Congenital and Hereditary Defects Flashcards
Genetic diseases of the epidermal basement membrane are collectively known as what?
Epidermolysis bullosa (EB)
EB Simplex (EBS - suprabasal) in dogs
Suprabasal EBS has been recognized only once in animals.
Mutations of PKP1 leading to plakophilin-1 deficiency were found recently to cause the ectodermal dysplasia-skin fragility syndrome in Chesapeake Bay retrievers
EBS in Friesian-Jersey cattle
EBS (basal) was diagnosed in 17 newborn Friesian-Jersey crossbred calves derived from sire-testing herds in New Zealand.
The trait was linked to a chromosomal region close to that containing KRT5.
All affected calves were heterozygous for the mutation, thereby confirming the autosomal dominant nature of the disease.
EBS in a quarterhorse
A single young quarterhorse foal was presented with erosions on the withers, back, chest and upper forelegs in Australia.n this foal, Indirect IF revealed the absent expression of plectin and the perinuclear condensation of keratin-14.
In this foal, clinical signs, microscopic and ultrastructural findings are suggestive of the diagnosis of a basal EBS. The lack of immunoreactivity for the intracellular protein plectin suggests that a mutation in the equine PLEC gene could cause skin lesions and laminitis in this foal.
EBS in Eurasier dogs
In these dogs, an homozygous nonsense mutation in the exon 27 of the PLEC gene, which was predicted to result in plectin truncation to 1,315 rather than its normal 4686 amino-acids
Junctional Epidermolysis Bulls (JEB)
At this time, in animals, JEB has been found to be caused by mutations of either LAMA3, LAMC2 and ITGB4 (Table 1). One kitten was also reported with a defective laminin beta-3 immunostaining.6
JEB in German shorthaired pointers
- Its mode of transmission is believed to be autosomal recessive.
- A sex predisposition has not been observed.
- In these dogs with JEB, lesions appeared usually within weeks of birth, but sometimes they developed after a few months of age.
- Electron microscopy not only confirmed that clefting occurs above the lamina densa, but it also revealed that the number and morphology of hemidesmosomes appeared similar to that seen in normal canine individuals.
- the defect of LAMA3 in affected dogs = reduced secretion of the alpha-3 chain and inadequate laminin-332 assembly.
JEB (“epitheliogenesis imperfecta”, EI) in American saddlebred horses
- Equine “epitheliogenesis imperfecta” is now known to represent lethal JEB in this species
- It is transmitted as an autosomal recessive trait in this breed
- Sequencing of LAMA3 in foals with EI revealed a large deletion base pair that eliminates exons 24, 25, 26 and 27 from the laminin alpha-3 chain
JEB of Belgian blue cattle
- Sequencing of this region revealed a missense mutation creating a premature stop codon (p.R2609*) in the exon 60 of the LAMA3 gene.
- This mutation, which results in a 22% shortening of the laminin alpha-3 chain, was found to be causative of JEB in this breed.
JEB of draft horse breeds of European origin
- the mode of transmission is consistent with an autosomal recessive inheritance
- In affected draft horses of these various breeds, skin lesions appear within days of birth and consist of severe ulceration pressure points of the limbs, in the oral cavity and at mucocutaneous junctions of the mouth, anus and vulva.
- Studies confirmed the decreased secretion of the laminin gamma-2 chain. These results were consistent with a failure of laminin-5 (Lm332) assembly and indicated the equine LAMC2 as the suspected causative gene of this disease.
JEB in a cat
- One domestic shorthaired was found to exhibit pinnal erosions, oral ulcerations and severe onychomadesis.
- Histopathology, electron microscopy and/or indirect immunoperoxidase revealed subepidermal clefting with the lamina densa remaining attached to the floor of the vesicles.
