autosomal chromosomes carried by humans. At least some of these genes are located close to genes that control important pathways controlling certain kinds of cell behaviour.
- Dolmans, G.H., Werker, P.M., Hennies, H.C., Furniss, D., Festen, E.A., Franke, L., Becker, K., van der Vlies, P., Wolffenbuttel, B.H., Tinschert, S., et al. (2011). Wnt signaling and Dupuytren’s disease. New England Journal of Medicine 365, 307–317.
- Ojwang, J.O., Adrianto, I., Gray-McGuire, C., Nath, S.K., Sun, C., Kaufman, K.M., Harley, J.B., and Rayan, G.M. (2010). Genome-Wide Association Scan of Dupuytren’s Disease. The Journal of Hand Surgery 35, 2039–2045.
Are mutations similar?
Genes are sections of DNA.
DNA is like a spiraling ladder whose rungs are called "base pairs". They're called "pairs" because one half of each rung, which is attached to one side of the ladder, can only be attached to a particular molecule, its pair, which is attached to the other side.
A short gene may contain about 1000 base pairs, while a long one may be made up of, say, 2.5 million base pairs. Many genes consist of about 10000 to 15000 base pairs.
Genes aren't inherited individually and independently, like a handful of buttons drawn at random from a huge bag. Instead, the buttons are threaded together in long sequences, so when you pull out a handful from the bag, you get entire necklaces of buttons. The genes tend to travel together in these necklaces from one generation to the next.
Genetic evolution happens when one of those base pairs in a gene is substituted for another (a chunk of the ladder is flipped upside down, for example, or a rung is swapped out for another one, or a bit of the ladder is repeated, or cut out, or any other change) and the change is inherited through successive generations and spreads in the population.
Changes like these are called mutations. The word "mutation" comes from the Latin word mutare which simply means "to change". When a change survives and becomes common in a population we talk of alleles of the same gene. "Allele" simply means "version". Most of our genes have a single version - evolution has trimmed away all experiments and come up with a single version of the gene that has proven its worth over all other possible versions. But some genes have one or more alleles.
When scientists look at the genetics of a disease like Dupuytren's, they compare the genes of people with and without the disease. But they have no technical means, as yet, to compare gene by gene. Instead, they pull out "necklaces" of genes from the bag and compare the necklaces of people with the disease to those of people without it.
When they discover that people with the disease are more likely to have a gene necklace that is consistently different from the gene necklace of people without it, they have discovered a genetic link to the disease.
At this point, they look at the necklace they have pulled out and work out where in the DNA it came from. Thus, they can say that people with Dupuytren's disease tend to have a particular marker for the disease (the variety of necklace) at a particular place (within a few tens of millions of base pairs) on a particular chromosome.
What they can't say, without a huge amount of further research, is which gene along that necklace is different, or what alleles of that gene tend to link with Dupuytren's disease. They'll get to it, but it takes time and effort.
Thus the question, "are mutations similar", has no answer at this point.
Imagine a BMW dealership.
Each year the dealership sends out a questionnaire to all the customers who bought one of the M-range cars - the Coupé, the Gran Coupé, the Sedan, the Convertible, the X5 and X6. One of the questions asks how many speeding tickets the owner picked up this year - these are temptingly fast cars. Each year about 2% of the owners admit to a speeding ticket.
Every M-range BMW has the capacity to drive very much faster than the speed limit on the fastest road, but the temperament of some drivers makes them invariably obey the speed limit, the luck of others lets them get away with speeding year after year, and the behaviour of others (using radar detectors, perhaps) keeps them out of trouble.
Down the road from the BMW dealership is Mothercare Baby Carriage Co.
Each year the dealership sends out a questionnaire to all the customers who bought one of the Xpedia Tusk Special Edition baby carriages. The Mothercare questionnaire was designed by the consultant who created the BMW one. One of the questions asks how many speeding tickets the owner picked up this year. Each year 0% of the baby carriages owners admit to a speeding ticket.
Irrespective of the temperament, luck or behaviour of the person pushing the baby carriage, they lack the capacity to push fast enough to get into trouble.
In a somewhat similar way, having the alleles that give you the capacity to have Dupuytren’s or Ledderhose disease is not enough.
You also have to have the temperament, the luck (or lack of it) or the behaviour that triggers the disease (and earns you the speeding ticket).
So maybe one of your great grandfathers had Dupuytren’s contracture, or a great, great grandmother limped about on Ledderhose-afflicted feet. But none of your ancestors, or their siblings, or your siblings or cousins, had the temperament, the misfortune or the behaviour that triggered the disease - even though they had the capacity, because they had the alleles.
You, for some reason, had both the capacity and the trigger. Here’s your speeding ticket. Deal with it.
It’s also possible that others in your family did indeed have the disease (or are living with it today) without realising it.
