Skin Diseases in Domestic Animals PDF

CHAPTER 17 The Integument molecule 1, and intercellular adhesion molecule 1 [ICAM 1]) on cytokine-activated endothelial cells in the dermal vessels at the site of initial injury, thus providing a way for the effector memory T lymphocytes to find their way back to the site of the injury and pathogen...

CHAPTER 17 The Integument molecule 1, and intercellular adhesion molecule 1 [ICAM 1]) on cytokine-activated endothelial cells in the dermal vessels at the site of initial injury, thus providing a way for the effector memory T lymphocytes to find their way back to the site of the injury and pathogen entrance. Once in the skin and after receipt of a renewed antigenic stimulus by the professional antigen-presenting cells, the effector memory T lymphocytes undergo clonal expansion, resulting in the generation of protective effector mechanisms. Most of the lymphocytes in the skin are T helper lymphocytes, but various types of T and B lymphocytes contribute to adaptive immunity. Lymphocytes recognize pathogens (i.e., antigens) via cell surface receptors. The B lymphocytes have immunoglobulin (Ig) molecules as the receptors for antigen, and on activation, B lymphocytes secrete Ig, which provides defense against pathogens (often bacteria) in the extracellular spaces. Antibody facilitates pathogen neutralization, complement activation, and enhanced endocytosis by phagocytes. In contrast, T lymphocytes have receptors that recognize foreign antigens expressed as peptide fragments bound to MHC proteins (see Chapter 5, Diseases of Immunity). One class of T lymphocytes expresses the CD8 molecule on their surface (i.e., CD8+ T lymphocytes). These CD8+ T lymphocytes recognize peptide fragments bound to MHC I, then kill the cell, and thus are also called cytotoxic T lymphocytes. Another class of T lymphocytes expresses the CD4 molecule on their surface. This class of T lymphocyte is divided into subclasses. One subclass, the CD4+ T lymphocyte subset (TH1 [helper]), recognizes peptide fragments (e.g., microbial antigen) bound to MHC II and releases cytokines, including IFN-γ, resulting in an inflammatory response via macrophage activation. A second subclass, CD4+ T lymphocyte subset (TH2 [helper]), recognizes peptides (including allergens) bound to MHC II and releases cytokines, including IL-4, IL-5, and IL-13. This results in inflammatory responses in which eosinophils predominate and stimulates B lymphocytes to secrete Ig. Another subclass, the T regulatory lymphocyte, acts to suppress responses of other T lymphocytes. Most antigens require an accompanying signal from helper T lymphocytes before they can stimulate B lymphocytes to proliferate and differentiate into antibody-secreting plasma cells. Thus, T lymphocytes are crucial to adaptive immunity by destroying pathogen-infected cells, by activating macrophages, and by activating B lymphocytes. Thus, complex interactions between host cells, pathogens or other antigens, and inflammatory mediators of the innate and adaptive immune system typically result in appropriate host defenses, the removal of the inciting pathogen, and the generation of differentiated memory lymphocytes through clonal expansion, allowing faster specific immune responses in future encounters with the same offending antigen. Impaired host defense mechanisms can lead to increased susceptibility to infection, to development of neoplasia, or to chronic inflammatory or autoreactive disorders such as atopic dermatitis (E-Figs. 17.15 and 17.16), contact hypersensitivity, or lupus erythematosus. Skin as a Physical Barrier First and foremost, the skin is a barrier that prevents loss of water and fluid components (e.g., electrolytes, macromolecules) from the body, and without this function, terrestrial animals would die. The lipid envelope of the deeper layers of the stratum corneum seals the epidermis and prevents major water loss. In addition, viable epidermal layers such as the stratum granulosum, for example, also contribute to this function via a tight junction layer. Normal intact skin has many natural defense mechanisms and barriers that protect the body from physical and chemical injury. The skin prevents entry of foreign materials, parasites, and infectious 1149 agents. It is impenetrable to most microbial organisms. It also protects the body from a variety of environmental insults that include pressure, friction, mild mechanical trauma, temperature extremes, UV light exposure, and chemical absorption (see Fig. 17.9). To do this, the epidermis and dermis provide the resiliency of the skin, and the hair reduces frictional injury. The panniculus provides a cushion to injury, especially in pawpads. Skin pigment and hair block damaging UV-solar radiation. Diseases Affecting Multiple Species of Domestic Animalsg In the context of discussing diseases of the skin, it is important to understand the different types of diagnoses used by clinicians and pathologists. A clinical diagnosis is a diagnosis made of a disorder or disease affecting a living animal or a group of animals in a herd, flock, kennel, or cattery. It is a diagnosis based on information gathered from the history, clinical signs, physical examination (including assessment of the skin), response to treatment, and ancillary laboratory testing such as microbial cultures and biopsies as examples. A gross (macroscopic [using unaided eyes]) diagnosis is a diagnosis made in a dead animal after macroscopic evaluation of its tissues, organs, and organ systems for lesions during a postmortem examination. A histologic (microscopic) diagnosis is a diagnosis based on the microscopic (histologic) evaluation of glass slides containing specimens of tissues, organs, and organ systems obtained via biopsy or during a postmortem examination. Congenital and Inherited Disorders The terms congenital and inherited (hereditary) are not synonymous. Congenital lesions develop in the fetus (in utero), are present at birth, and have a variety of causes. An example is hypotrichosis (i.e., partial absence of hair) in the fetus associated with maternal dietary iodine deficiency. Inherited conditions are transmitted genetically and may be manifested phenotypically in utero or at birth, but may also develop later in life. One example of the latter is uveodermatolic syndrome in Nordic dog breeds, which may not develop until 1 to 2 years of age or later. E-Table 17.3 provides a comprehensive list of inherited cutaneous diseases of animals, in which the underlying gene variant has been identified. There are many other examples, in which predisposition to develop the disease (e.g., atopic dermatitis, cutaneous and renal glomerular vasculopathy in greyhounds, sebaceous adenitis, alopecia X) is inherited, but the mode of inheritance and the underlying gene variants have not been documented. E-Table 17.4 provides a list of examples of these disorders (also see E-Table 1.2). Collagen Dysplasia Collagen dysplasia comprises a group of clinically, genetically, and biochemically heterogeneous diseases with an inherited defect of collagen synthesis or processing. This situation leads to structurally abnormal dermal collagen. Variations in several genes have been identified as underlying cause in some but not all collagen dysplasia syndromes (see E-Table 17.3).These genes encode for extracellular matrix proteins and their processing enzymes. Specific enzyme defects affecting collagen synthesis or processing are the cause of most collagen dysplasia syndromes. Diseases with collagen dysplasia include cutaneous asthenia (weakness), hyperelastosis cutis, dermatosparaxis, Ehlers-Danlos– like syndrome, and hereditary equine regional dermal asthenia gSee E-Appendix 17.1 for a description of postmortem examination of the skin, claws, pawpads, and hooves. CHAPTER 17 The Integument A 1149.e1 B E-Figure 17.15 Atopic Dermatitis, Skin, Dog. A, This golden retriever has erythema, alopecia, and erosions affecting the skin around the eye and muzzle. The lesions are caused by self-trauma from rubbing and scratching as a result of pruritus. B, Photomicrograph from experimentally induced lesion of atopic dermatitis in the skin of a dog. The epidermis has acanthosis, mild spongiosis, a few lymphocytes, and clustered Langerhans cells (arrow). Focal parakeratosis (arrowhead) is secondary to spongiosis. The superficial dermis contains a mild perivascular infiltrate (exudate) of small lymphocytes, plasma cells, mast cells, and fibroblasts. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. D. Duclos, Animal Skin and Allergy Clinic. B courtesy Dr. T. Olivry, College of Veterinary Medicine, North Carolina State University.) E-Figure 17.16 Illustrating the Defective Epidermal Barrier in Individuals with Atopic Dermatitis. The epidermal barrier is formed by the lower layers of the stratum corneum and is composed of differentiated keratinocytes, termed corneocytes (yellow-beige rectangles), held together with corneodesmosomes (purple half-spheres). The hyperactivity of degradative proteases (light red hexagons) found within the epidermis and contributed to by exogenous proteases (dark red hexagons), from house dust mites and Staphylococcus spp. bacteria, for example, facilitate the cleavage of the corneodesmosome junctions. This is just one event in the breakdown of the epidermal barrier that permits the penetration of allergens. Dendritic cells (green) found in the dermis take up and present these allergens (red stars) to helper T lymphocytes type 1 (TH1) (purple) and recruit more CD4+ T lymphocytes (blue). Activated dendritic cells and interleukin 4 (IL-4), expressed by CD4+ T lymphocytes, promote T lymphocyte type 1 (TH1) to T helper lymphocyte type 2 (TH2) switching with the subsequent release of proinflammatory cytokines and elevation of immunoglobulin E concentrations. (Revised and redrawn from Cork MJ, Danby SG, Vasilopoulos Y, et al: Epidermal barrier dysfunction in atopic dermatitis, J Invest Dermatol 129:1892-1908, 2009.) 1149.e2 SECTION II Pathology of Organ Systems E-Appendix 17.1 Postmortem Evaluation of the Skin, Claws, Pawpads, and Hooves The skin is the first organ encountered in the autopsy procedure, and examination of the skin occurs at the time of patient identification. Before beginning the postmortem examination, confirm the identity of the body and record the breed, sex, and neuter status. Record the body condition, state of hydration, degree of autolysis, and the death-to-postmortem interval. Photograph the body, including the head, and any skin marking or identifying labels, such as collars, tags, or tattoos. Photograph surgical sites, catheters, or medical devices, if present. Photograph the incisor teeth of horses as well as any mucosal lip tattoo. To further document the identity of the animal, record skin markings (pigmentation patterns), coat color, any physical deformations (e.g., scars, amputations) as well as any tattoos or animal tags, including their location, color, and text/symbol. Assess for a microchip in stray small animal pets. Small tags that are water stable are collected into the autopsy formalin container as an additional means, other than the required container label, to maintain the identification of the autopsy samples. The skin should be examined systematically and thoroughly before opening the body cavities in the postmortem procedure to identify lesions. As with other organs, record the characteristics of all lesion types as well as their distribution, placement on the body, and symmetry, if present. Photograph the lesions. Examine both sides of the body (if possible): this requires flipping the body of small animals on the autopsy table and assessing large animals while still suspended on the autopsy service hoist. Both visually inspect and palpate the skin to identify lesions, running your hands over large areas of the body, especially in well-haired animals. Look for deformations of the hair coat and for wet or dried exudates on the skin surface as clues to the locations of small hidden lesions below the hair coat. Part the hair coat in several locations and observe the epidermal surface. Do not forget to determine if there are also lesions involving the oral, ocular, and anogenital mucocutaneous junctions or mucosae as well as any involvement of specialized skin structures, including the ear canal, nasal planum, digital or pawpads, claws, and/or hooves. Record the quality and quantity of the hair