History of science of polydactyly

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The second most common malformations in humans are those of the extremities and, among them, polydactyly , i.e. additional hand and / or foot limbs. Polydactyly is therefore one of the earliest research subjects in science. The first traces go back almost 10,000 years to prehistoric times. In the course of the history of science, different priorities in polydactyly research become clear, from inheritance rules to evolutionary significance, exact anatomical analyzes to the investigation of molecular causes and, more recently, the development of extremities. The analysis of the variation in the number of toes and the genotype-phenotype relationship are also moving back into the focus of research. As an evolutionary variation , polydactyly cannot be explained with Darwin's theory of evolution , nor with the synthetic theory of evolution . Only the extended synthesis in the theory of evolution finds EvoDevo mechanisms that describe how the phenotype is generated during development. According to Yale University, more than 1,000 new scientific publications on polydactyly have been published annually since 2011 .

Prehistory and antiquity

Earliest mentions

The oldest known representation of a figure with 6 toes comes from Ain Ghazal , today's Jordan 7500 years before our era. A numerical foot with 6 toes is known from the time 2600 years before Christ. He carries in cuneiform the sentence: "What can I do (for my child with six toes)?" From the Neo-Assyrian king dynasty Ashurbanipal exist 24 panels with 2800 teratological omens under the name Summa izbu that are congenital malformations Belief in the The truth of such omina was deeply and indubitably rooted in priestly society. Whether the malformation occurs on the left or right side of the body or on both sides played a fate-determining role both for the child and, under certain circumstances, for the family and the state. Two of the predictions from Šumma izbu are:

"If a woman in a palace gives birth to a child with six toes on her left foot, her father's house will grow old."

- Tablet IV, No. 60

"If a woman in a palace gives birth to a child with 6 fingers and 6 tens on her hands and feet, the prince will conquer the land of an unknown enemy."

- Tablet IV, No. 61

Aristotle - earliest discussion of development and anomalies

Aristotle (384–322 BC)

The Greek philosopher Aristotle (384–322 BC) was an important natural philosopher in ancient Greece. His importance as a natural scientist for embryology, which extends into the modern age of science, lies primarily in the fact that he strictly rejected the doctrine of preformation , according to which the shape of the fetus is already formed in the semen. Aristotle took up the subject of polydactyly in his work, translated as de generatione animalium into Latin, in which he deals with the procreation and embryology of animals. He did not use the term polydactyly, but spoke of both "too many" and fewer toes in connection with monstrosities. Monstrosities are not monster formations here, rather Aristotle always uses the term when it comes to exceptions to the rule. A child who does not look like his parents is in a certain sense a monstrosity to him like twins, but also a human being who looks more like an animal than a human due to malformations. Too many toes are used in the same sense as any other duplication of a body part. He uses the phenomenon as an example. In his opinion, the doubling of parts of the embryo has the same cause as the doubling of the embryo itself. In a monstrosity, more material is aggregated in any point of the embryo than is required for the natural development of the part. In this case, larger or more parts can arise, depending on the movement of or in the embryo. The principle of movement is an important basic principle of development among others, the central one of which is the difference between heat and cold in the uterus . The principle of movement becomes clear when Aristotle compares the development of an anomaly in the embryo with eddies in the water of rivers. There a potential obstacle can create two vortices of the same movement from one when water flows past with a certain movement. “A new part can be tied to the part that it duplicates. However, it can also be at a certain distance from it, namely if the movement in the embryo is strong enough and also because of the abundance of material that finds its way back to the place from which it was moved while the part takes its shape, the it found when it arose through abundance, retained. "

Aristotle thus uses the phenomenon of polydactyly as a test field on which he can substantiate his development principles, such as the principle of movement or the principle of abundance. If the principle satisfies the natural case and the exceptional case, it is verified to a higher degree. The aggregation of sufficient material for the formation of a doubling could be understood as cell proliferation according to modern view . In a form of pre-axial polydactyly with the mutation of a Sonic hedgehog cis element, it is a prerequisite for the formation of one or more new fingers or toes. The skeletal form is then formed in the course of the self-organization ability of the tissue in the bud ( genetic causes of polydactyly) . The tight connection or the absence of a polydactyl finger from one of the regular fingers may well look like what Aristotle describes. The case of the appendage is syndactyly in the hand ( polydactyly Fig. 7), the case of its absence exists with a widely spread bifurcation, but also in the spread out, elongated, polydactyled first toe of the Maine Coon cat (polydactyly Fig. 5). It is not known from which examples Aristotle derived his statements, or whether he even saw them in extremities; he does not provide any further details. In each case, polydactyly shows specific forms of variation, such as those commonly used by Aristotle.

