JPC SYSTEMIC PATHOLOGY
Signalment (JPC 21474-5/6): Mature male springer spaniel
HISTORY: This dog was undergoing treatment for a large gaping skin wound; he also had a striking amount of excessive skin, especially on the lower extremities. The owner reported that the dog is prone to such wounds and that the skin has been “peculiar” since birth.
HISTOPATHOLOGIC DESCRIPTION: Haired skin: Diffusely the dermis is thin with a paucity of collagen fibers and close approximation of adnexa with moderately decreased numbers of sebaceous glands. Collagen fibers are haphazardly arranged, thin, wispy, pale, often fragmented, and widely separated by clear space. Apocrine glands are frequently ectatic. There are low numbers of lymphocytes scattered throughout the dermis. There is mild, multifocal epidermal thinning to as few as one to two cells, as well as diffuse, mild orthokeratotic hyperkeratosis.
MORPHOLOGIC DIAGNOSIS: Haired skin, dermis: Collagen hypoplasia and dysplasia, diffuse, marked, springer spaniel, canine
CAUSE: Hereditary dermal collagen dysplasia
CONDITION: Collagen dysplasia
SYNONYMS: Ehlers-Danlos syndrome (EDS), cutaneous asthenia, dermatosparaxis, collagen dysplasia
- Inherited congenital defect of dermal collagen that produces clinically evident cutaneous fragility and hyperextensibility
- Genetic disorder manifesting as abnormal collagen synthesis or disturbed collagen metabolism
- The most common inherited connective tissue disease, but rare in both dog and cat
- Disease tends to be most severe in sheep, less severe in cattle, followed by dogs and cats, and least severe in horses
- Very similar to human Ehlers-Danlos syndrome (EDS)
- Characteristic thin, pale wrinkled scars
- Cattle, sheep and horse: Autosomal recessive inheritance
- Cat: Both autosomal dominant and recessive forms of inheritance
- Dog: Autosomal dominant inheritance, but a recessive type has recently been postulated
- Cattle: Mutation in the gene for procollagen I N-proteinase (procollagen aminopeptidase), enzyme which excises the amino-propeptide of type I and type II procollagens > defect in processing of type I procollagen to collagen results in abnormal precursor molecules with peptide extensions which inhibit formation of uniform fibers and fibers capable of producing normal cross-links > diffuse loss of collagen tensile strength
- Sheep: Prosposed that the V15M substitution is likely responsible for modifications in the ADAMTS2 enzymatic activity > leading to ovine autosomal recessive inherited dermatosparaxis
- Dog/cat/horse/sheep: Definitive biochemical defect has not been determined
TYPICAL GROSS FINDINGS:
- Appearance and history are usually diagnostic
- Skin hyperextensibility
- Decreased tensile strength
- Easily bruised
- Tissue fragility - large gaping “fish mouth” wounds with little hemorrhage
- Healing with thin or “papyraceous (like paper)” scars that are abnormally pigmented
- Nontraumatic hernias
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Paucity of collagen fibers in dermis with fragmentation and disorganization of haphazardly arranged collagen fibers
- Abnormal collagen fibers are shortened, in disarray, curled, non-uniform size often thin and wispy
- Collagen fibers may be widely separated, finer and paler than normal
- Hair follicles are in kenogen and markedly atrophied
- Many cases have subtle or no distinct histological abnormalities
- Dermal thickness is usually thin, but occasionally thickened due to accumulation of matrix
- Increase in proportion of elastic fibers
- Epidermis is often unremarkable
- In most cases, ultrastructural examination is required to confirm the collagen abnormality
- Fused, branched, unraveled, loosely packed, fragmented or twisted fibers
- Longitudinal sections: Collagen fibrils may be loosely wound and flat or helical and disorganized with abnormal fibril contour
- Cross sections: May have several irregular thin projecting arms; a typical finding in ovine and referred to as “hieroglyphic” appearance