coat, hooves and claws, which are general indicators of systemic health. In this regard, also consider assessing the growth status of the hair: this is done by determining the anagen-to-telogen ratio via trichogram. Tent the skin and note its stiffness and recoil to assess for dehydration and physical elasticity of the skin. Apply strong tractional force to pinched skin (attempt to tear it) to assess for skin fragility. During the process of opening the body, reflect large areas of skin in the subcutaneous plane and examine the subcutaneous tissues for lesions, including for those lesions that are hard to see externally, such as puncture wounds and/or subcutaneous hemorrhage. Collect both lesional and nonlesional survey samples of skin for histology. If available, collect a minimum of three full-thickness skin samples of each skin lesion type into 10% neutral buffered formalin. Collect small lesions in their entirety. For large lesions, collect samples that consist 70% of lesional skin and 30% of normal marginal skin. Additional information is provided in the textbook on where and how to specifically sample different skin lesion types (see Function, Diagnostic Procedures, Skin Biopsy Procedures). In all patients, with or without skin lesions, collect three survey samples of skin for histology, one each from the mid dorsal back, the mid ventral abdomen, and a distal limb. These skin samples should be rectangular (at least 2 × 4 cm), and the long axis of the skin sample should align with the angle of growth of the hair shafts to allow for optimal trimming for histology to capture hair follicles. To prevent skin folding or curling of thin skin, first place samples of skin flatly on cardstock paper (or very thin cardboard), with the subcutaneous side stuck to the card, and then float the sample upside down in formalin with the skin surface facing down (submerged). Note, after partial fixation, the skin sample will often fall off of the card, which is acceptable, because by this time the sample is fixed enough to maintain a flat shape. For claw or digit lesions on small animals, collect three digits intact with affected claws, and one with a nonaffected claw, into formalin. Do not cut off the claw or claw tip before histology. After adequate fixation, the digit should be decalcified, the claw softened chemically, and the digit sectioned in the paramedian sagittal plane along the surface of the bones of the first and second phalanx but not into the claw. This allows the histotechnologist to section into the digit on the microtome until just before the claw midline in the sagittal plane, before collecting the first histologic section for assessment. To sample lamellae of the hoof of the horse, use a saw to collect 1-cm thick, 2-cm wide, transverse sections, perpendicular to the toe surface, that is located at the mid-dorsal toe (halfway between the coronary band and the toe tip) (see Fig. 17.61, A, arrows). After fixation, trim excess outer cornified hoof wall away, if nonlesional, and chemically soften the sample before histology. This sectional plane is important to visualize the primary and secondary hoof lamellae. A similar sampling approach applies to the claws of ruminants as well. Consider the collection of additional samples for ancillary diagnostic tests, such as for microbiologic testing, at the time of the postmortem exam; these tests are detailed elsewhere in the text (see Function, Diagnostic Procedures, Ancillary Procedures). Consider banking frozen skin samples of lesional skin at (−80° C for long periods or at −20° C for short periods of time) for later testing. Additional tests to consider performing at the time of the postmortem include trichograms, as well as skin surface touch or acetate tape impression cytology, skin scrape cytology, and touch or aspiration cytology of space-occupying lesion types or exudates. E-Table 17.3 Inherited Cutaneous Diseases of Animals, in Which the Underlying Gene Variant Has Been Identified OMIA ID* https://omia.org Reference Breed Gene Acrodermatitis enteropathica Congenital hypotrichosis and short life expectancy Ehlers-Danlos syndrome, classic type 1 Epidermolysis bullosa simplex Inflammatory linear verrucous epidermal nevi Hypotrichosis Lanceolate hairs Acral mutilation syndrome (hereditary sensory neuropathy resulting in skin lesions) CHILD’s like syndrome (congenital cornification disorder) Darier disease Dermal mucinosis; fever Dermoid sinus Cat Cat Turkish van Birman SLC39A4 FOXN1 AR AR 000593-9685 001949-9685 Kiener et al, 2021 Abitbol et al, 2015 Cat Cat Cat Domestic shorthair Domestic shorthair Domestic shorthair COL5A1 KRT14 NSDHL AD Unknown Unknown 000543-9913 002185-9685 Spycher et al, 2018 Dettwiler et al, 2020 De Lucia et al, 2018 Cat Cat Dog Lykoi Domestic Shorthair German shorthaired and English pointers; English springer and French spaniel Labrador retriever; Chihuahua HR hairless DSG4 GDNF AR AR AR 002229-9685 002452-9685 001514-9615 Buckley et al, 2020 Kiener at al, in press Plassais et al, 2016 NSDHL 002117-9615 001561-9615 000272-9615 Dog ATP2A2 HAS2 FGF3, FGF4, FGF19 MLPH Bauer et al, 2017; Leuthard et al, 2019 Linek et al, 2020 Olsson et al, 2011 Salmon Hillbertz et al, 2007 Dilute coat color (predisposing risk factor for color dilution alopecia) Ectodermal dysplasia (X-linked hypohidrotic) Irish terrier Shar Pei Rhodesian ridgeback; Thai ridgeback Many breeds X-linked semidominant AR AR AR (complex) AR (complex) 000031-9615 Drögemüller et al, 2007 Dog German shepherd, Dachshund, and several other breeds EDA X-linked recessive 000543-9615 Ectodermal dysplasia/skin fragility syndrome Ehlers-Danlos syndrome, classic type 1 Ehlers-Danlos syndrome Ehlers-Danlos syndrome, type VII (Dermatosparaxis) Epidermolysis bullosa simplex, basal Epidermolysis bullosa simplex, suprabasal Epidermolysis bullosa, junctional Epidermolysis bullosa, dystrophic Dog Chesapeake Bay retriever PKP1 AR 001864-9615 Casal et al, 2005; Waluk et al, 2016; Hadji Rasouliha et al, 2018 Olivary et al, 2012 Dog Dog Dog Labrador retriever, Mongrels Mongrel Doberman pinscher COL5A1 TNXB ADAMTS2 AD AD AR 002165-9615 002203-9615 000328-9615 Bauer et al, 2019 Bauer et al, 2019 Jaffy et al, 2019 Dog Dog Eurasier Chesapeake Bay retriever PLEC PKP1 AR AR 002080-9615 001864-9615 Mauldin et al, 2016 Olivry et al, 2012 Dog Dog LAMA3 COL7A1 AR AR 001677-9615 000341-9615 Exfoliative cutaneous lupus erythematosus Hairlessness Dog UNC93B1 AR 001609-9615 Capt et al, 2005 Baldeshi et al, 2003; Niskanen et al, 2017 Leeb et al, 2020 SGK3 AR 001279-9615 Hereditary footpad hyperkeratosis Hereditary foot pad hyperkeratosis and ichthyosiform dermatosis (and keratoconjunctivitis sicca) Hereditary nasal parakeratosis Dog Dog German shorthaired pointer Golden retriever; Central Asian shepherd German shorthaired pointer, viszla American terrier; Scottish deerhound Irish terrier, Kromfohrlander Cavalier King Charles spaniel FAM83G FAM83H AR AR 001327-9615 001683-9615 Dog Labrador retriever, greyhound SUV39H2 AR 001373-9615 Hyperkeratosis (nonepidermolytic palmoplantar) Dog Dogue de Bordeau KRT16 AR 002088-9615 Dog Dog Dog Dog Dog Parker et al, 2017; Hytönen and Lohi 2019 Drögemuller et al, 2014 Forman et al, 2012 Jagannathan et al, 2013; Bauer et al, 2018 Plassais et al, 2015 Continued 1149.e3 Species CHAPTER 17 The Integument Phenotype Mode of Inheritance Inherited Cutaneous Diseases of Animals, in Which the Underlying Gene Variant Has Been Identified—cont’d Species Breed Gene Mode of Inheritance OMIA ID* https://omia.org Reference Ichthyosis Dog German shepherd dog ASPRV1 AD 002099-9615 Bauer et al, 2017 Ichthyosis (epidermolytic) Ichthyosis (lamellar) Ichthyosis Ichthyosis Dog Dog Dog Dog Norfolk terrier Jack Russell terrier Golden retriever American bulldog KRT10 TGM1 PNPLA1 NIPAL4 AR AR AR AR 001415-9615 000546-9615 001588-9615 001980-9615 Ichthyosis Ichthyosis Improper coat Lethal acrodermatitis Musladin-Lueke syndrome (geleophysic dysplasia) Oculocutaneous albinism 2 (photophobia) Oculocutaneous albinism 4 (risk factor for melanomas) Dog Dog Dog Dog Dog Great Dane Shar pei Portuguese water dog Bull terrier; miniature bull terrier Beagle FATP4 KRT1 RSPO2 MKLN1 ADAMTSL2 AR AD AR AR AR 001973-9615 002425-9615 001498-9615 002146-9615 001509-9615 Credille et al, 2005 Credille et al, 2009 Grall et al, 2012 Mauldin et al, 2015; Casall et al, 2017 ; Briand et al, 2019 Metzger et al, 2015 Affolter et al, submitted Parker et al, 2010 Bauer et al, 2018 Bader et al, 2010 Dog German spitz OCA2 AR 002130-9615 Caduff et al, 2017 Dog SLC45A2 AR 001821-9615 Winkler et al, 2014, Wijesena et al, 2015, Caduff et al, 2017 Renal cystadenocarcinoma and nodular dermatofibrosis Absence of pigmentation associated with microphthalmia Ectodermal dysplasia, anhidrotic Dog Doberman pinscher; bull mastiff; Lhasa Apso; Pekingese; Pomeranian German shepherd FLCN AD 001335-9615 Lingaas et al, 2003 Cattle Holstein MITF AD 001931-9913 Wiedemar et al, 2014 Cattle Holstein; Japanese black; crossbred calves EDA X-linked 000543-9913 Drögemüller et al, 2001, 2002, 2006; Barlund et al, 2007; Ogino et al, 2011, 2012; Escouflaire et al, 2019 Ectodermal dysplasia, anhidrotic, EDAR-related Ehlers-Danlos syndrome, Holstein variant Ehlers-Danlos syndrome, classic type Epidermolysis bullosa simplex, basal Cattle Charolais EDAR AR 002128-9913 Bourneuf et al, 2017 Cattle Holstein EPYC AD 001716-9913 Tajima et al, 1999 Cattle Cattle Holstein Friesian-Jersey COL5A2 KRT5 002295-9913 002081-9913 Jacinto et al, 2020 Ford et al, 2005 Epidermolysis bullosa simplex, junctional Epidermolysis bullosa simplex, junctional Epidermolysis bullosa simplex, junctional Epidermolysis bullosa simplex, dystrophic Ichthyosis fetalis (Harlequin ichthyosis) Ichthyosis Hypotrichosis (hairless streaks) Cattle Belgian blue LAMA3 AD AD with mosaicism AR 001677-9913 Sartelet et al, 2015 Cattle Danish Hereford LAMC2 AR 001678-9913 Murgiano et al, 2015 Cattle Charolais ITGB4 AR 001948-9913 Cattle COL7A1 AR 000341-9913 Cattle Rotes Höhenvieh; Vorderwälder Chianina; Shorthorn ABCA12 AR 002193-9913 Cattle Cattle Chianina Pezzata Rossa FA2H TSR2 AR X-linked semidominant 002450-9913 000542-9913 Michot et al, 2015, Peters et al, 2015 Menoud et al, 2012; Pausch et al, 2016 Charlier et al, 2008; Woolley et al, 2019 Jacinto et al, 2021 Murgiano et al, 2015 SECTION II Pathology of Organ Systems Phenotype 1149.e4 E-Table 17.3 Phenotype Species Breed Gene Mode of Inheritance OMIA ID* https://omia.org Hypotrichosis Hypotrichosis with coat-color dilution (rat-tail syndrome) Cattle Cattle Hereford KRT71 MC1R/ PMEL Unknown AD 002114-9913 001544-9913 Markey et al, 2010 Knaust et al, 2016 Joli et al, 2008 Oculocutaneous albinism type 4 Tricho-dento-osseus-like syndrome Zinc deficiency-like syndrome Brindle 1 hair coat (hypotrichosis) Cattle Cattle Cattle Horse Braunvieh Brown Swiss Fleckvieh Quarter horse SLC45A2 DLX3 PLD4 MBTPS2 001821-9913 002109-9913 001935-9913 002021-9796 Rothammer et al, 2017 Hofstetter et al, 2017 Jung et al, 2014 Murgiano et al, 2016 Curly coat with hypotrichosis Horse KRT25 on SP6 002175-9796 Thomer et al, 2018 Epidermolysis bullosa, junctional Epidermolysis bullosa, junctional Horse Horse American Bashkir Curly horse, Missouri Foxtrotter American saddlebred Belgian draft horse; Trait Breton; Trait Comtois; Italian draft horse AR AD AR X-linked semidominant Unknown LAMA3 LAMC2 AR AR 001677-9796 001678-9796 Hereditary equine regional dermal asthenia Hoof wall separation syndrome Incontinentia pigmenti Horse Quarter horse PPIB AR 000327-9796 Graves et al, 2008 Spirito et al, 2002; Milenkovoc et al, 2003; Cappelli et al, 2015 Tryon et al, 2007 Horse Horse Connemara pony Quarter horse; warmblood SERPINB11 IKBKG 001897-9796 001899-9796 Finno et al, 2015 Towers et al, 2013 Lavender foal syndrome (lethal coat color dilution) Lethal white foal syndrome, megacolon Horse Arabian MYO5A AR X-linked semidominant AR 001501-9796 Brooks et al, 2010 Horse American paint EDNRB AR 000629-9796 Naked foal syndrome Warmblood fragile foal syndrome (Ehlers-Danlos syndrome, Type VIA) Epidermolysis bullosa, junctional Epidermolysis bullosa, junctional Ehlers-Danlos syndrome, Type VII Hypotrichosis Horse Horse Akhal-Teke Warmblood ST14 PLOD1 AR AR 002096-9796 001982-9796 Metallinos et al, 1998, Purdy et al, 1998, Santschi et al, 1998, Yang et al, 1998. Bauer et al, 2017 Dias et al, 2019 Sheep Sheep Sheep Sheep German black headed Churra White Dorper Valle del Belice