Genetic Welfare Problems of Companion Animals

English Springer Spaniel

Ehlers-Danlos Syndrome (Cutaneous Asthenia)

Related terms: primary connective tissue disease; cutaneous asthenia; dermatosparaxis, collagen dysplasia; fragile skin syndrome

VeNom term:  Ehlers-danlos syndrome (VeNom code: 683).

Outline: Ehlers-danlos syndrome is a group of connective tissue disorders that are characterised by fragile, stretchy and loose skin, caused by a genetic defect in the production of collagen. In dogs affected with Ehlers-danlos syndrome, this defect results in the collagen fibres having an abnormal structure.  This weakens the skin reduces its structural properties, and makes it prone to damage.

The clinical signs of Ehlers-danlos syndrome are fragile skin and laxity in the joints, due to the alterations to collagen structure and density. Even the slightest scratch can damage and tear the skin of affected animals, leading to scarring. The deficiency in collagen can also affect other tissues of the body, such as the eyes, heart and blood vessels. Ehlers-danlos syndrome can be diagnosed with a skin extensibility test and laboratory examination of skin samples to determine changes to collagen. Severely affected puppies usually will not survive, but dogs with a mild or moderate form will generally live a normal lifespan, but they will be at risk of frequent skin tears and injury. Skin tears and bruising are common, and the tears can be painful and cause irritation. Owners of affected dogs can reduce the risks of skin damage by removing sharp or rough objects in the dog’s environment and restricting activities such as vigorous exercise or play, but this may affect the dog’s welfare.

It is not clear how many dogs suffer from Ehlers-danlos syndrome, but it is a rare condition. We do know that the condition affects English springer spaniel dogs more than other breeds, and is inherited in an autosomal dominant manner. Severely affected dogs should not be bred from (i.e. dogs which suffer extremely fragile skin).

Summary of Information

(for more information click on the links below)

1. Brief description

Ehlers-danlos syndrome is a group of connective tissue disorders characterised by fragile, stretchy and loose skin. The underlying defect is that of an abnormality of collagen structure. Collagen is the main structural protein in various connective tissues of the body, including the skin, where it provides strength, elasticity and durability. Normal collagen allows tissue to be stretched but resists over-stretching and helps in the tissue return to its normal shape. In dogs affected with Ehlers-danlos syndrome, there is a genetic defect in one of the enzymes that produces collagen, procollagen-peptidase leading to an abnormal structure of collagen fibres. This abnormality weakens the skin and reduces its structural properties, resulting in stretchy, loose skin which is prone to damage.  

The clinical signs of Ehlers-danlos syndrome are fragile skin and laxity in the joints, due to the alteration to collagen structure and density. Even the minor scratches can damage and tear the skin, leading to the formation of scars and subcutaneous haematomata, which are hard masses of blood under the skin surface. There can be internal problems associated with hollow muscular walled structures, such as herniation (rupturing) of muscular diaphragm and perineum, since collagen is important for their structural integrity. There may be increased susceptibility to infections because of poor wound healing. Administration of intra-venous fluids may also be more difficult in these dogs due to weakened blood vessels.

2. Intensity of welfare impact   

Affected dogs show symptoms from birth, with fragile skin, delayed wound healing and pendulous skin. Skin tears and bruising are common, and such tears can be painful and cause irritation. Affected dogs may become lame due to loose joints but they do not appear to suffer pain. The severity of the condition is variable, and some animals may encounter minimal problems with skin looseness or fragility if, for example, they live in carefully controlled environments. 

Bitches affected with Ehlers-danlos syndrome may suffer complications during pregnancy and birth due to the deficiency in collagen, with predisposition to uterine prolapsed or rupture.

Owners of affected dogs can try to reduce the risk of skin damage by removing sharp or rough objects from the dog’s environment and avoiding activities which may result in injury. This may mean that the dog’s quality of life so far as being able to play and exercise, as it normally would, is reduced.

Large or deep tears require stitching by a veterinary surgeon, and dogs may need general anaesthesia in order to suture wounds. There may be complications of treatment or surgery due to weakened blood vessels, and secondary effects of infections due to poor wound healing.

3. Duration of welfare impact

There is no cure for Ehlers-danlos syndrome in animals. Severely affected puppies usually will not survive, but dogs with a mild or moderate form generally live a normal lifespan, but are at risk of frequent skin tears and injury.

4. Number of animals affected

It is not clear how many dogs suffer from Ehlers-danlos syndrome, but it is a rare condition. We do know that the condition affects English Springer spaniel dogs more than other breeds. Ehlers-danlos syndrome affects both males and females.

5. Diagnosis

Skin extensibility can be tested by a veterinarian to diagnose hyper-elasticity of the skin. Ehlers-danlos syndrome can be diagnosed with a laboratory examination of skin samples to determine changes to collagen density and structure.

6. Genetics

Ehlers-danlos syndrome is inherited as an autosomal dominant trait. This means that dogs which inherit only one copy of the gene mutation, from either the mother or father, will be affected. If a heterozygous-affected dog, which carries one copy of the affected gene, is bred with an unaffected dog, there is a 50% chance that any one of the offspring will be affected with the condition.