- Indirect immunofluorescence revealed reduced staining for laminin-332’s gamma- 2 subunit in one cat, suggesting that a mutation in LAMC2 might have been present
- A second cat with a phenotype and histopathology identical to that of the cat described in section exhibited a decrease in cutaneous laminin beta-3 immunostaining, suggesting a mutation in LAMB3, which was not characterized further.
JEB in German black head mutton sheep
- autosomal recessive transmissio
- immunohistochemical staining for collagen VII was similar in affected and control lambs while staining for laminin-332 was reduced in diseased lambs.
- Linkage and genomewide association studies mapped the trait to a region containing the LAMC2 gene.
- This mutation is located within the alpha-helix of laminin gamma-2 and it shortens the chain 13 codons downstream of the deletion. It is predicted to alter the assembly of laminin gamma-2 to the other two laminin chains thereby leading to altered function of laminin-332
JEB in Danish Herefords
The whole genome sequencing of one affected calf revealed a 2,433 base-pair deletion on chromosome 16, which caused the complete removal of the exon 1 of LAMC2 containing the start codon and the first 79 coding bases of the mRNA transcript.
JEB in Charolais cattle
- Antigen immunomapping was consistent with clefting occurring in the lamina lucida of the basement membrane, which established the diagnosis of JEB.
- The immunoreactivity for the alpha-6 integrin chain, but not that of laminin-332 chains or collagen XVII, was reduced in this calf compared to nonaffected bovine controls.
- These observations suggested that a mutation in the ITGA6 or ITGB4 genes encoding the integrin alpha-6 and beta-4 pair could be the cause of lesions in this patient
JEB in Churra sheep
- A genome-wide study revealed the association of the trait with an homozygous region of chromosome OAR11.
- A four base-pair delation was eventually found in the exon 33 of the ITGB4 gene.
Dystropic Epidermolysis Bulls
There are several subtypes of DEB in humans, all are due to varying mutations of COL7A1 that encodes for collagen VII. Over the last four decades, DEB has been reported sporadically in many animal species
DEB in white Alpine sheep
- Electron microscopy established that clefting occurred in the sublamina densa and that well-formed anchoring fibrils could not be found.
- Immunomapping confirmed clefting below the lamina densa, thereby establishing the diagnosis of DEB.
- Immunoblotting for collagen VII confirmed the absence of this protein in affected sheep tissue.
DEB in a Persian cat
- Microscopic examination of skin biopsies revealed dermo-epidermal separation without keratinocyte cytolysis.
- Collagen IV immunostaining revealed the lamina densa at the top of the clefts, which confirmed the diagnosis of DEB.
- Immunostaining for collagen VII revealed a markedly reduced intensity of basement membrane fluorescence in this cat’s skin compared to normal feline tissue
DEB in Assaf sheep
Immunostaining for collagen VII was negative in affected lambs.
DEB in Rotes Höhenvieh cattle
- Genomewide homozygosity mapping was consistent with a COL7A1 mutation.
- While it was unclear if the shortened protein was expressed, it was found to miss several collagen triple helix repeats that likely impaired collagen VII function and anchoring fibril formation.
DEB in Vorderwald cattle
Whole genome sequencing from two affected calves revealed an haplotype association on chromosome BTA22. Among candidate causal variants, the same mutation in COL7A1 as that seen in the Rotes Höhenvieh cattle.
DEB in golden retrievers
- Screening for genetic mutations demonstrated a homozygous nucleotide change in COL7A1, which co-segregated with the disease in affected individuals.
- This mutation predicts the substitution of a glycine into a serine (1906G-to-S) within the collagenous triple helix of collagen VII
Suprabasal Acantholytic Epidermolysis Bullosa in Bovidae
- Three separate occurrences of a congenital hereditary disease resembling human suprabasal EBS have been reported in bovidae: the so-called “familial acantholysis” in Angus calves 5, “hereditary suprabasal acantholytic mechanobullous dermatosis” in Brazilian Murrah buffaloes 6 and an unpublished report of “acantholytic EB” in Texan Brangus calves.