LAMC2 ITGB4 ADAMTS2 HR AR AR AR AR 001678-9940 001948-9940 000328-9940 000540-9940 Mömke et al, 2011 Suarez-Vega et al, 2015 Joller et al, 2017 Finocchiaro et al, 2008 CHAPTER 17 The Integument AR, Autosomal recessive; AD, autosomal dominant. Full reference citations at: https://omia.org *Online Mendelian Inheritance in Animals (OMIA) is a catalogue/compendium (https://omia.org) of inherited disorders. Reference 1149.e5 Examples of Suspected Inherited Cutaneous Diseases of Animals, in Which the Underlying Gene Variant Has Not Been Identified OMIA ID https://omia.org Species Breed Mode of inheritance Congenital hypotrichosis with thymic aplasia Collagen dysplasia Cat Cat Dermoid sinus Epidermolysis bullosa Ichthyosis Nasal hyperkeratosis Ochronosis-like Sebaceous gland dysplasia Primary seborrhea-oleosa Urticaria pigmentosa Acantholysis, familial Acrochordonous plaque Alopecia X Anal furunculosis Atopic dermatitis Cat Cat Cat Cat Cat Cat Cat Cat Dog Dog Dog Dog Dog Unknown AD, AR Unknown AR suspect Unknown Unknown Unknown Unknown Unknown Unknown AD Unknown Unknown Unknown Unknown 000272-9685 No No No No 001710-9685 000822-9685 001289-9685 No 001370-9615 No 001589-9615 000269-9615 Bald thigh syndrome Black hair follicle dysplasia Cutaneous and renal glomerular vasculopathy in greyhounds Dermatofibrosis, nodular Dermatomyositis Exfoliative cutaneous lupus erythematosus Focal metatarsal fistulas Follicular dysplasia Dog Dog Dog Birman Domestic shorthair, Himalayan Burmese Siamese Abyssinian Bengal, Egyptian Mau Domestic shorthair Various breeds Persian Sphinx English setter Pug, bulldogs Pomeranian German shepherd Boxer, bulldog, German shepherd dog, Labrador retriever, pug, West Highland white terrier Greyhound and related breeds Various breeds Greyhound Multifactorial AR AR 002168-9615 000110-9615 No Dog Dog Dog Dog Dog Unknown AR Unknown Unknown 001195-9615 000270-9615 001609-9615 000389-9615 No German shepherd dog pyoderma Ichthyosis, nonepidermolytic Ichthyosis, epidermolytic Lymphedema Schnauzer comedo syndrome Sebaceous adenitis Dog Dog Dog Dog Dog Dog Unknown Unknown Unknown Unknown Unknown AR 001877-9615 No No 000613-9615 001272-9615 001563-9615 Sebaceous gland dysplasia Stiff skin syndrome Systemic lupus erythematosus Symmetric lupoid onychodystrophy Dog Dog Dog Dog Unknown AR Multifactorial Multifactorial No 002018-9615 000968-9615 001989-9615 Zinc-responsive dermatosis Dog Unknown 000593-9615 Acantholysis, familial Alopecia areata Collagen dysplasia Cattle Cattle Cattle AR suspect Unknown AR No 001702-9913 No German shepherd Collie and related breeds German shorthair pointer, vizsla German shepherd Curly coated retriever, Chesapeake Bay retriever; Irish water spaniel, Lagotto Romagnolo, Pont Audemer spaniel, Wetterhound German shepherd Various breeds Rhodesian ridgeback, Labrador retriever Various breeds Schnauzer Standard poodle, Havanese, Hovawart, Akitainu, and others Various breeds West Highland white terrier Nova Scotia duck-tolling retriever Border collie, bearded collie, Gordon setter, Rhodesian ridgeback Alaskan malamute, Siberian husky Angus Eringer Belgian, Charolais, Hereford, Simmental, crossbreeds 000544-9685 No SECTION II Pathology of Organ Systems Phenotype 1149.e6 E-Table 17.4 Phenotype Species Breed Mode of inheritance OMIA ID https://omia.org Dermoid sinus Ectodermal dysplasia (congenital hypotrichosis and incisor anodontia) Epidermolysis bullosa, junctional Epidermolysis bullosa, simplex Ichthyosis fetalis Ichthyosis congenita Hyperhidrosis Hypotrichosis, congenital Hypotrichosis, congenital Hypotrichosis, lethal Oculocutaneous albinism (Chédiak-Higashi syndrome) Rat-tail syndrome (hypotrichosis with coat-color dilution) Zinc deficiency, hereditary Chronic progressive lymphedema Insect bite hypersensitivity Linear epidermal nevi Collagen dysplasia (Ehlers-Danlos-like syndrome) Cattle Cattle Unknown Holstein-Friesian Unknown AR 000272-9913 No Cattle Cattle Cattle Cattle Cattle Cattle Cattle Cattle Cattle Ayrshire, Jersey, Angus, shorthorn Simmental and crossbred Norwegian red poll, Friesian, Brown Swiss Jersey, Holstein-Friesian, Pinzgauer, Chianina Shorthorn Hereford, polled Hereford Guernsey, Jersey, Holstein, Ayrshire Holstein-Friesian Hereford, Brangus, and Japanese black cattle AR AD AR AR Unknown AD AR AR AR No No No No 001231-9913 No No No No Cattle Various breeds AD 001544-9913 Cattle Horse Horse Horse Sheep AR Unknown Multifactorial Unknown AR; AD No 000613-9796 001664-9796 000604-9796 000327-9940 Epidermolysis bullosa, dystrophic Hypotrichosis, congenital Ichthyosis fetalis Lethal grey/gray Epidermolysis bullosa, dystrophic Sheep Sheep Sheep Sheep Goat Friesian, Black pied Danish, shorthorn, Angus Draught horses Various breeds Belgian draught horse Norwegian Dala, Finnish crossbred Merino, and others; New Zealand Romney Unknown Dorset, polled Unknown Karakul Unknown AR AR Unknown Autosomal Unknown No No 002193-9940 000591-9940 000341-9925 AR, Autosomal recessive; AD, autosomal dominant. CHAPTER 17 The Integument 1149.e7 1150 SECTION II Pathology of Organ Systems (HERDA). These diseases are rare but occur in most domestic animal species. In each disease, the affected skin grossly exhibits variable hyperextensibility, laxity, and/or fragility. Skin is often easily torn, even from normal handling or activity, leading to open wounds, seromas, and hematomas, which exhibit poor wound healing (Fig. 17.31). Secondary scars may be numerous. Microscopic lesions vary among these disorders and include collagen bundles that vary in size and shape, contain abnormally tangled fiber patterns, and/or are separated by wide spaces, some being associated with laminar splits in the dermis (see Fig 17.31). However, in some disorders, the skin has no detectable microscopic alterations; in such cases, electron microscopy is sometimes helpful and biochemical analyses or genetic tests, if available, may be required to make a definitive diagnosis. Hereditary equine regional dermal asthenia (HERDA), one of the more common collagen dysplasia syndromes in horses, is further discussed in the section on Diseases of Horses; Congenital and Inherited Disorders. Congenital Alopecia and Hypotrichosis Congenital alopecia is the complete absence of hair in areas of haired skin at birth. Hypotrichosis refers to reduced density of hairs in areas of haired skin. These disorders can occur in all domestic animal species, are present at birth, and are the result of an abnormal development of hair follicles or hair shafts during hair follicle morphogenesis (Fig. 17.32 and see Fig. 17.28). Congenital alopecia may be inherited or caused by a metabolic imbalance or in utero infection. The inherited forms are discussed in the section Diseases Affecting Multiple Species of Domestic Animals, Follicular Dysplasia (Inherited Alopecia/ Hypotrichosis) and are summarized in Table 17.5 and E-Tables 17.3 and 17.4. In herd health management and disease prevention, it is important to differentiate the congenital inherited disorders from the nongenetic alopecia and hypotrichosis disorders. The latter include congenital hypotrichosis caused by maternal iodine deficiency in foals, calves, lambs, and pigs; in utero infection with bovine virus diarrhea or hog cholera virus; and defects in other systems such as adenohypophyseal hypoplasia in some breeds of cattle (see Table 17.5). A diagnosis of these disorders is usually made by a combination of clinical or gross examination (e.g., of the thyroid glands, pituitary gland, or dental abnormalities), microscopic examination of skin lesions (e.g., presence of absence of hair follicles or other adnexa), and in some instances evaluation for infectious agents (e.g., immunohistochemical evaluation of hair follicles for bovine virus diarrhea virus in calf skin). In newborn animals it is important to biopsy, if possible, the most alopecic areas as well as the most haired areas, in similar anatomic locations, and to submit the samples in separate and labeled containers to achieve a correct histologic diagnosis. Cornification Defects A B Figure 17.31 Collagen Dysplasia, Skin, Dog. A, The skin is hyperextensible and can be stretched more than the skin of a normal dog. B, The collagen bundles are irregular in size and shape and are arranged haphazardly. Not all cases of this heterogeneous genetic disorder show obvious changes affecting collagen on histologic evaluation. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. B. Baker, Washington State University. B courtesy Dr. M.M. Welle, Institute of Animal Pathology, Vetsuisse Faculty Bern.) Primary Idiopathic Seborrhea. Seborrhea is a clinical term that is used to describe excessive scaling of the skin. Seborrhea is classified as either primary or secondary. Primary seborrhea is diagnosed when other causes for excessive scaling or for secondary seborrhea, such as nutritional factors, allergies, and/or infections, can be ruled out. Primary idiopathic seborrhea is poorly described and characterized by excessive cornification of the epidermis, hair follicle epithelium, and/or claws. Clinical presentation of seborrhea overlaps with those of some ichthyoses (see later), and thus some cases may turn out to be ichthyoses. Primary idiopathic seborrhea occurs most commonly in dogs and rarely in cats, horses, cattle, goats, and sheep. In dogs, a breed predisposition for American cocker spaniels, English springer spaniels, basset hounds, West Highland white terriers, Dachshunds, Labrador and golden retrievers, Chinese Shar Peis, and German shepherds is seen. This clear breed predilection and familial history often associated with seborrhea suggest that genetic factors are involved in pathogenesis of the disease. In cocker spaniels, results of research studies show a hyperproliferation of basal cells, which results in a strikingly shortened epidermal turnover time (e.g., from 22 days to 8 days); however, the molecular basis of this hyperproliferation and the clinical and histologic lesions has not been studied. In primary seborrhea, quantitative studies on sebum production have not been performed, but it is known that there is a relative increase in free fatty acids and a relative decrease in diester waxes on the surface of the seborrheic skin of various breeds. In addition, the skin microbiome changes and nonpathogenic resident bacteria are replaced by pathogenic, coagulasepositive staphylococci. The disease begins at a young age and typically progresses throughout the animal’s life. Secondary bacterial and yeast infections are also common. CHAPTER 17 The Integument 1151 B A C Figure 17.32 Ectodermal Dysplasia, Hypohidrotic, X-linked (XHED) Characterized by Congenital Hypotrichosis and Anodontia, Calf. A, The hair coat is sparse and short. Eyelashes and tactile hairs are also sparse and very short. The tail switch (not in this photograph) was approximately one-third the normal length. B, Radiograph, skull. Note that most of the teeth are missing (i.e., anodontia). C, Affected skin. Note the lack of hair follicles and other adnexa. Hematoxylin and eosin (H&E) stain. (A courtesy Professor T. Leeb, Institute of Genetics, Vetsuisse Faculty, Bern; and Drögemüller C, Kuiper H, Peters M, et al: Congenital hypotrichosis with anodontia in cattle: a genetic, clinical and histological analysis, Vet Dermatol 13:6;307-313, 2002. B courtesy Radiology, TiHo Hannover. C courtesy Dr. F. Seeliger, Department of Pathology, Tieraerztliche Hochschule Hannover.) Clinically, a dry form (seborrhea sicca) and a greasy form (seborrhea oleosa) of seborrhea have been described. The dry form has dry skin and white-to-gray scales that exfoliate. The greasy form has scaling and excessive brown to yellow lipids that adhere to the surface of the skin and hair. An animal can have seborrhea sicca in some areas of the body and seborrhea oleosa in others. Microscopic lesions are not specific, and the clinical history is important to make the diagnosis. The epidermis is mildly to moderately hyperplastic and has a papillary appearance. The epidermis is also covered by marked orthokeratotic hyperkeratosis, which involves the follicular infundibulum, and may progress to small comedones. At the edges of the follicular ostia, foci of parakeratosis form over a spongiotic epidermis containing a few scattered leukocytes. In cases with secondary yeast or bacterial infections, superficial dermal congestion and edema may occur along with a perivascular inflammatory cell