CANINE KERATINISATION DISORDERS
There are 3 parts to keratinisation – Cornification, Maturation and Desquamation.
It takes dogs 20-25 days from basal layer to stratum corneum, humans take 40-56 days.
- Corneocytes stack with slight overlap, except on the tail and pads
- In development corneocytes loose water and there is collapse of cytoskeleton.
- There are 20 overlying cells in this layer.
- basket weave appearance is an artefact of processing because of corneodesmosomes which are at the edge of the cells.
- there is normally lipid between corneocytes forming the mortar between the bricks of corneocytes
- is hydrophobic
- is responsible for innate immunity
- has a barrier function which is critical
- desquamates
Cornification
- the process of cornification involves compacting of intracellular keratin.
- Filligrin is involved and forms quantified envelope
- plasma membrane quantifies
- formation of the lipid, cholesterol, free fatty acids and ceramides.
- involve fusion of lamellar bodies to cell membrane that releases lipids and enzymes
- occurs at the junction of the stratum granulosum
- forms the “continuous lipid layer”
Maturation
Desquamation
corneodesmosomes bind corneocytes and lysis is by serine proteases
defects in quantification have three components
compact keratin
lipid loss
desquamation
See nasal diseases
There are 2 parts to cornification
- Increased epidermal turnover - hyperproliferation of epidermis.
- altered skin barrier results in increased production of corneocytes and lipids.
- Failure to desquamate - retention of corneocytes
Mauldin EA, Elias PM. Ichthyosis and hereditary cornification disorders in dogs. Vet Dermatol. 2021; 32: 567-e154.
In veterinary medicine, ichthyosis is only for hereditary disease.
True ichthyosis has hypogranulosis. do not mistake parakeratosis or hyperkeratosis and hypergranulosis as ichthyosis
there are two forms – epidermolytic and non-epidermolytic
there is swelling in the granular layer and this is extremely rare
caused by failure of the lipid to fill lamellar bodies
reported in Norfolk terriers
Autosomal recessive congenital ichthyosis - PNPLA1 (Patatin-like phospholipase domain containing 1) mutation.
has a thick layer of the stratum corneum.
Jack Russel terriershave a qualified envelope defect
Golden retrievers
very common and can occur at any age
typically have pigmented scale on their abdomen
keratin bars of the stratum corneum are thicker
have a PNPLA-1 mutation
Mauldin et al (2008) The clinical and morphologic features of nonepidermolytic ichthyosis in the golden retriever. Vet Pathol 45: 174-180
46 cases – 22 <1 yr, 3 were 1-3 yrs, 13 >2 years
Primary cornification defect.
Marie-Christine Cadiergues, Anita Patel, David H. Shearer, Ruth Fermor, Suhel Miah and Anke Hendricks (2008) Cornification defect in the Golden retriever: clinical, histopathological, ultrastructural and genetic characterisation. Vet Dermatol 19 120–129
20 dogs with scaling and 5 generation pedigree.
Characterization as nonepidermolytic ichthyosis.American Bulldogs
identified at birth
have lots of Mallasezia infection and atopic dermatitis
have a NIPAL4 mutation (ichthyin)
Great Dane puppies
Vet Pathol 2016; 53: 614-620
legal defect and is very severe
Cavalier king Charles Spaniel
Curly coat CKCS
Abnormal keratohyaline granules
Easily missed.
Hereditary nasal parakeratosis
Nasal parakeratosis of Labrador retrievers
Follicular parakeratosis of labrador retrievers aka congenital follicular parakeratosis
Palmoplantar keratoderma
dogues de Bordeaux
orthokeratotic hyperkeratosis
Irish terrier
Kromfohrlander
Rottweiler
Ear margin parakeratosis of the French Bulldog
Puppies at 8 weeks
Ear margin
Responsive to Vit A
Corneocyte related ichthyosis
Epidermolysis is often a keratin problemNorfolk terrier – keratin 10
Epidermolytic hyperkeratosis
Fragility of corneocytes
Dogues de Bordeaux
Palmoplantar keratoderma
Pad only
Church spire hyperkeratosis
CKSS
Dry eye curley coat
Have fragility of corneocytes – vacuolation/epidermolysis
Labrador retrievers
Hereditary nasal parakeratosis
Young, parakeratosis, keratin lakes
Greyhounds
Nasal parakeratosis
Bull terriers
Lethal acrodermatitis
MKLN1 defect
ZN ???maybe not. Not a zinc transporter problem.