7. How do you know if an animal is a carrier or likely to become affected?

A specific genetic test to diagnose Ehlers-danlos syndrome is not available, and so there is so way to tell genetically which animals are affected or likely to become affected. The gene mutation is dominant, and so if an animal carries the mutation (either with one copy of the gene from one of the parents, or two copies of the gene, one from each of parent) then this animal is likely to experience Ehlers-danlos syndrome and therefore show clinical signs. However, the severity of the condition is variable, and some animals may not have severe problems with skin fragility.

8. Methods and prospects for elimination of the problem

This condition is rare in dogs and severely affected dogs (i.e. dogs which suffer extremely fragile skin) should not be bred from, since they are likely to produce some affected offspring even if mated with a healthy dog. In addition, bitches affected with Ehlers-danlos syndrome may suffer complications during pregnancy and birth due to the deficiency in collagen. Affected dogs should not be bred from, since 50% of their puppies will inherit the gene, and will therefore be affected by the condition.

For further details about this condition, please click on the following:
(these link to items down this page)

• Clinical and pathological effects
• Intensity of welfare impact
• Duration of welfare impact
• Number of animals affected
• Diagnosis
• Genetics
• How do you know if an animal is a carrier or likely to become affected?
• Methods and prospects for elimination of the problem
• Acknowledgements
• References

1. Clinical and pathological effects

Ehlers-danlos syndrome is a group of connective tissue disorders characterised by fragile, stretchy and loose skin. The underlying defect is that of an enzyme important in the formation of collagen which results in an abnormality of collagen structure. Collagen is the main structural protein in various connective tissues of the body, including the skin, where it provides strength, elasticity and durability. In animals with normal collagen, collagen allows tissue to be stretched but resists over-stretching and helps in the tissue return to its normal shape.

Collagen in the skin is made up of elongated fibrils which lie parallel to the skin’s surface and these are formed through the following process. Initially, the pre-cursor for collagen, procollagen, principally made up of the amino acids glycine and proline, is formed inside cells. When procollagen leaves the cell and enters the extracellular space outside, it is trimmed by the enzyme collagenase, and a single collagen fiber is formed (tropocollagen). Multiple tropocollagen molecules then come together to form collagen fibrils via cross linking and these may be attached to cell membranes. In dogs affected with Ehlers-danlos syndrome, the collagen fibres are smaller, with lower collagen content. There is an abnormal, fragmented shape and size of the collagen bundles with large spaces between the fibres and altered orientation of the collagen (Counts 1980; Matthews & Lewis 1990). There are also reduced levels of the enzyme collagenase (Counts 1980) which prevents the formation of tropocollagen and therefore the subsequent formation of collagen fibrils.

The clinical signs of Ehlers-danlos syndrome include skin fragility and joint laxity. The tensile strength of affected dogs’ skin is reduced to approximately 1/27^th of that of skin in normal animals. A skin extensibility test can be used to test the percentage of stretch in the skin, with values greater than 14.5% being indicative of Ehlers-danlos syndrome (see Figure 1; Hegreberg et al 1970b).  Even the slightest scratch can damage and tear the skin, leading to the formation of scars with a sunken appearance, due to the diminished deposition of collagen (atrophic scars). At the site of trauma, there may be a localised collection of blood that forms a hard mass under the surface of the skin (subcutaneous haematomata, or ‘pseudotumours’).  

There can be internal problems, such as blood vessel rupturing or ocular problems, such as bilateral lens luxation, cataracts and corneal oedema, due to a deficiency of collagen, since collagen is important for their structural integrity (Barnett & Cottrell 1987), although these have been rarely reported in dogs. 

Figure 1. Skin hyperextensibility in a dog with Ehlers-danlos syndrome. The skin extensibility index was 28% while anesthetized. (Matthews & Lewis 1990). © Brendan Mathews, reproduced with permission .

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2. Intensity of welfare impact

Affected dogs will show symptoms from birth, with fragile skin, delayed wound healing and pendulous skin. Skin tears and bruising are common, especially in areas that are readily subjected to trauma such as the back, ears, head and legs (Matthews & Lewis 1990). The tears can be painful and cause irritation, and dogs may scratch or rub these areas, causing further irritation and damage. The skin may be hypersensitive, and affected dogs may experience discomfort when sensitive or fragile areas of the skin are touched. Affected dogs may become lame due to loose joints but they do not appear to suffer pain. There is variation between individuals in the severity of the condition, and some animals may not encounter significant problems with skin fragility if, for example, they live in carefully controlled environments. 

Bitches affected with Ehlers-danlos syndrome may suffer complications during pregnancy and birth due to the deficiency in collagen, with uterine prolapsed or rupture.

Owners of affected dogs can try to reduce the risk of skin damage by removing sharp or rough objects in the dog’s environment and avoiding activities including vigorous grooming, rough and tumble play or vigorous exercise. This may mean that the dog’s quality of life so far as being able to play and run, as it normally would, are reduced

Large or deep tears require stitching by a veterinary surgeon or nurse, and dogs may need general anaesthesia in order to suture wounds, especially since lidocaine – a local anaesthetic treatment used to numb the skin area – appears to be less effective in dogs with Ehlers-danlos syndrome. There may be increased susceptibility to infections due to poor wound healing (Paciello et al 2003). Administration of intra-venous fluids may also be more difficult in these dogs due to weakened blood vessels..