infiltrate (exudate). Ichthyosis. Ichthyoses encompass a heterogeneous group of inherited and generally congenital skin diseases with altered epidermal cornification. They occur most commonly in the dog but also occur rarely in cattle, sheep, horses, pigs, and cats. Ichthyosis is caused by a primary defect in the formation of the stratum corneum. The stratum corneum is continuously being formed by terminal differentiation of keratinocytes into corneocytes (dead cells) that are shed from the skin surface to maintain its thickness and integrity. Genetic mutations that affect the biochemical and structural properties of the stratum corneum alter the dynamic differentiation of keratinocytes into corneocytes and lead to stratum corneum buildup (less often excessive loss), altered function of the skin, and the clinical signs of ichthyosis. The clinical signs of ichthyoses are scaling, dry skin, and variable erythroderma (reddening of the skin). The lesions of ichthyosis are often similar to the lesions of primary seborrhea, some examples of which may be forms of ichthyosis. Scaling ranges from subtle to severe, where it can be disfiguring and lethal (Fig. 17.33 and E-Fig. 17.17). A minority of disorders with ichthyosis may also have mild signs of epidermal fragility and/or hyperkeratotic lesions that are restricted to the pawpads and/or nasal planum. Secondary microbial infections are common. Ichthyoses sometimes mimic, and are thought to potentiate, allergic disease in human beings because of barrier disruption and altered allergen exposure. Similar injury likely occurs in some ichthyoses of dogs. 1152 Table 17.5 SECTION II Pathology of Organ Systems Categories, Causes, and Age of Onset of Hypotrichosis and Alopecia Category Cause Age of Onset Species Congenital hypotrichosis or alopecia Inherited absent or abnormal hair follicle morphogenesis, involving either hair follicle induction, organogenesis or cytodifferentiation during embryonic life. May affect only hair follicle morphogenesis or may be accompanied by odontogenic, thymic, genital, or other defects, then classified as ectodermal dysplasia. Maternal dietary deficiency (e.g., iodine deficiency) Secondary to other defects (adenohypophyseal hypoplasia) In utero infection with bovine virus diarrhea or hog cholera virus Inherited (SGK3 mutation) or genetic predisposition Present at birth All species Present at birth Calves, piglets, lambs, foals Guernsey and Jersey calves Calves, pigs Months to first few years after birth Dogs Genetic predisposition Months to first few years after birth Described only in dogs and cats Abnormal function of pituitary, thyroid, adrenal glands, or gonads; or exposure to exogenous hormones (iatrogenic systemic or topical administration, or accidental topical exposure to creams used on human skin) Unknown Hair cycle is impaired by factors such as antimitotic drugs (chemotherapy); stress, fever, illness Develops in all ages, but seen mostly in older dogs (exception hyposomatotropism and exposure to exogenous hormones) Adult Typically adults Predominantly dogs Ischemia due to vasculitis or impaired blood flow (traction alopecia—seen in dogs, posttraumatic alopecia—seen in cats) Hypersensitivity reactions, psychogenic causes, occasionally feline hyperthyroidism Follicular infection (bacteria, fungi, demodex, other parasites, viruses), Immune-mediated mural folliculitis, bulbitis (alopecia areata) Poor hair shaft quality resulting from lack of sebum and impaired hair follicle cycling Severe protein or calorie deficiency Any age Mostly dogs, rarely cats Any age Mostly cats Any age Any species; dogs most frequently affected with follicular infection Mostly dogs; Cats (sebaceous gland dysplasia) Any species Inherited or genetically predisposed hair follicle regeneration with postnatal clinical manifestation Dysplasia associated with insufficient hair shaft quality Acquired hair cycle disorders of endocrine origin (hypothyroidism, hyperadrenocorticism, hyperestrogenism, hyposomatotropism) Hair cycle disorders of unknown origin Hair loss disorders resulting from trauma, stress, medication or systemic disease (traction alopecia, alopecia related to chemotherapy, telogen effluvium, anagen defluxion) Alopecia related to trauma and impaired nutrition (ischemiainduced follicular atrophy) Excessive grooming Inflammation of the hair follicle Inflammation or dysplasia of sebaceous glands Poor nutrition Neoplasia Paraneoplastic: internal malignancy, often of pancreas Direct involvement of epidermis, dermis, or adnexa (e.g., lymphoma) Ichthyoses are classified primarily based on clinical features and molecular genetics. As with other genetic disorders, if only skin lesions occur, then the ichthyosis is classified as nonsyndromic; when lesions affect the skin and other organs, the ichthyosis is classified as syndromic. Histopathologic evaluation of skin biopsies can group disorders morphologically, based on the pattern of cornification and the presence of epidermolysis, but morphology does not differentiate individual conditions. Genetic testing leads to a Present at birth Present at birth Adult in sebaceous adenitis; Young in sebaceous gland dysplasia Any age, especially young or pregnant Aged Usually adult to aged Dogs Mostly dogs, any species Cats Dogs, cats specific diagnosis, but gene variants have not been identified for of all ichthyoses in animals and spontaneous (de novo) mutations continue to occur. In animals, the majority of ichthyoses have a laminated pattern of orthokeratotic hyperkeratosis and no changes in the other layers of the epidermis (nonepidermolytic). They resemble lamellar ichthyosis in human beings (classified with autosomal recessive congenital ichthyosis [ARCI]) (see Fig. 17.33). Where known, similar CHAPTER 17 The Integument A 1152.e1 B E-Figure 17.17 Ichthyosis, Skin, Dog. A, Abdomen. The skin is covered with adherent plates of scale (arrows), and the skin surface is wrinkled. B, Compact hyperkeratosis is present. Plates of stratum corneum are separating from each other and are lifting off the surface (arrows). Hematoxylin and eosin (H&E) stain. (A courtesy Dr. D. Lewis, College of Veterinary Medicine, University of Florida. B courtesy Dr. A.M. Hargis, DermatoDiagnostics.) CHAPTER 17 The Integument A B C Figure 17.33 Ichthyosis, Skin, Calf. A, Nonepidermolytic ichthyosis fetalis in a calf. The skin of the entire body is covered with hard grey plaques of scale (hyperkeratosis) that fold and fracture to create deep red fissure lines in geometric patterns (also known as harlequin ichthyosis). B, Nonepidermolytic ichthyosis fetalis in a calf. A thick layer of compact orthokeratotic hyperkeratosis covers the mildly hyperplastic epidermis. Hematoxylin and eosin (H&E) stain. C, Epidermolytic ichthyosis, skin, dog. Note that in contrast to the nonepidermolytic hyperkeratosis depicted in B, the papillated epidermis presents with vacuolar changes in the granular and spinous layers (arrows). Cases can have large, irregularly sized keratohyalin granules and/or eosinophilic granules of aggregated intermediate filaments (that latter is not visible at this magnification). The epidermis is covered by abundant compact to laminated orthokeratotic hyperkeratosis. H&E stain. (A courtesy Institute of Animal Pathology, Vetsuisse Faculty Bern. B courtesy Dr. M.M. Welle, Institute of Animal Pathology, Vetsuisse Faculty Bern. C courtesy Dr. E. Mauldin, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine.) 1153 genes are involved in animals as in human beings; these include ichthyoses of the golden retriever (PNPLA1), American bulldog (NIPAL4), Chianina cattle (harlequin ichthyosis, ABCA12), Great Dane (FATP4), and the Jack Russell terrier (TGM1). The majority of these conditions are thought to affect epidermal lipid metabolism, similar to ACRI in human beings, and alter formation of the cornified lipid envelope, which is an essential lipid layer needed for sealing corneocytes together in the stratum corneum. While most ichthyoses are rare, ichthyoses of the golden retriever and the American bulldog are considered relatively common, and the latter sometimes mimics an allergic patient by presenting with erythroderma, pruritus, and secondary infections occurring with scaling. Some ichthyoses in animals with a lamellar pattern of cornification involve genes thought to control profilaggrin and filaggrin protein processing. Filaggrin is a keratin intermediate filament aggregating protein stored as profilaggrin in keratohyalin granules. These types of ichthyoses occur in the German shepherd dog (ASPRV1) and the Akhal-Teke horse (ST14). The latter is a syndromic ichthyosis, with other organ defects, which is not a feature of autosomal recessive congenital ichthyosis (ACRI) in human beings. Keratopathic ichthyoses occur with mutations in keratin genes that are expressed in the superficial epidermis in human beings. Similar diseases are recognized in animals. Histologically, lesions are either epidermolytic (see Fig. 17.33, C), and present with vacuolation and degeneration of the superficial epidermal keratinocytes, or are nonepidermolytic. Examples in animals are epidermolytic hyperkeratosis of the Norfolk terrier (KRT10) (E-Fig. 17.18) and hereditary footpad hyperkeratosis of the Dogue de Bordeaux dogs (KRT16) that is nonepidermolytic. Not all hereditary footpad hyperkeratosis disorders are related to keratin gene mutations in animals, as is the situation in human beings with analogous palmoplantar keratodermas. In the Kromfohrländer and Irish terrier breeds (FAM83G) footpad hyperkeratosis occurs, but a nonkeratin gene is affected and the mechanism of injury is unknown. In some conditions, like congenital keratoconjunctivitis sicca and ichthyosiform dermatosis of Cavalier King Charles spaniels (FAM83H), the histologic lesions mimic those occurring in epidermolytic ichthyosis. This shared morphology with diseases in which the keratin genes are mutated suggests that the protein (FAM83H) affected may structurally interact with keratins. The results of early experimental studies in human beings supports this possibility. For certain unique conditions, like hereditary nasal parakeratosis in Labrador retrievers and the Australian greyhound, with different mutations in SUV39H2, the mechanism of injury is uncertain. Parakeratotic hyperkeratosis is restricted to the nasal planum of these dogs (see Fig. 17.75). Similarly, in lethal acrodermatitis of bull terriers and miniature bull terriers (MKLN1), a syndromic disorder, the mechanism for distal extremity parakeratotic hyperkeratosis and skin lesion formation is unknown (see the section on Diseases of Dogs). Parakeratosis suggests premature cornification or possibly disrupted autophagy. Congenital Inflammatory Linear Verrucous Epidermal Nevi Congenital inflammatory linear verrucous epidermal nevi (inflamed linear epidermal nevi) are a subgroup of epidermal nevi. They have a genetic origin, have been described in dogs and cats, and resemble a mild form of CHILD syndromeh described in human beings. The underlying cause for CHILD syndrome are variants in the NSDHL gene. This gene regulates an enzyme localized in the endoplasmic reticulum of cells that is involved in cholesterol biosynthesis. Clinically, focal or hCongenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) is a birth-onset genetic disorder occurring almost entirely in females. CHAPTER 17 The Integument A B E-Figure 17.18 Epidermolytic Hyperkeratosis, Skin, Dog. A, Lateral thorax of Rhodesian ridgeback. There are fronds of keratin adherent to papillary projections of the epidermis (arrows). B, Papillary epidermal hyperplasia with disruption and clefting of the granular layer and large keratohyalin granules. The papillary hyperplasia with epidermal papillae and hyperkeratosis (arrows) contribute to the accumulation of keratin attached to the hairs in this breed of dog. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. A.M. Hargis, DermatoDiagnostics.) 1153.e1 1154 SECTION II Pathology of Organ Systems A B Figure 17.34 Inherited Epidermolysis Bullosa, Calf. A, Ulcers are present because of sloughing of the epidermis over the extremities (arrows). B, Oral mucosa. Junction of normal and affected mucous membrane. Epithelium is present on the right (arrow) but is abruptly missing on the left. The partial lack of epidermis is due to an adhesion defect between the epidermis and the underlying dermis that leads to subsequent blister formation, which ruptures and then the epidermis sloughs away. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) multifocal lesions are seen all over the body, including the face and/or paws. Nonsymmetric linear plaques tend to follow curved parallel lines (Blaschko’s lines). Early plaques are mildly erythematous and progress rapidly to irregular verrucous, alopecic, and hyperpigmented plaques with a scaly surface. Occasionally, plaques are eroded and crusted with an erythematous margin. Pruritus is mild to moderate and may be caused by bacterial overgrowth and Malassezia infection. Histologically, there is diffuse, moderate to severe, regular to irregular hyperplasia of the epidermis and hair follicle infundibula as well as a thick layer of mostly orthokeratotic compact hyperkeratosis with distension of hair follicle infundibula. Secondary infection promotes inflammation and epidermal leukocyte exocytosis, pustules, and crusts. Congenital Lymphedema Congenital lymphedema, an inherited disorder of the peripheral lymphatic system, has been reported in cattle, pigs, dogs, and cats, and it is associated with lymphatic malformations of the dermal and/ or subcutaneous lymph vessels. Lesions occur at birth or within the first few months of life, are generalized or regional, and are dominated by variable swellings of the skin and subcutis. Vesicles and papules oozing lymph fluid may be present (see Fig. 2.10). Epidermolysis Bullosa (Red Foot Disease) Epidermolysis bullosa refers to a group of mechanobullous diseases resulting in the development of cutaneous blisters (vesicles and bullae) in response to minor mechanical trauma. Blisters develop as a result of poor cohesion of the epidermis and dermis as a consequence of structural defects at the basement membrane zone and/or stratum basale. The structural defects arise from mutations in genes responsible for the synthesis of structural proteins that stabilize this anatomic region of the skin. These mutations involve genes for keratin intermediate filaments, proteins associated with hemidesmosomes, and anchoring fibrils (type VII collagen) (see Fig. 17.4). The diseases vary in mode of inheritance, clinical manifestations, and anatomic location of the blisters. Animals affected with the diseases usually die because of their inability to obtain nourishment because of oral lesions, loss of fluid and protein, and secondary infection leading to bacteremia. Epidermolysis bullosa has been reported in horses, cattle, sheep, dogs, and cats. Lesions can be present at birth or develop shortly thereafter and are located where epithelial surfaces are subjected to mechanical trauma, such as oral mucosa, lips, and extremities, and can include sloughing of claws, hooves, or pawpads (Fig. 17.34). Shearing forces that normally cause no problems are sufficient to cause injury in these animals. Microscopic lesions are those of an epidermal vesicular disease in which vesicles form in different locations (subepidermal or intraepidermal), depending on the specific disease (see Fig. 17.34). The vesicles progress to ulcers, because they are easily ruptured, and secondary exudation and crusts develop over the ulcers. Disorders of Radiation, Chemical, or Physical Injury Radiation Injury Radiation is energy that travels in the form of waves or particles. Animals and human beings are constantly exposed to low levels of cosmic, solar, and naturally occurring radiation from earth sources (e.g., uranium and its decaying radon gas in rocks). In addition, man-made radiation is widely used in industry, research, and medicine (e.g., x-rays, radio waves). This amount of background radiation that is constantly present varies tremendously worldwide and within countries. So far, it has not been proven that background radiation causes injury. However, it is presumed that increased exposure results in additional risk of cancer. Depending on the level of energy, two types of radiation, namely ionizing and nonionizing radiation, are distinguished. Ionizing radiation (e.g., x rays) has a short wavelength and enough energy to detach electrons from atoms or molecules. Ultraviolet radiation (UVR) has a longer wavelength than ionizing radiation, and its photons lack the energy to ionize atoms. Nevertheless, UVR causes chemical reactions and damages DNA leading to skin injury and cancer with sufficient exposure and time. Solar Injury. The sun emits three types of UVR that reach the earth: (1) long-wavelength UVA radiation (400 to 315 nm), (2) medium-wavelength UVB radiation (315 to 280 nm), and (3) shortwavelength UVC radiation (280 to 100 nm). As sunlight passes through the atmosphere, all UVC radiation and approximately 90% of the UVB radiation are absorbed. UVA rays accounts for about 95% of the UV light that reaches the earth, and UVB light accounts for only 5%. The amount of UVR reaching the skin depends on host factors (amount of hair coat and melanin pigmentation, anatomic body site) and environmental factors (cloud cover, ozone level, altitude, latitude) that limit or enhance exposure. Melanin absorbs UV light (photoprotectant) and prevents UV photons from directly disrupting chemical bonds in the DNA and from indirectly damaging DNA by generating free radicals. UVA rays penetrate deep into the dermis, whereas UVB rays penetrate only into the epidermis and superficial dermis. UVB radiation damages DNA directly in keratinocytes by causing the formation of aberrant covalent bonds between adjacent thymine or cytosine bases and producing pyrimidine dimers in DNA. Some pyrimidine dimers escape the DNA repair process and trigger cells to either to undergo CHAPTER 17 The Integument apoptosis (so-called “sunburn cells” as seen in sunburn and actinic keratosis) or accumulate as DNA replication errors leading to mutations in tumor suppressor genes or oncogenes, which can result in subsequent neoplasia. UVA can generate highly reactive chemical intermediates, such as hydroxyl and oxygen radicals, which also damage DNA. Both UVA and UVB rays contribute to photoaging and carcinogenesis. Sunburn. Direct UV light damage of the skin can be either acute and result in sunburn or chronic and cause solar dermatitis, actinic keratosis, and/or neoplasia. Sunburn results from excessive exposure to UVB radiation and the subsequent direct DNA damage and inflammatory mediator activation. DNA damage by UVB light results in the formation of pyrimidine dimers (usually between thymine bases). In response, the body triggers defense mechanisms, including DNA repair to revert the genetic damage, apoptosis to remove unrepairable cells, and melanin production to prevent future damage. The inflammatory response triggered by sunburn includes the production of prostanoids, bradykinin, and cytokines derived from UVR-damaged keratinocytes, mast cells, and superficial endothelial cells. These chemicals increase the sensitivity to heat by reducing the activation threshold of the heat receptor (TRPV1). The pain associated with sunburn is caused by an increased production of CXCL5, which activates nerve fibers. Sunburn lesions occur in sparsely haired, poorly pigmented, or nonpigmented areas of the skin of cats, dogs, pigs, horses, cows, and goats. In cats, nonpigmented ear, nose, eyelids, and lips are most often affected, especially in white cats. In dogs, lightly pigmented short-coated breeds develop lesions on an unpigmented planum nasale, the bridge of the nose, and on any sparsely haired ventrolateral skin of the abdomen and thorax, hocks, and flanks. In goats and cows, the unpigmented udder may develop sunburn lesions. In pigs, light-colored suckling and weaner pigs reared outdoors develop lesions on the ears and back. Clinical symptoms vary depending on the duration and intensity of UV light exposure and range from mild transient erythema to more severe lesions of skin warming, tenderness, pain, and blisters. With time, alopecia, lichenification, hyperpigmentation, and scaling develop. Microscopically, in early UV-induced injury, apoptotic cells (sunburn cells) are scattered in the epidermis, which occasionally can be numerous and form a band. In addition, intercellular edema, vacuolation of keratinocytes, and loss of the granular cell layer are seen. By 72 hours postexposure, ortho- and parakeratotic hyperkeratosis and epidermal hyperplasia are present and with dermal hyperemia, edema, perivascular mononuclear cell infiltrates (exudates), capillary endothelial cell swelling, and hemorrhage. Chronic Solar Dermatitis. Chronic solar dermatitis, solar elastosis, and actinic comedones are caused by chronic exposure to the UV spectrum of sunlight. Lesions generally develop in poorly haired and lightly pigmented skin. Chronic solar dermatitis is characterized epidermal hyperplasia covered by ortho- and parakeratotic hyperkeratosis. Dermal lesions include hyalinized or sclerotic vessel walls with missing endothelial cells (solar vasculopathy), altered collagen in the superficial dermis, solar elastosis, and actinic comedones. A superficial, mixed, perivascular mononuclear inflammatory infiltrate (exudate) may or may not be present. Solar elastosis may develop intermixed with or below a linear band of dermal scarring parallel to the epidermal surface (laminar fibrosis, collagen hyalinization) (Fig. 17.35, E-Fig. 17.19). Lesions of solar elastosis consist of increased numbers of thick, interwoven, basophilic elastic (thus the name “solar elastosis”) fibers. The pathogenesis of solar elastosis is complex and not well understood; it is thought that the deposited elastotic material (elastin, fibrillin, and glycosaminoglycans) is mostly newly formed by sun-damaged fibroblasts, but that degradation of preexisting dermal matrix proteins contributes to the lesion. Solar elastosis occurs in lightly pigmented, poorly haired sun-exposed skin of the nose and eyelids of horses, 1155 the lower eyelids of Hereford cattle, and the poorly haired inguinal region of sunbathing dogs. Actinic comedones primarily occur in dogs with chronic sun exposure. They can be of an open or closed type, have hyperplastic, pale infundibular walls, and are surrounded by a thin layer of fibrosis. A B Figure 17.35 Solar Dermatosis, Skin, Dog. A, The nonpigmented and sparsely haired skin is severely thickened by dermal fibrosis and the epidermis has an irregular undulating surface as a result. Alopecia and erythema are present along with multifocal small dark red papules and mild crusts. Comedones are mild and some have developed folliculitis and/or furunculosis to create the papules and crusts. Black pigmented spots are normal pigmentation. B, The epidermis is hyperplastic, is topped by laminated to compact orthokeratotic hyperkeratosis, and several pale swollen keratinocytes are seen in the spinous layer. Subepidermally, laminar fibrosis merges with pale dermal collagen that is hypocellular and has a homogeneous appearance. Numerous elastin fibers are seen in the superficial dermis (arrows). Many superficial blood vessels lack endothelial cells (not easily visible at this magnification). Hematoxylin and eosin (H&E) stain. (A courtesy Dr. P. Bizikova, Dermatology, College of Veterinary Medicine, North Carolina State University. B courtesy Dr. M.M. Welle, Institute of Animal Pathology, Vetsuisse Faculty Bern.) CHAPTER 17 The Integument A 1155.e1 B C E-Figure 17.19 Solar Dermatosis, Skin, Dog. A, Ventral abdomen and thorax. The nonpigmented and lightly pigmented spots are affected, but the densely pigmented black spots are clinically unaffected. The nonpigmented and sparsely haired skin is erythematous, has comedones and crusts, and is palpably thickened. Comedones can rupture (furunculosis), releasing follicular contents that cause a foreign body inflammatory response and secondary bacterial infection (arrows). Clinically, the inflammation is prominent (erythema and furuncles) and can be misinterpreted as primary. Clinically, the distribution pattern of affected nonpigmented sparsely haired skin and unaffected haired or pigmented skin is supportive of the diagnosis of solar dermatosis. B, Ventral abdomen. Solar dermatosis with a solar (actinic) keratosis that has formed a cutaneous horn. Cutaneous horns are keratoses formed from multiple layers of compacted stratum corneum. They may arise from benign or malignant lesions in the epidermis (solar actinic keratosis, squamous cell carcinoma) or adnexa (infundibular keratinizing acanthoma). C, The epidermis is thickened by acanthosis, and three comedones (follicular distention and hyperkeratosis) are present. If comedones rupture, a large amount of endogenous foreign material (stratum corneum, hair shafts, and sebum) is released into the dermis, causing a foreign body inflammatory response. Bacteria are also released and cause a secondary bacterial infection. Hematoxylin and eosin (H&E) stain. (Courtesy Dr. A.M. Hargis, DermatoDiagnostics.) 