- Clinical signs occurred shortly at or within a few weeks of birth, and they consisted of erosions and ulcers with hair loss occurring principally on pressure points of all limbs and, occasionally, the tail.
- Light microscopy of affected skin biopsy specimens revealed suprabasal acantholysis resulting in intra-epidermal blistering
- Desmosomes were absent or rare in basal keratinocytes, and this lack of desmosomes was associated with the detachment of keratin intermediate filaments from desmosomal plaques.
Hereditary blistering dermatosis Chesapeake Bay retriever (CBR)
- Present at birth and puppies euthanized by 3 months of age
- Histopathology revealed a severe disintegration of the epidermis with extensive acantholysis of suprabasal keratinocytes.
- The immunomapping profile of affected dogs was consistent with lesion formation due to an absence of PKP1 leading to a detachment of desmoplakin from the desmosomal plaque and its retraction to the cell cytoplasm.
Darier Disease in Dogs
- In humans, autosomal dominant mutations of the genes encoding the calcium pumps SERCA2 cause Darier (DD) and Hailey-Hailey diseases.
- In DD, there is prominent suprabasal acantholysis resulting either from the impairment of desmosomal function or from secondary alteration in epidermal differentiation.
- Disintegration of the intermediate filament cytoskeleton also is associated with the formation of dyskeratotic keratinocytes named either “corps ronds” (e.g. round bodies) or “grains”.
- In HHD, there is widespread acantholysis in suprabasal epidermal layers, and ultrastructural examination also reveals perinuclear keratin rings following the detachment of filaments from desmosomal plaques.
- While most cases of DD and HHD have been convincingly associated with mutations of the ATP2A2 and ATP2C1 genes encoding SERCA2 and SPCA1,
- Published reports suggest the existence of a dermatosis in an English setter and its crossbreds, which resembled DD in humans
Idiopathic and presumably hereditary facial dermatosis of what breed of cat has been described?
Persian and Himalayan Cats
Affected cats have a. dirty face with adherent black exudate on skin and distal portions of the hair shafts.
Ulcerative Nasal Dermatitis is a rare disease and restricted to what breed of cat?
Bengal cats
Most cases have been recognized in Sweden.
Hyperkeratosis and fissuring are common clinical signs.
Ichthyosis in the Golden Retriever revealed numerous ______ retained in the epidermis, suggesting that a delay in their degradation is response for the clinical disease.
corneodesmosomes
Ichthyosis affected Norfolk Terriers show decreased staining for ____ in the epidermis secondary to a mutation in the gene encoding ____.
keratin 10
K10
Ichthyosis in the JRT, the thin cornfield envelope is associated with a mutation in the ____ gene. These dogs have a decreased free fatty acid and acyleramide levels and increased ceramics III levels in the stratum corneum.
TGM1
Ichthyosis in the CKCS indicates epidermal _____ with altered numbers and morphologic atypic of keratohyalin granules, curvilinear structures in the stratum corneum and alteration in the intercoryneocyte spaces.
hyperproliferation
What is the difference between Norfolk Terrier presentation of Ichthyosis compared to CKCS?
NT have the hyper pigmented scaly skin typical of ichthyosis but develop blisters and erosion in areas of mild skin trauma.
CKCS have a harsh crimpy coat with little or no visible scale early in life. The vibriassae are also affected. Their claw are often abnormal. Addiiotnally, these dogs ALSO have KCS.
What disease is a congenital hereditary disorder of cornification that has been described in multiple Rottweiler puppies, Siberian husky puppy and several Labrador Retrievers?
Follicular parakeratosis
All cases have occurred in females suggesting this is an X-linked trait.
Psoriasiform-lichenoid dermatosis is rare and recognized only in what breed? It is proposed to be an exaggerated response to staphylococcal infection.