Of course, Aristotle was wrong in equating the principle of doubling in a finger or toe with that of doubling the entire fetus as in twins.

First classification by Galenus

After Aristotle, the Roman Pliny the Elder (23–79 AD) also treated the subject of polydactyly in his 37-volume natural history work Naturalis historia . He called the phenomenon Sedigita , meaning six fingers . Pliny was the first in the history of medicine to point out that some vertebrates have 6 toes on their front legs. The Greek-born Roman physician Galenus (129–216 AD) was the first to classify malformations in his 14-volume work De Methodo Medendi (About the therapeutic method). He differentiated according to shape, number and size and, for example, correctly and incorrectly formed additional fingers. Galenos spoke out clearly that malformations are caused during embryonic development. He mentioned intact tissue in the case of a correctly formed finger and non-intact tissue in the case of an incorrectly formed finger. This means that his teaching contradicts the preformation theory . The shape of the body does not exist a priori .

middle Ages

Albertus Magnus, Thomas Aquinas, Nicholas of Oresme

Antipode with 9 toes on both feet pointing backwards from the Arnstein Bible from 1172

In the early Middle Ages, polydactyly appeared in Augustine in the early 5th century. The oldest known image of a polydactyl human in Europe can be found in the Arnstein Bible from 1172. The picture shows a man from the south side of the earth ( antipode ) with nine toes on each foot, the feet pointing backwards. He has 5 fingers on each hand. There was no doubt at the time that such beings called monsters actually existed. Albertus Magnus brought a new idea into play in the 13th century. According to this, polydactyly arises not from physical deficiencies, but from a lack of mental control over the body. Thomas Aquinas , also in the 13th century, was the first to notice that extra fingers can be useful and even an integral part of a person's being. Another revolutionary idea for the development of polydactyly came from the French bishop and scientist Nikolaus von Oresme in the 14th century . He argued that the physical environment matters, it is either too dry, too fluid or too sparse.

Avicenna - Natural Causes

Avicenna (980-1037)

The Persian doctor and polymath Avicenna (Ibn Sina) used polydactyly as an example in a little-known text that shows that rare medical occurrences still have a natural cause. He insisted that the causes must always be the same regardless of the rarity of the occurrence. So for him the characteristic had no accidental and even less a supernatural cause. With this approach, Avicenna was 600 to 800 years ahead of European thinking. It was only with the Enlightenment - apart from early exceptions - that rational thinking gained acceptance in explaining processes in nature.

Early modern times and enlightenment

Natural research into causes and controversy over preformation or embryogenesis

Oldest illustration in Europe of a symmetrical polydactyl animal, here a chicken with 5 toes on both feet by Bartolomeo Ambrosini (1642)

In the second half of the 16th century, numerous works with images of deformities (monsters) were created in the course of book printing in Germany, Italy and France. The first picture of a tripod bird with five toes instead of the regular four on its third foot was made by Ulisse Aldrovandi in 1574.

In 1595, the German doctor Martin Weinrich stood out from his contemporaries by placing the natural causes of all malformations in the foreground. That was unusual, since the 16th century was still marked by supernatural explanations for the majority of extraordinary phenomena. Weinrich thus ushered in a turning point from the hitherto teleological to a natural approach. It will take a long time, however, for such thinking to take hold.

From 1759 to 1777 Albrecht von Haller and Caspar Friedrich Wolff led an extensive dispute in letters about the nature of embryonic development . Haller advocated the preformation theory , according to which the embryo is fully developed in its shape from the start and only has to grow out, while Wolff was an avowed representative of embryogenesis . According to this view, which is valid today, the embryo first has to find its shape in a complicated embryogenesis process. The increasingly frequent mentions of polydactyly in humans and animals and also other malformations helped to raise doubts about the doctrine of preformation, which, however, could persist for a long time. The preformation theory could not explain why an embryo already created in the egg cell should show malformations.