1156 SECTION II Pathology of Organ Systems Actinic comedones can rupture (actinic furunculosis), sometimes as a result of secondary bacterial infection, and induce a focal, hemorrhagic, and pyogranulomatous dermatitis. Preneoplastic Solar (Actinic) Keratosis, and Neoplasia. Chronic sun exposure can induce mutations in the DNA of epidermal keratinocytes (and other skin cells) leading to solar (actinic) keratosis and potentially skin neoplasia. Such mutations affect cell survival and proliferation and can ultimately lead to their transformation into neoplastic cells. Both UVA and UVB radiation have been implicated as causes of actinic keratosis and subsequent neoplasia, and the pathogenetic mechanisms implied in this process are as follows: 1. UVB radiation causes DNA damage by the formation of pyrimidine dimers in keratinocytes, and also in Langerhans cells, dermal dendritic cells, and other skin cells. More information on this topic is available at www.expertconsult.com. A 2. Solar-induced DNA damage leads to mutations in tumor-suppressor genes, in particular p53, to cause cancer. More information on this topic is available at www.expertconsult.com. 3. Exposure to UV radiation suppresses specific immune responses thought to protect against neoplasia. More information on this topic is available at www.expertconsult.com. Sun-induced preneoplastic and neoplastic lesions occur in all domestic animal species and are located almost exclusively in white or sparsely haired areas of the skin that receive chronic sun exposure. In horses, lesions occur most frequently on the eyelids and nose. In cattle, the eyelids (cancer eye) are most commonly affected. Lesions occur also in dairy goats (lateral aspects of the udder and teats), in dogs (nose, ventral abdominal, inguinal, and perineal areas), and in cats (ear tips, eyelids, nose, and lips), most severely in white cats (Fig. 17.36). Grossly, the first clinical lesions are those similar to sunburn erythema, scaling, and crusting. Papular or plaquelike, indurated foci (actinic keratoses) covered with thick scales subsequently develop. Histologically, in actinic keratosis, a hyperplastic epidermis is covered with compact, mostly orthokeratotic, hyperkeratosis. Epidermal dysplasia, characterized by atypical keratinocytes with anisocytosis, anisokaryosis, enlarged nucleoli, and increased mitoses, starts in the basal cell layer and later involves the spinous layers leading to an irregularly stratified epidermis with a few scattered apoptotic keratinocytes. Progression to in situ carcinoma, squamous cell carcinoma, or less often basal cell tumors, can occur in the site of preneoplastic actinic keratosis. Keratinocytes transform to neoplastic cells in the epidermis first, creating in situ carcinoma (i.e., carcinoma limited to the epidermis with an intact basement membrane) and is recognized by more prominent epidermal dysplasia, increased mitoses, atypical mitoses, and displaced mitoses occurring above the basal layer. In situ carcinoma progresses to invasive squamous cell carcinoma or basal cell tumor when atypical keratinocytes cross the basement membrane and invade the dermis. Invasive carcinoma, once formed, can extend to the subcutis and/or invade lymphatic vessels, leading to regional or distant metastases, involving lymph nodes, lungs, and/ or other organ systems. Solar-induced hemangiomas and hemangiosarcomas have been described in the nonpigmented conjunctiva of horses and dogs and in the dermis of sparsely pigmented and sparsely haired skin of sunbathing dogs (abdomen and flanks) and much less often goats and cats. It is noteworthy that the prognosis of UV induced hemangiosarcomas is much better than the prognosis of non–sun-induced hemangiosarcomas. B Figure 17.36 Actinic Keratosis, Skin, Cat. A, Hemorrhagic crusts cover eroded plaques on the convex surface of the white-haired erythematous pinna. B, Focal hyperplasia and dysplasia of the epidermis is characterized by a disorganized basal cell layer with irregularly sized and shaped basal keratinocytes. Compact hyperkeratosis is present. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. S. Rüfenacht, Dermavet, Oberentfelden. B courtesy Dr. M.M. Welle, Institute of Animal Pathology, Vetsuisse Faculty Bern.) Unlike in human beings, it is not clear if melanomas in domestic animals can be sun induced. However, melanomas develop in the skin, lips, eyelids, and iris in Doberman pinschers with autosomalrecessive oculocutaneous albinism, suggesting melanomas may be solar induced in these dogs. Photosensitization. Photosensitization is skin injury from sun exposure that activates a photodynamic chemical in the skin to highly reactive intermediates that cause skin necrosis and inflammation. For disease to occur, animals must acquire a photodynamic chemical and be exposed to solar radiation, and then lesions develop in poorly pigmented, poorly haired, sun-exposed areas of skin. Longwavelength UVA rays and less frequently UVB rays or visible light can react with light-energy absorbing molecules (so-called photodynamic molecules). This process releases energy that produces reactive oxygen intermediates, such as superoxide anion, singlet oxygen, and free hydroxyl radicals that damage cell membranes, nucleic acids, proteins, and organelles, causing cell activation, degeneration, and/or death. The result is initiation of an inflammatory reaction cascade with tissue damage, called photosensitization. Most photodynamic molecules are either ingested (primary photosensitization) or metabolized in the liver (secondary hepatogenic photosensitization, hepatogenous photosensitization). They enter the dermis via the systemic circulation. Since the majority of photodynamic CHAPTER 17 The Integument Pyrimidine dimers are formed from thymine or cytosine bases in DNA via photochemical reactions. During this reaction, covalent linkages between two consecutive bases on one strand of doublestranded DNA bind together. Thus, the normal base-pairing doublestrand structure in that area is destroyed, which leads to faulty base pairing during replication. Two common UV dimers are cyclobutane pyrimidine dimers and 6–4 photoproducts. A third type of photochemical is Dewar pyrimidinone. It is formed by a reversible isomerization of the 6–4 photoproduct upon further exposure to light. Pyrimidine dimer mutations are characterized by the replacement of cytosine with thymine (C to T) or double-base changes in which a cytosine dimer is replaced by two nondimerized thymine bases (CC to TT). All of these premutagenic lesions impair the structure and the base-pairing of DNA strands. It has been calculated that up to 100 such reactions per second occur in a keratinocyte during exposure to sunlight. Fortunately, most of them are corrected within seconds by photolyase reactivation or by the nucleotide excision repair enzyme system. However, if the cell undergoes mitosis before the damage is repaired, a gap in the DNA strand is left at the location of the photoproduct. The gap is repaired by an error-prone postreplication repair method and may lead to mutations and the development of neoplasms. Factors that irritate the skin and increase the rate of cell division increase the number of cells repaired by the postreplication repair method and therefore can enhance development of neoplasms. Normally, p53 mediates cell cycle arrest and apoptosis of cells with excessive unrepaired damaged DNA by removing the defective cells. With time, p53 gene mutations develop and accumulate in keratinocytes when UV ray–induced dimers and photoproducts are not properly repaired. These mutations must be corrected before affected keratinocytes go through mitosis or neoplasms may develop. Although p53 gene mutations occur in a variety of types of tumors, mutations caused by UV rays (the C to T or CC to TT mutations) are unique to skin tumors and do not occur with other types of DNA damage or in tumors unassociated with UV rays. Thus, they are termed UV signature mutations. Other molecular markers, in addition to those markers for neoplasia, have been associated with the development of actinic keratosis in human beings. They include the expression of p16ink4, p14, the CD95 ligand, TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors, and the loss of heterozygosity. 1156.e1 The pathways leading to this type of immunosuppression are complex and not yet completely understood. In the initiating step, UV photons are absorbed by chromophores in the skin and the chromophores change their structure. UVA and UVB radiation activate and alter different chromophores, and thus different pathways that lead to immunosuppression are involved. UVB rays reach the epidermis and superficial dermis, where it affects or activates three chromophores: DNA, trans-urocanic acid (UCA), and less-defined membrane components. UVA rays reach the deep dermis and activate chromophores that are not yet known. The structural changes in the chromophores upon UV absorption result in the synthesis of a range of chemical mediators derived from keratinocytes, antigenpresenting cells, mast cells, and several other cell types. In addition, platelet-activating factor is activated early; binds to receptors on monocytes, mast cells, and keratinocytes; and regulates prostaglandin release. Subsequently, several immunosuppressive cytokines are released, including interleukin (IL)-4 and IL-10, along with histamine, tumor necrosis factor-α (ΤΝF-α), IL-1β, neuropeptides, and neurohormones. Activation of C3 compliment promotes dermal infiltration by CD11b+ monocytes/macrophages. UVA also activates the alternative complement pathway resulting in increased concentrations of properdin and complement factor B. UVA irradiation can also block glycolysis in keratinocytes, leading to low ATP concentrations and an energy crisis in these cells. After UV exposure, antigen-presenting epidermal Langerhans cells and dermal dendritic cells migrate to local draining lymph nodes or even die by apoptosis with high UV doses. In lymph nodes, these Langerhans cells induce the NK-T lymphocytes to produce IL-4. Concurrently, mast cells and IL-10–producing monocytes increase briefly in the dermis and draining lymph nodes. As a consequence, antigen presentation in the epidermis, dermis, and draining lymph nodes is altered. Also, in lymph nodes, IL-12 and IL-23 production are decreased. These cytokines are key molecules for T lymphocyte activation, and T helper lymphocyte cytokines are reduced in number, thus limiting T lymphocyte activation crucial for elimination of DNA damaged cells. T regulatory cells (T regs) are stimulated, which are specific for antigens encountered shortly after UV exposure, and work actively to repress this needed T lymphocyte activation, for example, by being cytotoxic for antigen presenting cells and by producing IL-10. UVB activates B regulatory cells that further inhibit antigen-presenting dendritic cells. The end result is significant suppression of immunity with an inhibition of the expansion of effector CD4+ and CD8+ T lymphocytes in lymph nodes draining the skin and an impaired development of peripheral memory T lymphocytes in the skin. Once generated, this immunosuppression is long lasting, leading to tolerance, so, if the same antigen is encountered in the future, the T lymphocyte response to it is suppressed. CHAPTER 17 The Integument molecules are derived from plants, photosensitization is seen most often in grazing herbivores and is also called phytophotodermatitis. Skin lesions are observed in lightly haired or white-haired areas of sun-exposed animals grazing on plants (Fig. 17.37). Percutaneous absorption of photodynamic molecules can also cause a localized contact photosensitization (e.g., contact with plants containing furanocoumarins such as giant hogweed). Photosensitization can be further categorized as phototoxic, which is much more common, or photoallergic. Phototoxicity develops after UV rays have been absorbed by a photodynamic molecule or by a complex of a photodynamic molecule and a biologic substrate in the skin. The released energy directly results in inflammation and cell damage. Photoallergy is an immunologically mediated photosensitivity reaction resulting either from an immediate-type hypersensitivity (Type I, antibody mediated) or from a delayed-type hypersensitivity (Type IV, cell mediated), or both, that develops to a photoactivated compound. The photoactivated compound acts either as a hapten or a full allergen. 