English Springer Spaniels
Describe the histopathology of Psoriasiform-lichenoid dermatosis in English Springer Spaniels
Superficial perivascular to interstitial dermatitis with psoriasiform epidermal hyperplasia and areas of lichenoid interface dermatitis, intraepidermal microabssess (containing eosinophils and neutrophils) and ‘monro’ microabssess.
What syndrome affects the backs of some miniature schnauzers and it typified by multiple comedones that may become crusted, non-painful papule?
Schnauzer Comedo Syndome
This syndrome may be a developmental dysplasia of hair follicles,
What disease causes severe hyperkeratosis by 6 months of age. all pads of all feet are involved and an autosomal recessive inheritance has been identified in Irish Terriers and Dogue de Bordeaux.
Foodpad hyperkeratisis
Severe hyperkeratosis, fissures and secondary infection can occur and cause lameness.
Treatment is symptomatic.
What uncommon condition causes hyperkeratosis of the dorsal aspect of the nasal planum of the Labrador retriever or their crosses (suspected autosomal recessive model of inheritance)?
Hereditary Nasal Hyperkeratosis of the Labrador Retriever
What is the classical histopathologic findings in Hereditary Nasal Hyperkeratosis of the Labrador Retriever?
Mild to marked parakeratotic hyperkeratosis, moderate lymphocytic and neutrophilic exocytosis, and multifocal serous lakes within the upper epidermis. A superficial interstitial interface dermatitis is present.
What disease is a congenital inherited discontinuity of squamous epithelium and is considered autosomal recessive in cattle, horses, sheep and pigs.
Aplasia Cutis
**Histologically, ulcerated areas are distinguish by complete absence of epidermis, hair follicles and glands.
What is a neutral tube defect resulting from incomplete separation of the skin and neutral tube during embryonic development?
Dermoid Sinus
It is a tubular indentation of skin extends from the dorsal midline downwards and can extend to various depths.
Type 1 - End on the supra sinus ligament/nuchal ligament
Type 5 - Dermoid cyst
Dermoid Sinus has be reported mostly in what breed? The autosomal DOMINANT mutation involves what factors?
Rhodesian and Thai Ridgeback
FGF3, FGF4 and FGF19
(rare in cat but Burmese is overrepresented concurrently with neurologic deficits)
How is a dermoid sinus confirmed diagnostically?
fistulogram
Epidermolysis Bullosa Simplex is the mot superficial disorder, with cleating occurring in the ____ layer of the epidermis.
basal
In ______ disease, blisters form within the lamina lucida of the dermoepidermal basement membrane. Ulcerative lesions are most marked over bony prominences of the face, pinna, pressure points on the limbs and food pads.
Junctional EB
**lesions can also arise in the oral cavity and claws may be abnormal.
In what breed is JEB us autosomal recessive associated with a decreased expression of what structure?
GSHP
laminin 332 (laminin 5)
This condition is an autosomal recessive trait associated with decreased expression of collagen VII due to mutation in the COL7A1 gene.
Dystrophic epidermolysis bullosa
** In all animals skin biopsy showed a sub-basilar DEJ separation with the separation occurring BELOW the lamina densa with a reduction in the number of anchoring fibrils.
What disease is a hereditary, idiopathic, inflammatory disorder of the skin and muscles of your collies and Shetland Sheep Dogs?
Familial Canine Dermatomyositis
Autosomal DOMINANT
The most common sign in dermatomyositis of myositits is what finding?
asymptomatic atrophy - especially the muscles of mastication and distal limbs.
Describe histopathology of dermatomyositis
Scattered hydropower denervation of basal cells. Apoptotic basal cells (Civatte bodies) occasionally are visible. With marked hydropic degeneration - clefting may form. Dermal inflammation can be absent. Follicular atrophy and perifollicular fibrosis are common findings and may be the only findings in chronic lesions.
Muscle biopsy may show mixed inflammatory exudates accompanies by muscle fiber necrosis and atrophy.