Pierre-Louis Moreau de Maupertuis - Mathematical study of the inheritance of polydactyly

Pierre-Louis Moreau de Maupertuis (1698–1759)

The French polymath Pierre-Louis Moreau de Maupertuis analyzed in a study in 1751 in his work Système de la nature ou Essai sur les corps organisés . ( From the universal system of nature or essay on the organic bodies ). the inheritance of polydactyly in several generations of the Berlin family Ruhe. He calculated the extremely small probability that polydactyly would occur in a given family over three generations by chance alone. This eliminated chance, the trait had to be inheritable, both through the father and through the mother.

Maupertuis developed a theory that the embryo, as well as a malformation such as polydactyly, are the result of a change in the smallest heritable particles of an individual. These would attract each other in a Newtonian way (gravitation) and through chemical compounds. He took the view that life arises spontaneously through the accidental aggregation of these particles. Maupertuis already associated evolutionary ideas with polydactyly when he concluded that polydactyly were changes to an earlier “prototype” that did not yet have this characteristic. Only with sufficiently strong inheritance over many generations and through both sexes would there be a "species change". Maupertuis clearly spoke out against the preformation theory , according to which the form of the phenotype in the sex cells is already pre-formed in miniature.

19th century

Robert Chambers - A polydactyl scientist

Robert Chambers (1802-1871)

In Great Britain, the Scottish researcher Robert Chambers was himself polydactyl. He and his brother had 6 fingers and 6 toes, respectively, on both hands and feet. Chambers, an important predecessor of Darwin, published his main work Vestiges of the Natural History of Creation anonymously in 1844. According to Darwin's grandfather Erasmus, it was the first book on evolution and the descent of species from a common predecessor in Great Britain. However, he was not yet able to identify evolutionary mechanisms and only spoke generally of natural laws. It is possible that Chambers' own polydactyly led him to consider that natural conditions are the primary causes of evolutionary change. Chambers' book became one of the most successful popular science books of the 19th century.

Chambers gives the example of 6 fingers on one hand and 6 toes on one foot. He sees families who do not inherit the trait affected as well as those who inherit it over several generations. Chambers cites a thought by Lawrence that the inheritance of the trait from both parents could lead to the precursors of a new breed. So he discusses polydactyly in principle as a quality of variation that can lead to evolutionary change. Chambers is unable to name the causes by which such a variation could be produced. Perhaps it is “symply types in nature” that “can be realized under certain conditions”. But he immediately questions “that these conditions can be such that they attract attention in their entirety”, in today's words that they could be determined empirically in cooperation. So Chambers suspects several interacting factors, sees a rather complex scenario and does not try to reduce the phenomenon. “We are ignorant of the laws of the generation of variation, but we see them appear as a principle in nature.” Elsewhere Chambers speaks of “good conditions of the law in the development of the generative system” which advance it and “bad Conditions "that cause it to" wane ". For the latter case he calls the lengthening and shortening ("attenuation") of extremities, but does not refer to the discontinuous changes of fingers or toes in this context. Chambers is aware of the importance of embryonic development and points out that the very long-term spread of living things on earth is "linked in a certain way to the shorter-term process by which an individual is evoked from a cell". These are very early reflections on evolutionary developmental biology 150 years later.

Charles Darwin - No explanation for discontinuous variation inheritance

Charles Darwin knew the trait polydactyly. In his 1875 published the second edition of his book The Variation of Animals and Plants under Domestication (dt .: Varying de Animals and Plants under Domestication ) Darwin called polydactyly in dogs, especially in Great Danes and detailed in cats. He mentions that he has heard of several families with six-toed cats, with one family having inherited the peculiarity over at least three generations. Darwin assessed polydactyly as an atavism , a step backwards to earlier life forms that normally had more toes. This view was rejected by most of his contemporaries. Darwin only broke away from this idea late.

With the many physical characteristics that Darwin describes in breeding animals, of which polydactyly is just one, Darwin was aware that variations of such complex nature can develop and be passed on in a single generation. However, this did not flow into Darwin's theory of evolution and was also ignored by the later synthetic theory of evolution . Marginal changes have always been seen as the raw material basis for changing species. The original English version of the aforementioned work by Darwin mentions the inheritance of polydactyly, while the German translation by Victor Carus incorrectly omits this.