Lipid envelope
Ceramides
Fatty acids
Cholesterol
These come from lamella bodies – tubular network that develops that links Golgi with cell membrane.
Most lipids are synthesised in keratinocytes
Large amount of cholesterol
Cornified lipid envelope (CLE)
Located beneath the cell membrane
Combined with lipid envelope, forms a solid seal
Cornified lipid envelope is critical for ichthyosis
Lipid related ichthyosis (autosomal recessive form)
Labs
Blaschos lines
Footpads
Plaque like
Different ot follicular parakeratosis
X linked diseaseGoldens – lamellar ichthyosis.
American bulldogs (erythema with brown scale on abdomen of puppies)
Of the diagnosed with nonseasonal atopy.
Vacuolation of cells on top of SCGreat danes
Cell junctions – corneodesmosomes
Similar to desmosomes but are converted by a protgein\strucrural support with flexibility.
No animal examples
Maturation of Stratum corneum
Enzymes and enzymes of inhibitors are present at the superficial layers, corneocytes separate, corneodesmosomes is cleaved to allow separation.German shepherd dog
Lamellare ichthyosis
Lacks enzyme in corneodesmosome breakdown.
Idiopathic nasodigital hyperkeratosis
See nasal diseases
Idiopathic digital hyperkeratosis
See digit
Psoriasiform hyperkeratosis of pad
See digit
Unilateral nasal hyperkeratosis (parasympathetic nose
See nasal
Nasal hyperkeratosis is confined to the nose and presents as a variably thickened, fissured accumulation of dry, horny tissue. Foot pad hyperkeratosis is more variable in presentation. Frond-like proliferations of keratin may occur in both locations. Areas of hyperkeratosis may crack, leading to secondary bacterial or yeast infection. In old dogs with idiopathic disease, the periphery of the footpads is more severely affected.
Distemper nasodigital hyperkeratosis
Areco et al (2022) reported on 12 dogs with distemper and cutaneous hyperkeratosis. Footpads were most commonly affected, with lesions on the nose, muzzle. periocular region, ventral abdomen, scrotum and vulva being infrequently identified. Many had inclusion bodies and antigen was detected in all dogs. Most of the dogs had nervous signs.
Areco WVC, Aguiar A, Barraza V, Fighera RA, Kommers G, Flores MM, Flores EF. Macroscopic Distribution, Histopathology and Viral Antigen Expression in Dogs with Canine Distemper Virus-induced Hyperkeratosis in Nasodigital and Other Regions. J Comp Pathol. 2022; 193: 9-19.
Idiopathic digital hyperkeratosis
Pawpad keratoma (aka callus, pawpad corn)
Localised hyperplasia of stratum corneum due to chronic pressure or friction.
Typically in racing greyhounds
Circular plaques on metcarpal or metatarsal pads
Sometimes has epidermal depression = pawpad keratoma with epidermal depression.
Cf viral wart.
Syndrome in Griffon dogs.