- Dermal fibroblasts have dilated cisternae of rough endoplasmic reticulum; in the cisternae, sparse ribosomes distributed irregularly in clusters along membrane surfaces
ADDITIONAL DIAGNOSTIC TESTS:
- Ultrastructural and biochemical analysis are needed to characterize the collagen defect
- Histopathology: Massons’ trichrome may demonstrate birefringent abnormal collagen fibers as red or having red cores admixed with normal blue staining collagen
- Aplasia cutis (epitheliogenesis imperfecta) – discontinuity of the squamous epithelium
- Epidermolysis bullosa – (sheep) cutaneous blisters from minor trauma
- Mucinous degeneration (myxedema, mucinosis)
- DOG: One case of Ehlers-Danlos syndrome (EDS), associated with fatal spontaneous vascular rupture
- CATTLE: Dermatosparaxis is an autosomal recessive trait in Hereford, Charolais, Simmental and White-Blue breeds; the defect is a deficiency in amino-terminal procollagen peptidase, causing accumulation of soluble procollagens, which interfere with packing of collagen
- SHEEP: Two forms:
- Milder form: Observed when sheep are handled as adults, with clinical signs as dermatosparaxis in cattle, commonly Merino sheep
- Severe form: Appears in lambs typically after birth; severe form is noted in Norwegian Dala sheep, Border-Leicester-Southdown and White Dorper sheep; affected lambs have severe cutaneous and oral mucosal tears and usually die of septicemia within the first few weeks of life
- Mutation in ADAMTS2 shown in one affected flock
- CATS: Cutaneous asthenia (previously dermatosparaxis) is a recessive procollagen peptidase deficiency of Himalayan cats (similar to EDS type VIIC) that is similar to dermatosparaxis of cattle and sheep but with much milder clinical signs
- Hyperadrenocorticism in cats “feline skin fragility syndrome:” Thin, fragile, epidermis without evidence of hyperextensibility
- HORSES: Hereditary equine regional dermal asthenia (HERDA) is an unusual form of localized dermal collagen dysplasia with an autosomal recessive mode of inheritance; 6-12 months old horses develop frequent skin wounds and scarring; defect in quarter horses is associated with the Poco Bueno sire line; also reports in a thoroughbred gelding and an Arabian-cross filly; the defect is a missense mutation in equine cyclophilin B (PPIB) altering a glycine residue; PPIs are implicated in protein folding of collagens
- Corneal thinning has been reported in horses with HERDA
- PIGS: Reported in a litter of large white-Essex pigs; affected skin is very hyperextensible but not fragile
- MICE: Haploinsufficient Col3a1 knockout mice used as an animal model for vascular subtype Ehlers-Danlos syndrome type IV; type III collagen is found in walls of arteries, the gastrointestinal tract, uterus and the skin
- Badial PR, Oliveira-Filho JP, Pantoja JC, Moreira JC, Conceicao LG, Borges AS. Dermatological and morphological findings in quarter horses with hereditary equine regional dermal asthenia. Vet Dermatol. 2014; 25(6):547-554.
- Cooper TK, Zhong Q, et al. The haploinsufficient Col3a1 mouse as a model for vascular Ehlers-Danlos syndrome. Vet Pathol. 2010;47(6) 1028–1039.
- Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin diseases of the dog and cat. 2nd ed. Ames, IA: Blackwell Publishing Professional; 2005:386-389.
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- Mochal CA, Miller WW, Cooley AJ, Linford RL, Ryan PL, Rashmir-Raven AM. Ocular findings in quarter horses with hereditary equine regional dermal asthenia. J Am Vet Med Assoc. 2010; 237(3):304-310.
- Monteagudo LV, Ferrer LM, Catalan-Insa E, Savva D, McGuffin LJ, Tejedor MT. In silico identification and three-dimensional modelling of the missense mutation in ADAMTS2 in a sheep flock with dermatosparaxis. Vet Dermatol. 2015; 26(1):49-52.
- Rashmir-Raven A, Lavagnino M, Sedlak A, Gardner K, Arnoczky S. Increased susceptibility of skin from HERDA (hereditary equine regional dermal asthenia)-affected horses to bacterial collagenase degradation: a potential contributing factor to the clinical signs of HERDA. Vet Dermatol. 2015; 26(6):476-80.
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