Bateson (1894): Polydactyl cat forefoot left. A bifurcative toe d3 on the regular first toe d2 and a complete new toe d1 on the far left. Probably a Hemingway mutant

William Bateson on discontinuous variation

William Bateson (1861-1926)

An important piece of work on Darwin's theory of evolution, which was only 35 years old, was published in 1894 by William Bateson . Bateson, an evolutionist who distinguished himself from Darwin in that he assessed discontinuous versus gradual changes in characteristics as more important for evolutionary change, analyzed countless characteristics, including polydactyly on 40 pages in several species. For cats, Bateson describes in detail four polydactyl foot shapes each on the forefoot and rear foot, including the variation known today as the Hemingway mutant with 7 toes on the forefoot, a bifurcative toe on the first toe and an additional, completely new, very thin toe on the ( anterior) palm. Of course, Bateson could not yet know that some of the mutants he described could be traced back to the same mutation. In humans, Bateson discovered a new metacarpal bone that is necessary in order to be able to integrate these in an orderly manner into the handset and arm on a polydactyl hand with 7 fingers. A macaque monkey with 9 toes on one foot is described.

20th and 21st centuries

Exact anatomical studies

Prentiss (1903): Top view of the muscles of a preaxial polydactyl pig foot in front left. The left toe in the picture is polydactyl. His extensor muscle extensor proprior internus (ext. Prp. I.) Serves the small right first toe in the wild type. This muscle is redirected here to the new toe.

In addition to the studies mentioned, several papers on polydactyly appeared in the second half of the 19th century and the beginning of the 20th century, including the oldest English-language work dedicated to polydactyly by J. Struthers (1863). In 1902, F. Howe published a paper entitled A case of Abnormality in Cats' Paws. In it, Howe described in detail the anatomy of the cat's polydactyl front and rear paws, not restricting himself to the skeleton, but providing drawings and explanations of the muscles, nerves and blood vessels. Howe took extremely accurate measurements of the length and weight of each extremity, right down to each toe.

A similarly oriented study appeared in 1903, also in the USA, by CWPrentiss on polydactyly in humans and domesticated animals with special consideration of toe variations in pigs. Prentiss also focused on the anatomical description and drawings of polydactyl limbs. He first described as a muscle diversion of competent when wild-type for the first toe extensor muscle extensor proprior internus occurs to the new toe to use in swine. The work was arduous, as in vitro pigs' feet, which had been prepared in glass and had been stored in the museum for years, had to be dissected in layers to determine the course of muscles or nerves. Regarding inheritance, Prentiss ruled out external influences, especially polydactyly as an inherited trait of acquired traits in the Lamarckian sense . 8 years after the discovery of X-rays, Prentiss presented a series of such images from pigs to polydactyly.

Various forms of polydactyly had been described up to 1945, including those in humans (Förster 1861, Gegenbauer, 1888 and 1890, Bardeleben 1895, Stockard 1921, Cummins 1922) and in a number of animals, in addition to the studies mentioned, several others on cats and horses ( Arloing 1867, Boss 1895), beef (Boss 1890), chicken (Ánthony 1899, Gabriel 1946) and owls (Danforth 1919, Sturkie 1943, Warren 1944).

Sewall Wright - Threshold Effects in Development

In 1934, the American evolutionist Sewall Wright published the first of two papers on 23 lines of an inbred guinea pig population. Wright was the first to determine maternal and thus non-Mendelian effects in polydactyly. According to his results, polydactyly decreases significantly with the age of the mother. Wright was also able to determine a seasonal influence, according to which the proportion of polydactyl boys in winter with 37.5% of births is half higher than in summer with 25.5% of births. He concluded that the appearance of an atavistic toe was due to the combination of genetic effects and non-genetic threshold effects , a very modern view at the time. In 1947 a work on preaxial polydactyl cats was published by CH Danforth, Stanford University California. Danforth carried out an inheritance study of 97 polydactyl cats over several generations under laboratory control. He determined the autosomal dominant inheritance character of the trait in cats with a high penetrance and variable expression, assigned all observed forms of variation to the same gene mutation and was the first scientist to record and quantitatively describe the frequency of alternative toe formations in polydactyl Maine Coon cats. In a further study, Danforth devoted himself again intensively to the morphology of the preaxial polydactyl cat. Danforth described the expansion and subdivision of the saphenous nerve far proximally from the cat's foot and was thus able to contribute to the discovery of the high integrative capacity of embryonic development. Danforth speculated that the evolution of the foot is related to factors that regulate embryonic development of the toes, a careful anticipation of later EvoDevo thoughts.