1157 A More information on this topic is available at www.expertconsult.com. Ionizing Radiation Injury. Advances in the treatment of cancer in companion animals have made the possibility of radiationinduced skin injury more common. Ionizing radiation consists of electromagnetic radiation (x-rays, γ-rays) and particulate radiation (e.g., electrons, neutrons, protons) and is most damaging to rapidly dividing cells, such as the matrix cells in the anagen hair follicle, but epidermal basal cells and vascular endothelial cells are also affected. Available radiation modalities differ in the degrees of tissue penetration and thus differing potential for tissue injury. Some forms of radiotherapy penetrate to deeper tissues and while sparing the skin, and others are more concentrated in the superficial tissues or are preferentially absorbed by specific tissues. The type of radiation therapy and the source, dose, intensity, and duration of exposure dictate the range of possible side effects. Ionizing photons disrupt chemical bonds in cells, leading to injury or cell death. Some cells are not killed but sustain DNA damage to the extent that replication and/or replacement are not possible. The effects of radiation damage of exposed tissue can be divided into acute and chronic forms and mirror the lesions discussed previously in the sections on solar injury and photosensitization. B More information on this topic is available at www.expertconsult.com. Chemical Injury Chemical injury of the skin can result from local application directly onto the skin (irritant contact dermatitis), into the skin (injections, bites), or from absorption of chemicals via the gastrointestinal tract and subsequent distribution to the skin. Contact Dermatitis. Contact dermatitis results from chemicals that penetrate the protective layers of the skin that induce skin damage by altering the water-holding capacity of the epidermis, directly damaging cells and inducing skin inflammation. Penetration of the skin is enhanced by physical damage to the stratum corneum, especially damage caused by excessive moisture. There are two forms of contact dermatitis, allergic and irritant. Allergic contact dermatitis is immunologically mediated and requires prior exposure (sensitization) to the offending agent in a hypersensitive individual (see Diseases Affecting Multiple Species of Domestic Animals, Immunologic Skin Disorders, Selected Hypersensitivity Reactions, Allergic Contact Dermatitis). Irritant contact dermatitis is caused by direct contact of the skin with injurious substances. C Figure 17.37 Type III Photosensitization (Secondary Hepatogenic Phototoxicity), Skin, Cow. A, Epidermal necrosis has occurred in the white haired and nonpigmented skin areas (arrow). B, The necrotic epidermis can be peeled off from the underlying dermis. In this closer view of the area identified with the arrow in A, the chronic, partially healed ulcers with hemorrhage are still present dorsally and resolution of the ulcers has occurred ventrally where the skin surface has dried, and subsequent scar formation has led to dermal thickening and alopecia. C, Full-thickness epidermal coagulative to lytic necrosis is present, which also involves the hair follicle epithelium and the superficial dermis. In addition, there is fibrinoid degeneration of the dermal vessels and thrombosis. Hematoxylin and eosin (H&E) stain. (A and B courtesy Section of Dermatology, Vetsuisse Faculty Bern. C courtesy Dr. M.M. Welle, Institute for Animal Pathology, Vetsuisse Faculty Bern.) CHAPTER 17 The Integument Classification of the types of phototoxicity is based on the source of the photodynamic chemical. Type I or primary phototoxicity is caused by ingestion of a preformed photodynamic substance, such as chemicals present in plants or some drugs. Plant compounds are most common, and thus herbivores are most often affected. The plants causing phototoxicity usually contain helianthrone or furocoumarin-type pigments. The helianthrone pigments are red fluorescent pigments such as hypericin (found in, e.g., Hypericum perforatum [St. John’s wort]) and fagopyrin (found in, e.g., Fagopyrum esculentum [buckwheat]). Phototoxicity attributed to furocoumarin pigments is caused by the presence of psoralens, photodynamic agents found in a variety of plants, including Cymopterus watsonii (spring parsley), Ammi majus (bishop’s weed), and Thamnosma texana (Dutchman’s breeches). Furocoumarin pigments also form phytoalexins. Phytoalexins are a group of compounds that are formed in plants in response to fungal infection or other injury. The phytoalexins formed in fungus-infected parsnips and celery have caused phytophotodermatitis when they are absorbed into the skin and react with UV light. Primary phototoxicity can also occur with drug administration. In human medicine, numerous drugs are known to cause phototoxicity. In animals, drugs such as the anthelminthic phenothiazine, coal tar derivatives such as polycyclic aromatic hydrocarbons, tetracyclines, and some sulfonamides have been reported to cause primary phototoxicity. Most of the drugs are converted to a photoreactive metabolite in the intestinal tract. This metabolite is usually converted to a nonphotoreactive compound in the liver by mixed-function oxidases, but occasionally either the reactive metabolite bypasses the liver or mixed-function oxidase activity in the liver is compromised or insufficient, and the reactive metabolite reaches the skin. Type II phototoxicity has been reported in cattle, pigs, and cats. It develops as a result of abnormal porphyrin metabolism resulting from inherited or acquired defects in enzymes involved in heme synthesis. Abnormally processed porphyrins, including uroporphyrin and coproporphyrin, accumulate in the blood and tissues and act as the photodynamic agent. Examples include bovine congenital porphyria and bovine erythropoietic (hematopoietic) protoporphyria. Type III or secondary hepatogenic phototoxicity is by far the most frequent type of photosensitivity observed in herbivore livestock. It is caused by the impaired capacity of the liver to excrete phylloerythrin, which is formed in the alimentary tract from the breakdown of chlorophyll. Failure to excrete phylloerythrin because of hepatic dysfunction or bile duct lesions increases its amount in circulation and then in the skin, where it absorbs and releases light energy to initiate a phototoxic reaction. Hepatogenic photosensitization occurs secondary to primary hepatocellular damage, inherited hepatic defects, or bile duct obstruction. Toxic plants, including but not limited to Lantana camara (lantana) and Tribulus terrestris (puncture vine), and mycotoxins, such as sporidesmin, are the most common cause of the liver damage underlying this type of photosensitization. Sporidesmin is produced by the spores of the fungus Pithomyces chartarum, which lives on ryegrasses and plays an important role in the development of facial dermatitis in grazing animals including sheep, goats, cattle, 1157.e1 and camelids in Australia, New Zealand, and South America. Other plants that directly cause hepatic damage (e.g., those that contain pyrrolizidine alkaloids) can also induce development of hepatogenic photosensitization. Most forms of phototoxicity (photosensitization) cause lesions of nonpigmented skin and hair of sun-exposed areas. In cattle, lesions occur in white-haired areas and on the teats, udder, perineum, and nose. In sheep with heavy fleece, lesions occur on the pinnae, eyelids, face, nose, and coronary band, but in shorn sheep, lesions can occur on the back. Sheep can have extensive edema of the head, prompting terms that are synonyms: “swelled head” and “facial eczema.” Lesion onset may occur in only a few hours and initially include erythema and edema, followed by blisters, exudation, necrosis, and sloughing of necrotic tissue. The microscopic lesions consist of lytic to coagulative necrosis of the epidermis and possibly hair follicles, adnexal glands, and superficial dermis. Subepidermal vesicles and bullae can occur. Endothelial cells of the superficial, middle, and deep dermal vessels are swollen and necrotic, and fibrinoid degeneration and thrombosis can result in edema; infarction; sloughing of the epidermis, dermis, and adnexa; and secondary bacterial infection (see Fig. 17.37). Acute ionizing radiation injury can also be observed after accidents in nuclear power plants, and injury is caused by exposure to radioactive substances such as uranium, radon, and plutonium. Clinical signs depend on the time and dose of exposure to the skin. Clinical lesions of radiation dermatitis appear 2 to 4 weeks after exposure. Initially there is erythema, pain, edema, and heat, followed several weeks later by dry or moist desquamation, depending on the degree of injury. Histologically, the lesions resemble a seconddegree burn, with suprabasilar or subepidermal bullae formation, dermal edema with fibrin exudation, and a marked leukocytic infiltration. Re-epithelialization occurs over a period of 10 to 60 days. Injury of germinal cells of hair follicles and sebaceous glands leads to alopecia within 2 to 4 weeks after exposure. Hair regrowth follows over the next several months, but damage to sebaceous glands is not reversible and leads to permanent scaling manifesting histologically as hyperkeratosis. The chronic lesions of radiation injury are evident months to years after treatment and are primarily the result of damage to the microvasculature. Endothelial swelling, necrosis, and thrombosis lead to occlusion and excessive endothelial proliferation, which, when combined with the effects of vascular leakage, leads to vascular collapse. Telangiectasia and possibly deep arteriolar changes may also be seen. The progressive vessel abnormalities are referred to as obliterative endarteritis and are known to form a “histohematic” (tissue-blood) barrier to surrounding tissue, leading to continued anoxia and nutrient shortage, which results in epidermal atrophy, and/or chronic, nonhealing, exudative ulcers. Instead of granulation tissue atypical fibroblasts and telangiectasia are seen in the dermis. Chronic changes also include epidermal pigmentary alterations (hyperpigmentation with lower radiation doses, and epidermal hypopigmentation with higher doses) and leukotrichia (depigmentation of hair shafts because of loss of follicular melanocytes). Squamous cell carcinomas can develop in some sites of severe radiation damage because of sublethal DNA damage. 