Study after study shows that the great majority of people with Dupuytren’s or Ledderhose disease do not realise they have it. You might well discover that if you investigate the palms or the soles of all your living relatives, you will be able to tell someone you’re related to that they, too, have over-enthusiastic fibroblasts in the fascia of their palms or soles. Won’t you be popular?
Furthermore, some families may know that they have a genetic disease, but keep quiet about it. Some people see disease as a moral failure. Some people don’t like thinking that their family has a built-in defect. Combine them; admitting that a family is tainted by an inbuilt moral defect is not going to happen Add an answer to this item.
It’s not either/or. But the first point to make is that more is known of Dupuytren's disease than Ledderhose disease in this respect, and the following focuses only on DD.
Whenever people have looked at the genes of someone with Dupuytren's disease they have found alleles characteristic of the disease in one or more of 9 loci on 4 chromosomes. (An allele is a variant of a gene. A locus is a small chunk of a chromosome – locating a gene reasonably accurately is much easier than locating it exactly.) It seems, therefore, that you cannot have Dupuytren's and Ledderhose disease without having alleles that are characteristic of the disease; in short, the disease is genetic.
The genetics are complex, with some genes contributing more than others to one’s predisposition to the disease.
Nine genes on 4 chromosomes… what does that mean in terms of inheritance?
The chromosomes implicated are numbered 7, 19, 20 and 22, with 4, 1, 1 and 3 loci respectively. On chromosomes 7 and 22 the loci are physically close, so will normally be inherited as if they were a single gene. Essentially, then, one can imagine the genetics as 4 genes independently inherited, with 2 of them being particularly potent.
Some rather shaky evidence suggests that the disease can be expressed even if you only inherit alleles from one parent – that is, alleles for the disease are dominant over the recessive non-Dupuytren's alleles. If this is indeed the case then the weakest possible diathesis would be when only you receive only the least potent allele from just one parent. The strongest possible diathesis would be when you receive all of the Dupuytren's alleles from both parents.
If this model is correct and counting the gene groups on a single chromosome as a single genetic construct, then there are some 200 different combinations of alleles that would predispose you to the disease.
(You could picture this as if there are 4 normal alleles a, b, c, d and their Dupuytren's alleles A, B, C, D, of which you get one allele from one parent, and one from the other, giving a/a b/b c/c d/D, a/a b/b c/C d/d, through to A/A B/B C/C D/D.)
If we assume that getting an allele from both parents has an additive effect, and not, say, a multiplicative one, then these 200 combinations give rise to about 30 different levels of diathesis.
Having a genetic predisposition to the disease isn’t the whole story, though. It’s not like having blue eyes, long legs or blonde hair; something has to trigger the disease.
It’s possible that age alone is enough in some cases – something about the changes that take place in the cellular biology as tissues age might conceivably set the disease off. But there are many other possible triggers.
People often believe that an injury to their hand has caused their condition, and anecdotes abound of Dupuytren's disease occurring in the same place and shortly after an injury.
Dupuytren himself thought that the disease that came to be named after him might be caused by trauma such as that suffered by a wine merchant while he was lifting a cask. As explained in another FAQ, however, it is not easy to establish whether there really is a relationship between injury and disease, particularly when the injury occurred years before the disease appeared.
There is nevertheless some reason to believe that the relationship is real. For example, the creative thinker and hand surgeon John Hueston stated, from long experience, that providing that the person has the necessary alleles, “almost any injury to the limb associated with a period of swelling and disuse of the hand [ranging] from radical mastectomy through proximal limb ruptures, dislocations of shoulder or elbow joints, forearm fractures, superficial burns of the hand, to direct local tissue disruption with hematoma or open wounds and fractures in the hand itself” could presage the onset or worsening of Dupuytren's disease.
“The palm itself,” he said, “does not have to be the site of the injury.”
He goes on to remark that fasciectomy is an injury to the palm and fingers that is followed by swelling and disuse, and that recurrence occurs “very frequently within a few weeks” of the surgery.
Did the injury cause the disease? Or was it something to do with the swelling and enforced disuse after the injury?
One interesting idea that nobody seems to have further investigated was suggested by Hueston in 1990. He observed that a possible trigger was simply sudden disuse of the hand – brought about, for example, by hospitalisation or retirement from a manual job, which could “be followed within weeks by the onset or progress of DD often bilaterally”.
Not Dupuytren's disease at all?
To further complicate an already confused picture, some researchers think that traumatically induced disease of the palmar fascia may not be Dupuytren's disease at all, but something else. In a 2014 paper Findlay and his colleagues claim that these traumatically induced diseases tend to be unilateral and to have no preference for people of any particular ancestry. So far, there has been no examination of the genes of these “non-Dupuytren's” disease cases to show whether they indeed possess none of the alleles typical of Dupuytren's disease.
- Bennett, B. (1982). Dupuytren’s contracture in manual workers. British Journal of Industrial Medicine 39, 98–100.