Molecular causal research

Additional ectopic Shh expression on the later side of the thumb (arrow), here in the mouse.

After the discovery of DNA and with the advancing successes of molecular biology, interest since the 1960s has been to research the genetic causes of polydactyly. Significant breakthroughs increasingly occurred with the beginning of the new millennium. To date, more than 100 forms of polydactyly have been discovered, many of them as syndromes , which means that polydactyly and other malformations are associated with a certain genetic mutation. The mutation forms for polydactyly include mutations in various genes or proteins such as ( Sonic hedgehog , Indian hedgehog , bone morphogenetic proteins (BMP), Gli3 , Hoxa , Hoxd etc.) as well as those in cis elements that control specific gene expressions during hand development . The discovery of such cis-elements in connection with polydactyly contributed strongly since 2002 to increasing the understanding of non-coding DNA elements for development, after all, after the decoding of the human genome in 2002, these areas of DNA were prematurely classified as “DNA- Scrap ”. The studies by the Laura A. Lettice and Robert Hill team in Edinburgh are among the outstanding works. The researchers were able to assign the locus for polydactyly in the Hemingway mutant to a point mutation in a non-coding DNA element, the ZPA regulatory sequence (ZRS), a cis element that controls the expression of Sonic hedgehog ( Shh ). With a distance of more than 800,000 base pairs, this enhancer, which is highly conserved in evolution, is extraordinarily far from its target gene. The mutation occurs in humans, cats and mice. The additional ectopic expression of Shh on the anterior side of the bud was discovered in this context. In 2012, the same team was able to reveal the complex mode of action of this cis element in interaction with several transcription factors on the target gene Shh for the first time .

Laboratory experiments and computer simulations of limb development

The experiment by Saunders and Gasseling (1968): Toe doubling in the chicken wing after anterior transplantation of a ZPA

Polydactyly has always played a role in the study of extremity development. The idea was: if you could explain how a separate new finger is created, you could probably also explain how the hand was created. The 1968 experiment by Saunders and Gasseling was epoch-making, in which it was possible to double the number of toes in a chicken in the laboratory. The success of the experiment was the discovery of the zone of polarizing activity (ZPA) in the limb bud.

Takashi Miura (2012): Simulated finger bifurcation formations

Computer modeling of hand development based on Turing mechanisms has existed since 1974. If the development of the vertebrate hand can be simulated in the model, then, according to the researchers of this group, such models must also be able to show how hand malformations are induced and how polydactyly in particular can be shown Pattern formation influences the hand. As one of the first, Takashi Miura, Kyoto, Japan, was able to show in 2006 the conditions under which polydactyl fingers develop in a computer model and what they look like. For example, he demonstrated bifurcations, which are the forks of new finger elements from existing ones as well as thin new fingers or toes, as they typically occur in cats or mice (double-foot mutant).

A team led by Stuart A. Newman , New York, demonstrated in 2010 that polydactyly can be represented in simulation models by, for example , enlarging the width of the extremity bud - in the model this is called a domain - which means that more cell tissue is available, which in turn increases the Allows formation of new fingers or toes in the model. Another polydactyly model approach is shown by Sheth et al. 2012. It is also based on a Turing model. Thereafter, Hoxgene in the extremity bud influence the spacing of the fingers. Closer distances, caused by mutations in Hoxgenes, give more fingers space in a similarly large space.

Consequences for the theory of evolution

Preaxial polydactyly, Hemingway mutant: frequency of polydactyl toe numbers per individual: statistically skewed distribution

A study of the polydactyl toe numbers of 375 Hemingway mutants of the Maine Coon cat showed that firstly the number of additional toes is variable ( plastic ) and secondly the number of additional toes - statistically speaking - is not normally distributed .

The Maine Coon cat (as the basic model of the Hemingway mutants) has 18 toes as wild type. In some cases, polydactyly occurred with an unchanged number of toes (18 toes), the difference being that the extension of the first toe resulted in a three-jointed thumb. However, 20 toes were found much more frequently and, with decreasing frequency, 22, 24 or 26 toes. There were also, but much less often, odd total numbers of toes on the feet. There was also a statistical skew of the distribution in the difference in the number of toes on the front and rear feet. In addition, a left-right asymmetry in the number of toes could be observed. Based on model calculations, the authors of the study suggested that random bistabilities during the development process could explain the observed statistical skewness of the distribution.