1158 SECTION II Pathology of Organ Systems These substances include arsenic, mercury, thallium, and iodine, various herbicides, organochlorines and organobromines, poisoning by fungal-contaminated plants and plants containing selenium, and mimosine, acids, alkalis, soaps, detergents, body fluids (urine or diarrhea scald), wound secretions, and some topical medications. After penetration of the epidermis, these substances cause lesions by a wide variety of mechanisms, some of which are not known. It is important to realize that irritant and allergic contact dermatitis can produce very similar histologic lesions, thus differentiation between allergic (immune-mediated) and irritant contact dermatitis largely depends on the history (including possible exposures), clinical signs, and anatomic distribution of the lesions. Horses develop lesions on the nose, ventrum, lower limbs, perineum, caudal aspect of the rear legs, and where riding tack contacts the body. In dogs and cats, lesions of irritant contact dermatitis develop on the glabrous (sparsely haired) skin of the abdomen, axillae, flanks, interdigital spaces, perianal area, scrotum, ventral tail, ventral chest, legs, eyelids, and feet. Grossly, erythematous patches, papules, and rarely, vesicles develop, but self-inflicted trauma can lead to ulcers and crusts in pruritic/painful patients. Corrosive substances (strong acids or alkalis) can cause epidermal necrosis. Microscopically, lesions consist of epidermal spongiotic dermatitis, neutrophilic vesicopustules, small vesicles or neutrophilic pustules, and a superficial dermal perivascular neutrophilic inflammation. Chronic lesions consist of epidermal hyperplasia, hyperkeratosis, sometimes confluent parakeratosis, and superficial perivascular inflammation. Lesions can be obscured by self-inflicted trauma, making the histologic diagnosis difficult. More information on this topic is available at www.expertconsult.com. Injection Site Reactions. Injections of vaccines or therapeutic drugs into the subcutis can incite an exaggerated local immunologic response. There are no reported histologic descriptions of the acute or subacute inflammatory response to such injected materials. Importantly, reactions at injection sites can be due to local infection from contamination rather than to the injected material, which is the more common scenario in large animals. In these cases, abscesses often develop. Lesions may persist and become chronic, but most injection site reactions heal without complication. Histologic changes in chronic lesions vary, depending on the injected material. Often chronic postinjection site lesions are composed of lymphocytes arranged as nodules that center around deep dermal or subcutaneous necrosis. Sometimes basophilic granular material is found within the necrotic tissue. Macrophages and multinucleated cells may be seen intermixed with the lymphocytes and fewer plasma cells. In vaccine reactions, macrophages contain amphophilic granular material (aluminum hydroxide). Lymphoid follicles develop most prominently with vaccine reactions, and fibrosis can radiate deep into the panniculus. Repositol formulated medications can induce small sterile abscesses with a central neutrophilic infiltrate (exudate) bordered by a few macrophages and other leukocytes. Fibrosis is minimal, especially with steroid-containing formulations. Localized rabies vaccine–induced ischemic dermatopathy results from subcutaneous injection of killed rabies vaccine and possibly other vaccines that induce a vaccine injection site reaction (as described earlier) but also cause localized lymphoplasmacytic panniculitis, subtle vasculitis, and localized ischemia of the overlying dermis, leading to severe follicular atrophy (E-Fig. 17.20). These lesions are mostly seen in small, often soft-coated, breeds of dogs, especially poodles. Immunofluorescence (IF) staining has identified rabies antigen in local vessels and cells of the hair follicles. It is thought that rabies antigens stimulate a low-grade, immune-mediated vasculitis, with resultant tissue hypoxia, leading to the atrophic changes in the adnexa. Histologically, vascular lesions are characterized by hyalinization of the vessel walls, loss of endothelial cells, intramural karyorrhectic debris, and mild perivascular or less commonly mild intramural lymphocytic infiltrates (exudates). Generalized vaccine-associated ischemic dermatopathy can also result postvaccination. Lesions develop at the site of vaccination but also at distant sites, such as the face, ear tips, pawpads, tail tip, or pressure points; they, less often, may affect the oral cavity or become generalized. A similar vasculitis mechanism, as discussed previously, is proposed. Disease can be severe, with extensive skin erosions, ulcers, depigmentation, scarring, and secondary pyoderma. Revaccination is sometimes life threatening. Injection site eosinophilic granulomas with necrotic centers have been reported in horses 1 to 3 days after injections of various substances using silicone-coated needles. The reaction is suspected of be a delayed hypersensitivity to the silicone coating. Sarcomas occur after some injection site reactions (primarily to vaccines) and appear mostly in cats and very rarely in dogs. Vaccine-induced sarcomas can have varied histogenesis (fibrosarcomas, myxosarcomas, osteosarcomas, rhabdomyosarcomas, osteosarcomas, chondrosarcomas, and histiocytic sarcomas). The injected substance, inflammation, tissue injury, and eventual fibroblastic proliferation combined in some lesions are thought to be important factors predisposing to induce sarcoma formation. It has been speculated that tissue repair, stimulated during injury, activates fibroblasts or myofibroblasts at the injection site, and that this response in combination with other factors, such as oncogene alterations (possibly through oxidative injury) and unidentified carcinogens, leads to malignant transformation of cells. Tumor development can take months to years. Any type of vaccines are the most common cause, but other injectable materials, microchips, nonabsorbable suture, or other trauma has the potential to contribute to sarcoma formation. Very uncommonly, fibrosarcomas have developed in dogs in cutaneous sites of presumed previous vaccination. Envenomations: Snake Bites, Spider Bites, and Scorpion Stings. Envenomations occur regularly in animals with access to the outdoors. Effects depend on composition of the venom, the response of the affected animal, anatomic location of the envenomation, and specific characteristics of the offending snake, spider, or scorpion, which can be influenced by season of the year, geographic location, time since last inflicted bite or sting, depth of injury, and so forth. Different species of animals respond differently to the same venom. Systemically, some venoms affect the cardiovascular system, gastrointestinal tract, nervous system, respiratory and hematopoietic systems, and/or the skin. Snakebites. In a recent review, 34 snake species belonging to five different families were reported as responsible for bites in domestic animals. The snakes listed by the World Health Organization (WHO) as medically important venomous snakes were the ones most frequently involved. The families Elapidae (coral snake) and Viperidae (rattlesnake, water moccasin, and copperhead) contain the majority of the poisonous snakes in the United States. Snakebites are common in the horse and dog and to a lesser degree in cats. They most often involve the head and legs. Snake venom contains various enzymes, proteins, peptides, and kinins. Of the five genera of venomous snakes in the United States, crotaline venom (rattlesnake, copperhead, cottonmouth, and others) contains the highest concentration of proteolytic enzymes. Snakebite envenomation produces pain, edema, and erythema that, if severe, are followed by necrosis and sloughing of tissue, and sometimes death of the animal. Variable systemic effects occur, including paralysis, coagulation CHAPTER 17 The Integument A B 1158.e1 p E-Figure 17.20 Localized Alopecia Associated with Subcutaneous Rabies Vaccination, Skin, Haired, Dog. A, This type of alopecia (arrows) generally develops 3 to 6 months after vaccination and is the result of partial ischemia. B, Note panniculitis (p) with lymphocytes, plasma cells, and histiocytes that has resulted from subcutaneous injection of killed rabies vaccine. Small, atrophic hair follicles (arrows) are in the dermis. Hematoxylin and eosin (H&E) stain. (A courtesy Dr. L. Schmeitzel, College of Veterinary Medicine, University of Tennessee. B courtesy Dr. A.M. Hargis, DermatoDiagnostics.) An example is toxicity caused by systemic absorption of some organochlorine and organobromine compounds, such as highly chlorinated naphthalenes, which were used as additives in lubricants for farm machinery such as feed pelleting equipment. As a result, highly chlorinated naphthalenes were frequent feed contaminants. Toxicosis occurred most commonly in cattle, the most susceptible species, and was known as X-disease or bovine hyperkeratosis. Fortunately, this toxicosis is historically interesting because highly chlorinated naphthalenes have not been used in machinery lubricants since the 1950s. Lesions of chlorinated naphthalene toxicity are the result of the interference with the conversion of carotene to vitamin A, which results in vitamin A deficiency. Vitamin A is necessary for normal differentiation of stratified squamous epithelium. Clinical lesions consist of alopecia and lichenified, fissured, and scaly plaques that spare only the legs. Histologic lesions consist of marked hyperkeratosis of the epidermis and follicles. Squamous metaplasia of the epithelial lining of the glands and ducts of the liver, pancreas, kidneys, and reproductive tract also develop. CHAPTER 17 The Integument disturbances, shock, increased capillary permeability, myocardial damage, rhabdomyolysis, and renal failure. Spider Bites. The genera Latrodectus (e.g., black widow) and Loxosceles (e.g., brown recluse) are reported to be the most common venomous spiders causing cutaneous injury in animals. Spider bites occur most often on the face and legs. The venom of the brown recluse spider (Loxosceles reclusa) and some other spiders contains numerous enzymes, including lipase, hyaluronidase, and sphingomyelinaseD, which degrade tissue and induce dermal necrosis. A blister with a surrounding pale halo and more peripheral erythema characterizes initial reactions documented in human beings and some experimental animals. Necrosis and eschar formation occur within 5 to 7 days. Ulceration can be extensive. Histologically, there is hemorrhage and edema, neutrophilic vasculitis, and arterial wall necrosis. The epidermis and dermis undergo infarction, which can extend into the subcutis and underlying muscle. Panniculitis can be present. Eventually there is dermal scarring and replacement of the subcutis and muscle by hypocellular connective tissue. Brown recluse spider bites in human beings can also lead to massive hemolysis. Differential diagnoses include other venomous bites, vasculitis, slough caused by iatrogenic injection of irritating substances, thermal burns, necrotizing fasciitis or other cutaneous infection, septic embolization, or trauma. Some putative spider bites (and possibly wasp and bee stings) in the dog develop as acute, painful, swollen area(s) on face, limbs, or trunk that are small focal areas of skin necrosis, hemorrhage, edema that histologically also have mild neutrophilic inflammation. Necrosis is sometimes wedge shaped in the dermis, and it is sometimes associated with a hypersensitivity reaction, recruiting mononuclear inflammatory cells, often with a few eosinophils, leading to an indurated papule with a necrotic or crusted center and a longer clinical course. Some papules develop on the dorsal or lateral nose that often drain an exudate and that histologically consist of severe eosinophilic folliculitis and furunculosis (see the section on Diseases of Dogs, Immunologic Skin Disorders, Eosinophilic Furunculosis of the Face in Dogs), leading to the theory that these lesions are probably caused by hypersensitivity reactions to injected venom. Scorpion Stings. Clinical symptoms caused by scorpion stings are mainly attributed to 50 members of the Buthidae family, although all scorpions have venom glands. Scorpion stings are very painful, and clinical lesions in the skin vary from a small swelling to very severe tissue necrosis. Systemically, scorpion venom affects the cardiovascular, gastrointestinal, nervous, respiratory, and integumentary systems. Selenium Toxicosis. Selenium is an essential element that has a narrow margin of safety. It is also an essential component of more than 25 selenoenzymes and selenoproteins. Selenium poisoning is caused by an overdose of selenium in feed supplements or ingestion of seleniferous plants that have accumulated toxic concentrations of selenium. Some plants selectively accumulate selenium, regardless of soil selenium content. These selective accumulators (obligate accumulators; e.g., Astragalus, Stanleya) require selenium for growth, generally are not palatable, and are eaten only when other plants are unavailable. Many other plants (facultative accumulators; e.g., Aster, Atriplex) do not require selenium for growth but will accumulate toxic concentrations of selenium if grown in soil with high selenium concentrations. These facultative accumulator plants are commonly eaten by livestock and more often are the cause of selenium poisoning. Selenium toxicoses occur worldwide but are more frequent in Nebraska, Wyoming, and the Dakotas in the United States and in areas of western Canada. Acute or chronic selenium poisoning has been reported in most domestic animal species, although it is more common in 1159 forage-eating anima