We call this entity a parasympatic nose. It is often seen, at mid-age, predominantly in German shepherds or their crosses, unilateral or bilateral presentation. This entity is restricted to the nose (no involvement of ears). It has been said to result from parasympatic denervation of the lateral nasal glands. As far as I know, nobody did histopath on the nasal glands in these cases (we have a project on this). So diagnosis still depends on sight! Histopath of the affected nose is unrewarding and non diagnostic. Two clinical sequella can be seen if the nose is left untreated : a minor mucocutaneous pyoderma (mild pruritus) and more important the developement of fissures which can result in ve
ry nasty bleedings (presented as an emergency case mostly at night or in the weekend). Therapy is lifelong, local vaseline twice daily is in my hands the most effective.Nasal Hyperkeratosis Associated with Xeromycteria ("Parasympathetic" nose)- The lateral nasal gland of the dog is located in the mucosa of the maxillary recess, near the opening of this recess into the nasal cavity. This gland is mostly responsible for the moisture of the nasal mucosa and the moisture observed at the external nares of the dog. Moisture from here is thought to translocate over the surface of the planum. This gland receives parasympathetic innervation with its fibers coursing with the facial nerve through the petrous temporal bone. Lacrimal glands also receive parasympathetic innervation. Xeromycteria associated with KCS may suggest that the preganglionic parasympathetic fibers proximal to the pterygopalatine ganglion are likely to have been damaged. Clinically, the petrous temporal bone should be examined for evidence of disease. In the dog, this warrants the evaluation of the patient for otitis media. Lesions may be either unilateral or bilateral. In affected dogs, resolution of otitis media may result in spontaneous improvements in nasal secretions and hyperkeratosis of the planum. In those cases in which an association with otitis media is not noted, or where resolution of the otitis media does not improve the planum, topical therapy is as for idiopathic nasal hyperkeratosis. Pilocarpine therapy has also been noted to be of benefit.
Allergic
ectoparasitism
seborrheic dermatitis
vitamin A responsive dermatitis
thallotoxicosis
chlorinated naphthalene
Superficial Necrolytic Dermatitis
hereditary nasal hyperkeratosis in Labrador retrievers.
See below
Has a compact layer of keratin
Aka self trauma
Ectoparasitism
seborrheic dermatitis
No compact layer of keratin below stratum corneum
Syndrome 1 - Adult arctic breed - husky, malamute, Eskimo dog, but also Syndrome I has been reported also in other breeds, including a Boston terrier dog, German shepherd dog, flat coat retriever,7 great dane,10 Rhodesian ridgeback, 11 a litter of Pharaoh hounds12 and mixed breed dogs.7
genetic abnormal absorption
Facial - periorbital, perioral
Alopecia, plaques, pruritis
42 dogs had parakeratotis
15 also had orthokeratotic
Follicular parakeratosis in 21
Follicular orthokeratosis in 5
Acanthosis in 27
PVD in 37; lymphocytic plasmacytic PVD in 9 diffuse lymphocytic plasmacytic in 7
Lee FF, Bradley CW 2nd, Cain CL, White SD, Outerbridge CA, Murphy LA, Mauldin EA. Localized parakeratotic hyperkeratosis in sixteen Boston terrier dogs. Vet Dermatol. 2016 Oct;27(5):384-e96
Background – Although zinc responsive dermatosis is typically a disorder of Arctic breed dogs, this study identifies similar cutaneous lesions on the face and pressure points of Boston terrier dogs.
Hypothesis/Objectives – To document the clinical and histological features of localized parakeratotic hyperkeratosis of Boston terrier dogs, to determine if the lesions respond to zinc supplementation and to determine whether tissue zinc levels were decreased in affected versus unaffected dogs.
Material and methods – Sixteen Boston terrier dogs with similar gross and histological findings were identified retrospectively from two institutions. Follow-up information for nine dogs from one institution was obtained from referring veterinarians using a questionnaire. Tissue zinc levels were measured from formalin-fixed paraffinembedded skin biopsy samples of affected and unaffected dogs using inductively coupled plasma mass spectrometry.
Results – Mild to severe parakeratotic hyperkeratosis with follicular involvement was present in all 16 cases. Of the nine dogs for which follow-up information was available, five dogs received oral zinc supplementation and four dogs had documented clinical improvement or resolution of dermatological lesions. The median skin zinc levels were not significantly different between affected and unaffected dogs.