Although in biology and medicine polydactyly is regarded as a pathological undesirable development, many of its manifestations open up a broader view of how innovations can arise in evolution. Since polydactyl fingers or toes do not have a homologous feature, i.e. since there are neither cells nor tissue in the place of a new finger in the wild type , a polydactyl finger or toe can - technically speaking - also be viewed as a complete phenotypic innovation.

The way in which new toes were created in Hemingway mutants can therefore be seen as an example of how in other cases evolutionary new elements arise that are not only homologous to the previous generation but also to the same organism.

The fact that a mutation can initiate a variety of phenotypes and that these phenotypes are different and probably a statistical distribution obey the calls Advanced synthesis in the theory of evolution as directed development . Direction, as demonstrated empirically here, is one of the basic assumptions of modern evolutionary theory.

Modern surgery of polydactyly

As a malformation in humans, polydactyly was never a presentable characteristic. From the Middle Ages to the modern age, when a child was born, the question of whether it had ten fingers and ten toes was symbolic of whether the child was healthy. The question was still very common in the 20th century. While with postaxial polydactyly additional fingers can be embedded very nicely in the handset, this is not the case with preaxial polydactyly of the hand, since in most cases there is a partial, unsightly doubling of the thumb, and also a rare one full duplication of one or both thumbs looks unnatural. A first short medical scientific work on the treatment of polydactyly is therefore already in 1938. After further studies in 1969, 1977 and 1978, a study appeared in 1983 on 237 clinical operations on the polydactyl thumb, which took place over a period from 1960 to 1981 at the hand clinic of the Orthopedic Department of Osaka University, Japan. 7 forms of polydactyly on the thumb were largely differentiated here with reference to Wassel (1969), starting with a very distal bifurcation on the last phalanx, through increasingly proximal forms on the second phalanx, to bifurcations on the metacarpal bone of the thumb. The rare case that no bifurcation is formed on the thumb, but that this finger is completely doubled, was also described in this work. In this case, all the tendons and with them the muscles are doubled, which not only had to be considered medically, but in general represents a new finding for the analysis of the development of the forms of polydactyly, without the work of Tada et al. that I was trying to show. Exposed polydactyl bone elements that are not connected to the skeleton, similar to those found in Maine Coons, have also been identified by Tada et al. described and operated.

The report by Tada et al. mentions surgical interventions on 193 of 237 possible polydactyl hands and summarizes 130 results with regard to mobility, joint stability and postoperative alignment of the thumb. 75% of the treatments in a group of 93 hands led to good results, 4% to unsatisfactory results after 35 months. According to the study by Tada et al. In 2983 several other clinical reports (1992, 2006, 2007, 2013) on preaxial polydactyly on the thumb appeared.