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3. Duration of welfare impact

There is no treatment for Ehlers-danlos syndrome in animals. Severely affected puppies usually do not survive. Puppies with a mild form generally live a normal lifespan, but are at risk of frequent skin tears and injury due to skin fragility and joint laxity.

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4. Number of animals affected

It is not clear how many dogs suffer from Ehlers-danlos syndrome, and it is sporadically reported (Hegreberg et al 1970b, Matthews & Lewis 1990, Paciello et al 2003) which suggests it remains a rare condition. We do know that the condition is inherited in English Springer spaniels, and so they are more likely than other breeds to be affected. Ehlers-danlos syndrome affects both males and females (Hegreberg et al 1970b).

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5. Diagnosis

Skin extensibility can be tested using an index (vertical height of the skin fold ÷ body length × 100); for normal dogs the index value is less than 14.5% and a value above this threshold can indicate that the dog has Ehlers-danlos syndrome.

The collagen structure of skin can be examined histopathologically, with changes to the collagen amount and structure present in the skin of dogs with Ehlers-danlos syndrome. Histopathologic abnormalities are subtle and include low collagen content, large spaces between the fibers, abnormal, fragmented shape and size of the collagen bundles, and altered orientation of the collagen (Counts 1980).

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6. Genetics

Phenotypic studies have revealed that Ehlers-danlos syndrome is a heritable disorder in Springer Spaniels, and is inherited as an autosomal dominant trait with apparent complete penetrance (Hegreberg et al 1970a). This means that dogs which inherit only one copy of the gene mutation, from either the mother or father, will be affected. If a heterozygous-affected dog is bred with an unaffected dog, there is a 50% chance for the offspring to be affected with the condition. A dog that is homozygous, that has two copies of the defective gene – one from each parent – will always produce affected offspring..

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7. How do you know if an animal is a carrier or likely to become affected?

A specific genetic test to diagnose Ehlers-danlos syndrome is not available, and so there is so way to tell specifically which animals are affected or likely to become affected. The gene mutation is dominant, and so if an animal carries the mutation (either with one copy of the gene from one of the parents, or two copies of the gene, one from each of parent) then this animal is likely to experience Ehlers-danlos syndrome and therefore show clinical signs. However, the severity of the condition is variable, and some animals may not show significant problems with skin fragility.

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8. Methods and prospects for elimination of the problem

This condition is rare in dogs and severely affected dogs (ie dogs which suffer extremely fragile skin) should not be bred, since are likely to produce affected offspring even if mated with a healthy dog (Farrell et al 2015). In addition, bitches affected with Ehlers-danlos syndrome may suffer complications during pregnancy and birth due to the deficiency in collagen. Affected dogs should not be bred from, since 50% of their puppies will inherit the gene, and will therefore be affected by the condition.

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9. Acknowledgements

UFAW thanks Dr Emma Buckland (BSc PhD), Dr David Brodbelt (MA VetMB PhD DVA DipECVAA MRCVS) and Dr Dan O’Neill (MVB BSc MSc PhD MRCVS) for their work in compiling this section.

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10. References

Barnett KC and Cottrell BD (1987) Ehlers-danlos syndrome in a dog: ocular, cutaneous and articular abnormalities. Journal of Small Animal Practice 28: 941–946

Counts DF (1980) Isolation of collagen from the skins of Ehlers-danlos syndrome-affected dogs by acetic acid extraction and pepsin digestion. Biochimica Et Biophysica Acta 626: 208–17

Farrell LL, Schoenebeck JJ, Wiener P, Clements DN and Summers KM (2015) The challenges of pedigree dog health: approaches to combating inherited disease. Canine Genetics and Epidemiology 2: 3

Hegreberg GA, Padgett GA, Gorham JR and Henson JB (1970a) A connective tissue disease of dogs and mink resembling the Ehlers-danlos syndrome of man. II. Mode of inheritance. The Journal Of Heredity 60: 249–54

Hegreberg GA, Padgett GA, Ott RL and Henson JB (1970b) A heritable connective tissue disease of dogs and mink resembling Ehlers-danlos syndrome of man. I. Skin tensile strength properties. The Journal Of Investigative Dermatology 54: 377–80

Matousek JL (2004) 13 - Disorders of collagen and elastin. Small Animal Dermatology Secrets: 105–112. Elsevier

Matthews BR and Lewis GT (1990) Ehlers-danlos syndrome in a dog. The Canadian Veterinary Journal 31: 389–90

Paciello O, Lamagna F, Lamagna B and Papparella S (2003) Ehlers-danlos-like syndrome in 2 dogs: clinical, histologic, and ultrastructural findings. Veterinary Clinical Pathology 32: 13–8

© UFAW 2016

Credit for main photo above:

http://depositphotos.com/7961864/stock-photo-working-english-springer-spaniel.html ©Depositphotos.com/chrisga