Conclusions and clinical importance – To the best of the authors’ knowledge this is the first report of localized parakeratotic hyperkeratosis in Boston terrier dogs, some of which improved with oral zinc supplementation. Prospective studies in Boston terrier dogs are warranted to document potential zinc deficiency (serum and/or tissue levels, pre- and post-treatment) and to objectively assess response to zinc supplementation and other therapies.
Clinical
Young dogs 3.5 months
Ear margins especially and also dorsal nose.
Histopath
The consistent histopathological abnormality in all dogs was moderate (seven dogs) to severe (nine dogs) parakeratotic hyperkeratosis (Figure 1b) with intracorneal serum lakes evident in cases with more pronounced parakeratotic hyperkeratosis. Parakeratosis occasionally involved follicular infundibula. Focal to multifocal orthokeratotic hyperkeratosis was also evident (10 of 16 dogs). Epidermal and follicular acanthosis and spongiosis ranged from absent (two dogs) to severe. Mild to moderate superficial perivascular lymphoplasmacytic dermatitis was evident in all dogs with fewer neutrophils, perivascular mast cells and melanophages present, in some cases. Low numbers of Malassezia spp. were identified on H&E and PAS stains from the bridge of the nose in two dogs. Few scattered Gram-positive bacterial cocci were identified on the skin surface in two dogs.
Syndrome 2 “generic dog food dermatosis”
Zinc deficient diet in rapidly growing dogs.
Diet high in vitamins, minerals (Ca) and proteins of plant origin
Mariarita Romanucci, Laura Bongiovanni, Anita Russo, Silvia Capuccini, Luca Mechelli, Laura Ordeix and Leonardo Della Salda (2011) Oxidative stress in the pathogenesis of canine zinc-responsive dermatosis Vet Dermatol 22: 31–38
Abstract
Zinc deficiency causes skin diseases both in humans and in animals. The underlying pathogenic mechanisms remain unclear, but a growing body of evidence indicates a role for zinc in skin protection against free radical-induced oxidative damage. The immunohistochemical expression of heat shock proteins (HSPs; Hsp27, Hsp72, Hsp73 and Hsp90), Cu/Zn superoxide dismutase (SOD), metallothionein (MT), Ki-67 antigen and active caspase-3 were evaluated in normal canine skin and in samples from eight dogs with zinc-responsive dermatosis. All investigated HSPs showed intense cytoplasmic immunostaining in the affected epidermis. Focal nuclear positivity of Hsp72 was also detected in keratinocytes. Although Cu/Zn SOD expression was similar to that observed in normal skin, MT immunoreactivity occurred in both the cytoplasm and the nucleus of basal cells in normal skin but was absent from the affected epidermis. Caspase-3 activation was also absent in the involved epidermis, which revealed a high Ki-67 index (a 3.5- to 9-fold increase compared with normal skin). These results support the hypothesis that cellular response to stress, particularly oxidative stress, is involved in the pathogenesis of skin lesions in canine zinc-responsive dermatosis. The lack of MT immunoreactivity in the affected epidermis may be indicative of low zinc levels, thus resulting in vulnerability to oxidative damage. In contrast, high expression levels of HSPs in skin during zinc deficiency may confer protection against a variety of dangerous stimuli, contributing to inhibition of apoptosis and to cell cycle regulation of proliferating keratinocytes.
Peters J,* Scott DW, Erb HN, Miller WH (2003) Hereditary nasal parakeratosis in Labrador retrievers: 11 new cases and a retrospective study on the presence of accumulations of serum (‘serum lakes’) in the epidermis of parakeratotic dermatoses and inflamed nasal plana of dogs. Veterinary Dermatology 2003, 14: 197–203
Blackwell Publishing Ltd.