- Dolmans, G.H.C.G. (2014). The genetic origin of Dupuytren’s disease and associated fibromatosis. PhD. Rijksuniversiteit Groningen.
- Findlay, I., and Tahmassebi, R. (2014). Posttraumatic Disease of the Palmar Fascia. The Journal of Hand Surgery 39, 2086–2088.
- Hueston, J. (1990). Dupuytrens diathesis. In Dupuytren’s Disease Biology and Treatment, R.M. McFarlane, D. McGrouther, and M.H. Flint, eds. (Churchill Livingstone), pp. 246–252.
- Lucas, G., Brichet, A., Roquelaure, Y., Leclerc, A., and Descatha, A. (2008). Dupuytren’s disease: Personal factors and occupational exposure. American Journal of Industrial Medicine 51, 9–15.
- McFarlane, R.M. (1991). Dupuytren’s disease Relation to work and injury. The Journal of Hand Surgery 16A, 775–779.
- Milano, G., Gage, H., and Wilson, C. (1977). An investigation of occupational hand-arm vibration. Bulletin of the New York Academy of Medicine 53, 823.
- Palmer, K.T., D’Angelo, S., Syddall, H., Griffin, M.J., Cooper, C., and Coggon, D. (2014). Dupuytren’s contracture and occupational exposure to hand-transmitted vibration. Occupational and Environmental Medicine 71, 241–245.
If you’ve been diagnosed with Dupuytren's or Ledderhose disease, Garrod’s pads or Peyronie’s disease, you already know that you have one or more of the many genes implicated in these diseases.
Genetic testing could tell you how many of the genes you have, and although the test can’t determine whether the disease will progress or how fast, it might perhaps give some indication of how high or low your diathesis is likely to be.
If you were to get tested before evidence of the disease appeared in your palm or sole, and discovered that your genome contains alleles for one of the diseases, you might perhaps use the information to keep a regular watch on your palms and soles, and if nodules appeared, go quickly to a radiation oncologist for treatment.
Genetic testing doesn't substantially increase the information that you might pass on to family members – having the disease yourself means that some of your ancestors also had the genes - and relatives may also have inherited them from those ancestors.
Before submitting to genetic testing, it is important to think about the implications for other people.
In the countries where Dupuytren's and Ledderhose disease are prevalent, many families have undertaken genealogical studies and placed the results on the internet. Gene testing companies ask you to allow them to make the data public, without identifying who you are.
Studies have shown that the release even of a few markers can be combined with genealogical data to identify other people who you don’t know, but who are related to you. This means that they share genes with you. Your release of genetic data might therefore reveal genetic information about someone you’ve never heard of – let alone other people in your family.
- Anderson, E.R., Ye, Z., Caldwell, M.D., and Burmester, J.K. (2014). SNPs Previously Associated with Dupuytren’s Disease Replicated in a North American Cohort. Clinical Medicine & Research 12, 133–137.
- Billings, P.R., Kohn, M.A., De Cuevas, M., Beckwith, J., Alper, J.S., and Natowicz, M.R. (1992). Discrimination as a consequence of genetic testing. American Journal of Human Genetics 50, 476.
- Callaway E. (2012). Ancestry testing goes for pinpoint accuracy; Companies use whole genomes to trace geographical origins. Nature 486, 17
- Dolmans, G.H., Werker, P.M., Hennies, H.C., Furniss, D., Festen, E.A., Franke, L., Becker, K., van der Vlies, P., Wolffenbuttel, B.H., Tinschert, S., et al. (2011). Wnt signalling and Dupuytren’s disease. New England Journal of Medicine 365, 307–317.
- Dolmans, G.H., de Bock, G.H., and Werker, P.M. (2012). Dupuytren Diathesis and Genetic Risk. The Journal of Hand Surgery 37, 2106–2111.
- Gymrek, M., McGuire, A.L., Golan, D. Halperin, E., Erlich, Y. (2013) Identifying Personal Genomes by Surname Inference. Science 339: 321-324
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Contact information provided below for radiation oncologists who have treated for Dupuytren's Contracture or Ledderhose . Comments or opinions expressed here or on DART are not intended to diagnose or prevent disease. Advice or comments should not be relied upon unless confirmed by your treating physician. No doctor-patient relationship is intended and members are advised to consult their doctors for medical advice. No representation is made about the quality or professional competency of the listed doctors. This listing is compiled from referrals of DART members and is provided as a place for you to begin your own research. If you find the contact info outdated or in error, please comment on DART where it can be corrected. You might also google the doctor or clinic to find updated contact information. Many of these doctors also practice at secondary locations that may be closer to you. Check their website. In addition to their clinical practice, many of these radoncs are also on the faculty of local medical schools where they teach radiation oncology. If you have doctor or clinic information not listed below, please share with DART so it can be made available to others looking for treatment in that location. some photos from dupuytrens.org Thank you.
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