Web links

literature

Individual evidence

  1. ↑ M. Bamshad, RC Lin. et al .: Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome . In: Nature Genetics , 16, 1997, pp. 311-315.
  2. ↑ a b c d e f g h i Axel Lange, Gerd B. Müller : Polydactyly in Development, Inheritance, and Evolution . In: Q. Rev. Biol. , Vol. 92, No. 1, Mar. 2017, pp. 1–38, doi: 10.1086 / 690841
  3. ↑ Aristotle. De generatione animalium. Book IV. Engl .: On the Generation of Animals (eBook)
  4. ↑ A. Bitbol-Hespériès: Monsters, nature and generation from the Renaissance to the early modern period: the emergence of medical thought . In: JEH Smith (Ed.): The Problem of Animal Generation in Early Modern Philosophy . Cambridge University Press. Bonner JT, Cambridge UK 2006, pp. 47-62.
  5. ↑ Système de la nature or Essai sur les corps organisés
  6. ^ The History of Evolutionary Biology: Evolution and Genetics
  7. ↑ Mary Efrosiny Gregory: Evolutionism in Eighteenth-Century French Thought (Currents in Comparative Romance Languages and Literatures). Peter Lang Publishing, 2008.
  8. ^ Alan EH Emery: Portrait in medical genetics. Pierre Louis Moreau de Maupertuis (1698-1759) . In: Journal of Medical Genetics , 1988, 25, pp. 561-564.
  9. ^ Robert Chambers: Vestiges of the Natural History of Creation . 1844. Cosimo 2007 edition, p. 149
  10. ↑ John Zachariah Laurence (1829–1870), ophthalmologist at a clinic in London, is one of the discoverers of Laurence-Moon-Syndrome (1866), which is later associated with polydactyly as Laurence-Moon-Biedl-Bardet syndrome . The four patients named in the 1866 publication, however, had no polydactyly (Laurence Jz, Moon RC .. Four cases of retinitis pigmentosa occurring in the same family and accompanied by general imperfection of development. Ophthal Rev 1866; 2: 32-41). There is therefore no recorded document from Laurence on polydactyly
  11. ^ Robert Chambers: Vestiges of the Natural History of Creation . 1844. Cosimo 2007 edition, p. 150
  12. ^ Robert Chambers: Vestiges of the Natural History of Creation . 1844. Cosimo 2007 edition, p. 115
  13. ^ Robert Chambers: Vestiges of the Natural History of Creation . 1844. Cosimo 2007 edition, p. 107
  14. ^ CR Darwin: The variation of animals and plants under domestication . 2d edition. John Murray, London 1875, Volume 1.
  15. ^ William Bateson : Materials for the Study Of Variation: Treated with Especial Regard to Discontinuity in the Origin of Species . Macmillan and Co., London 1894
  16. ^ J. Struthers: On Variation in the Number of Fingers and Toes, and in the Number of Phalanges in Man . In: Edinb. New Phil. Journ. , New. Ser. Vol. 18, pp. 83-111, pl. 2
  17. ↑ Freeland Howe, Jr.: A case of Abnormality in Cats' Paws . Contributions from the zoological laboratory of the museum of comparative zoology at Harvard college. EL Mark, Director. No. 134
  18. ^ CW Prentiss: Polydactylism in Man and the Domestic Animals with Especial Reference to Digital Variations in Swine . Contributions from the zoological laboratory of the museum of comparative zoology at Harvard college. EL Mark, Director. No. 141. Cambridge MA 1903
  19. ↑ Harold Cummins, Joseph Sicomo: A case of hyperdactylism: Bilateral duplication of the hallux and first metatarsal in an adult negro . In: Anat Rec . , 23, 1922, pp. 211-235.
  20. ^ Sewall Wright: An Analysis of Variability in Number of Digits in an inbred Stain of Guinea Pigs . In: Genetics , 19 (6), 1934, pp. 506-536.
  21. ^ Charles H. Danforth: Heredity of Polydactyly in the Cat . In: The Journal of Heredity , 38 (4), 1947, pp. 107-112.
  22. ↑ Morphology of the feet in polydactyl cats . In: The american journal of anatomy , vol. 80, no.2, March 1947.
  23. ^ LG Biesecker: Polydactyly: how many disorders and how many genes? 2010 update. In: Developmental dynamics: an official publication of the American Association of Anatomists. Volume 240, number 5, May 2011, ISSN  1097-0177 , pp. 931-942, doi: 10.1002 / dvdy.22609 , PMID 21445961 , PMC 3088011 (free full text) (review).
  24. ↑ a b L. A. Lettice, AE Hill, PS Devenney, RE Hill: Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly . In: Human Molecular Genetics , 17 (7), 2008, pp. 978-985.
  25. Jump up ↑ LA Lettice, I. Williamson, JH Wiltshire, S. Peluso, PS Devenney, AE Hill, A. Essafi, J. Hagma, R. Mort, G. Grimes, CL DeAngelis, RE Hill: Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly . In: Developmental Cell , 22 (2), 2012, pp. 459-467.
  26. ^ W. Saunders, M T. Gasseling: Ectodermal-mesenchymal interactions in the origin of limb symmetry . In: Wilhelm Roux's archives of developmental biology 1977 , Volume 182, 1968, Issue 3, pp. 213-225.
  27. ^ SA Newman, HL Frisch: Dynamics of Skeletal Pattern Formation in Developing Chick Limb . 1979
  28. ↑ T. Miura, K. Shiota, G. Morris-Kay, PK Maini: Mixed-mode pattern in Double-foot mutant mouse limb - Turing reaction diffusion model on a growing domain during limb development . In: Journal of Theoretical Biology , 2006 Jun 21; 240 (4), pp. 562-273. Epub 2005 Dec 2006.
  29. ↑ J. Zhu, Y.-T. Zhang, MS Alber, SA Newman: Bare Bones Patterning Formation: A Core Regulatory Network in Varying Geometrics Reproduces Major Features of Vertebrate Limb Development and Evolution . Online 2010.
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