Abstract We report 11 new cases of hereditary nasal parakeratosis in Labrador retrievers. The disease was first observed when the dogs were 6 months to 2 years of age, and affected dogs of either sex and all coat colours. Hyperkeratosis and depigmentation were confined to the nasal planum, and affected dogs were otherwise healthy. The principal histological findings in biopsy specimens were marked diffuse parakeratotic hyperkeratosis, multiple intracorneal serum lakes and superficial interstitial-to-interface lymphoplasmacytic dermatitis. Topical applications of propylene glycol in water or white petrolatum were often effective for treatment of the dermatosis. However, continued applications were required to maintain a beneficial response. A retrospective histological study of parakeratotic inflammatory diseases of canine haired skin and inflammatory diseases of the canine nasal planum was performed. The degree of parakeratotic hyperkeratosis and the number and size of intracorneal serum lakes were evaluated. The degree of parakeratotic hyperkeratosis was greater in hereditary nasal parakeratosis specimens than that seen in discoid lupus erythematosus and Malassezia dermatitis. There were more serum lakes in hereditary nasal parakeratosis specimens than in specimens from dogs with discoid lupus erythematosus, Malassezia dermatitis, primary seborrheic dermatitis or zinc-responsive dermatosis. Significant differences in sizes of serum lakes (if present) were not seen.
NADIA PAGÉ*, MANON PARADIS†, JEAN-MARTIN LAPOINTE‡ and ROBERT W. DUNSTAN (2003) Hereditary nasal parakeratosis in Labrador Retrievers. Veterinary Dermatology Volume 14 Issue 4, Pages 197 - 203
Abstract Hereditary nasal dermatitis is reported in 14 Labrador Retrievers and 4 Labrador Retriever crosses. This appears to be a newly described inherited disorder for which an autosomal recessive mode of inheritance is suspected. The lesions were first noted between 6 and 12 months of age. Histopathological analysis revealed parakeratotic hyperkeratosis, often with marked multifocal accumulation of proteinaceous fluid between keratinocytes within the stratum corneum and superficial stratum spinosum. There was also a sub-basal lymphoplasmacytic infiltration within the superficial dermis. Immunohistochemistry staining for IgG (n = 4), distemper and papillomaviruses (n = 4) were negative, as were serum antinuclear antibody serology (n = 4) and fungal culture (n = 7). Electron microscopy revealed an altered cornification process: retention of nuclear chromatin, absence of lamellar bodies and marked intercellular oedema. Dogs did not respond to oral administration of zinc methionin (n = 3), cephalexin (n = 4), vitamin A alcohol (n = 1) or topical tretinoin (n = 1). Improvement of the lesions was obtained with topical vitamin E (n = 2), petroleum jelly (n = 2), and propylene glycol (n = 5).
‘a rare disorder of cornification. Published cases have been seen in Rottweilers and Labrador Retrievers; however to date not enough data has been published to be able to say whether there is a breed predilection. The condition is thought to be heritable as many of the cases reported have been in Rottweilers. All cases to date have been in female dogs. Linear lesions on the trunk were reported in some of the Rottweiler cases (Lewis, DT et al. 1998. Vet Dermatology No.9, 61- 72. Hereditary disorder of cornification and multiple congenital defects in five Rottweiler dogs). In your Pomeranian patient there are also multiple small sebaceous glands surrounding the affected follicles that are plugged with parakeratotic keratin; this also is described in one of the patient's in Diane Lewis' paper. A second possible differential although less likely I think is inflamed linear epidermal nevus. These linear nevi can look similar histologically; however generally have epidermal hyperplasia as well as the parakeratosis which is not the case in your Pomeranian. In one of the sectionsof skin submitted there is a secondary bacterial folliculitis and pyoderma with associated serocellular bacterial crusting; however this is secondary. I would certainly appreciate any followup you have on this case and if you have pictures I would appreciate seeing the clinical presentation of you patient.
Joanne Mansell, DVM, MS, DACPF
These linear nevi can look similar histologically to congenital follicular parakeratosis; however generally have epidermal hyperplasia as well as the parakeratosis which is not the case in your Pomeranian.
See transepidermal interface cytotoxic