PC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
August 2022
I-M07

Signalment (JPC 21474-32): 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 disorganized collagen fibers, abundant clear space, and close approximation of adnexa with 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. The overlying epithelium is diffusely thin and corrugated with abundant small folds over the loose dysplastic dermal collagen. There is diffuse moderate epidermal 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 (“weakness”), dermatosparaxis (“torn skin”).

GENERAL DISCUSSION:

• Inherited defect of dermal collagen synthesis or metabolism that produces clinically evident cutaneous fragility and hyperextensibility
• Very similar to human Ehlers-Danlos syndrome (EDS), but generally restricted to the skin in animals
• Reported in humans, cattle, sheep (most severe), horses, dogs and cats (rare, less severe), mink, rabbits
• Characteristic thin, pale, wrinkled scars

PATHOGENESIS:

• Cattle: Autosomal recessive mutation in procollagen I N-proteinase (procollagen aminopeptidase) gene, defect in enzyme which excises the amino-propeptide of type I and II procollagen > accumulation of soluble procollagens inhibit formation of uniform fibers that can cross-link > loss of collagen tensile strength
• Sheep: Autosomal recessive inheritance, in many breeds due to mutation in procollagen I N-proteinase (procollagen aminopeptidase) gene
• Horses: Autosomal recessive inheritance; unknown biochemical abnormality
• Cat: Both autosomal dominant and recessive forms; biochemical abnormality and methods of inheritance are mostly unknown
• Dog: Autosomal dominant inheritance; unknown biochemical abnormality

 

Phenotype	Species	Breed	Gene	Inheritance
EDS, type 1	Cat	DSH	COL5A1	AD
EDS, type 1	Dog	Labrador retrievers, mongrels	COL5A1	AD
EDS	Dog	Mongrel	TNXB	AD
EDS, type VII	Dog	Doberman pinscher	ADAMTS2	AR
EDS, Holstein variant	Cow	Holstein	EPYC	AD
EDS, classic	Cow	Holstein	COL5A2	AD
HERDA	Horse	Quarter horse	PPIB	AR
EDS, type VII	Sheep	White Dorper	ADAMTS2	AR
Collagen dysplasia	Cat	DSH, Himalayan	Unknown	AD, AR
Collagen dysplasia	Cattle	Belgian, Charolais, Hereford, Simmental, crossbreeds	Unknown	AR
Collagen dysplasia (Ehlers-Danlos-like syndrome)	Sheep	Norweigian Dala, Finnish crossbred Merino, New Zealand Romney	Unknown	AD, AR
Adapted from E-Tables 17.3 and 17.4, Pathologic Basis of Veterinary Disease.

TYPICAL CLINICAL FINDINGS:

• History of lacerations and trauma following routine handling
• Skin may be hyperextensible with decreased tensile strength

TYPICAL GROSS FINDINGS:

• Signs are variable
• Skin soft, velvety, and hangs in loose folds
• Tissue fragile with bruising, hematomas, and large gaping “fish mouth” wounds with little hemorrhage
• Poor wound healing with thin, “papyraceous” paper-like abnormally pigmented scars

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• May be pronounced or subtle; may require age matched control +/- EM to diagnose
• Dermal collagen fibers are sparse, widely separated, disorganized
• Dermal collagen fibers are pale, fragmented, non-uniform, and curled or thin and wispy
• Dermis is usually thin, but occasionally thickened due to accumulation of matrix
• Increase in proportion of elastic fibers
• Epidermis is often unremarkable

ULTRASTRUCTURAL FINDINGS:

• Non-specific
• Fused, branched, unraveled, loosely packed, fragmented or twisted fibers
• Longitudinal sections: fibrils loosely wound or helical, disorganized with abnormal fibril contour
• Cross sections: “hieroglyphic” appearance with several irregular thin projecting arms; a typical finding in ovine and bovine forms

ADDITIONAL DIAGNOSTIC TESTS:

• Biochemical analysis necessary to characterize the specific collagen defect
• Massons’ trichrome: collagen fibers red or have red cores admixed with normal blue staining collagen

DIFFERENTIAL DIAGNOSIS:

Gross differentials:

• Feline acquired skin fragility syndrome: the epidermis is thin and fragile without hyperextensibility; seen secondary to several disease including hyperadrenocorticism, diabetes mellitus, some neoplasms and inflammatory conditions; adult onset
• Aplasia cutis congenital (epitheliogenesis imperfecta): swine, rare, recessive, absence of epidermis +/- dermis typically on caudal half of body
• Epidermolysis bullosa (cattle, sheep, goats, horses, dogs, cats): genetic disease with recessive inheritance characterized by cutaneous blisters (subepidermal vesicles with minimal inflammation) from minor trauma; mutations in keratinocyte cytoskeleton and basement membrane proteins (plakophilin 1, desmoplakin, keratins 5 and 14, plectin, abB5 integrin, laminin, collagen XVII and VI);
• Cutis hyperelastica (pigs): one litter of Large White X Essex pigs

Histological differentials:

• Feline acquired skin fragility syndrome: dermal collagen, follicles, and epidermis are atrophic; follicles in kenogen
• Cutaneous mucinosis (I-M15) – excess mucin in skin; hyaluronan synthetase 2 (HAS2) defect; inherited and normal in Chinese Shar-Peis; mucin is Alcian blue (2.5) and mucicarmine positive; metachromatic with methylene blue and toluidine blue; PAS negative

COMPARATIVE PATHOLOGY:

• Cattle: Dermatosparaxis reported in in Hereford, Charolais, Simmental and White-Blue breeds
• Sheep: Dermatosparaxis has two forms
  • Mild form (adults): Normal elasticity but sheep develop lacerations during shearing; Merino sheep
  • Severe form (neonatal lambs): Soft and edematous skin with severe cutaneous and oral mucosal tears; death due to septicemia within the first few weeks of life; Norwegian Dala sheep (procollagen aminopeptidase deficiency like cattle), Border-Leicester-Southdown and White Dorper sheep
• Horses: Hereditary equine regional dermal asthenia (HERDA); unusual form of localized dermal collagen dysplasia; autosomal recessive in quarter horses; at 6-12 months affected horses develop skin wounds and scarring on legs, shoulders, saddle areas; reported in a thoroughbred gelding and an Arabian-cross filly
  • McElroy et al. demonstrated that horses have the same lesions in the filum terminale as EDS-affected humans with tethered cord syndrome (TCS); the filum terminale is a fibrous extension of the pia matter surrounds and anchors the conus medullaris/end of the spinal cord; TCS is associated with neurologic signs secondary to stretch-induced spinal cord injury in humans

References:

1. 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.
2. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6^th St. Louis, MO: Elsevier; 2016: 533-546.
3. McElroy A, Klinge PM, Sledge D, Donahue JE, Glabman RA, Rashmir A. Evaluation of the Filum Terminale in Hereditary Equine Regional Dermal Asthenia. Vet Pathol. 2021; 58(6):1-7.
4. Miller WH, Griffin CE, Campbell KL. Muller & Kirk's Small Animal Dermatology. 7th ed. St Louis, MO: Elsevier; 2013:603-604.
5. Welle MM, Linder KE. The Integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7^th St. Louis, MO: Elsevier; 2021:1149-1150.

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