The cornification process
represents morphologic changes in the whole life span of the keratinocytes. It
starts already in the basal cell layer keratinocytes and ends with the final
differentiated corneocytes of the ‘strong and compact’ stratum corneum. The
main functions of this layer are the toxin/microbe/trauma/UV light protection
and prevention of fluid loss (skin hydration). Four key steps are included in these
processes:
1. Formation of the protein core (aggregation
of keratins, with the help of fillagrin)
2.
Formation
of the protein envelope (replacement of the previous cell membrane with a
‘stronger’ one consisting of small peptides)
3.
Formation
of the lipid lamellar bilayers (consisting of cholesterol, long-chain fatty
acids, and ceramides, important role of lamellar bodies)
4.
Desquamation
(corneodesmosomes are cleaved by proteases, the corneocytes are shed into the environment)
Cornification disorders arise when
there is a problem in establishing a normal stratum corneum. They are usually
secondary, to an allergic, parasitic, metabolic, (para)neoplastic or endocrine
disease. Primary cornification disorders, the so-called ichthyoses are due to a
genetic defect somewhere in the cornification process or elements: structural
proteins, lipid metabolism, enzymes. Some investigators include abnormalities
in sebaceous gland function (eg, sebaceous adenitis, sebaceous gland dysplasia)
as primary cornification disorders as well. The diagnostic approach involves
thorough clinical assessment and ruling out secondary causes. Skin biopsies and
genetic test are usually inevitable to make a final diagnosis.
Icthyosis resembles primary
cornification disorders is at present subdivided into epidermolytic and
non-epidermolytic forms on the basis of light microscopy.
1. Epidermolytic ichthyosis in the Norfolk terrier is autosomal recessive and caused by
a mutation in epidermal keratin 10. It was also described in some other breeds
(Rhodesian ridgeback). These dogs have multifocal areas of hyperpigmented hyperkeratosis
(intertriginous areas) and dark scaling. The skin is sensitive to mechanical
trauma (erosions).
2. Non-epidermolytic
This group is corresponding to the autosomal recessive congenital ichthyosis
(ARCI) in humans, which is the official classification for a heterogeneous
group of disorders with overlapping phenotypes (e.g. lamellar ichthyosis,
congenital ichthyosiform erythroderma). A variety of mutations affecting lipids
and structural proteins cause similar phenotypes and light microscopic changes.
In humans, there are currently 8 known mutations, in comparison researchers characterized
3 in veterinary medicine. The current nomenclature used by pathologists in
veterinary medicine is to label these ARCI disorders by the breed predilection,
as described bellow. We will se if this will change in the future.
Golden retriever ichthyosis
Golden retrievers may presents with
usually mild-moderate non-pruritic generalised scaling (mild to moderate) disorder,
in the age from 3 weeks to 3 years (85% before 1 year of age). In France a high
prevalence (50%) was shown in this breed. The causing gene is now known to be
PNPLA1 (belonging to the patatin-like phospholipase
family). It is coding for a protein responsible for lipolytic and/or lipogenic activity of neutral lipids (not
triglycerides). These studies in dogs helped to reveal the cause also in human patients
with ARCI. In non-breeding animals a diagnosis based on clinical and
histopathological findings is sufficient. Performing a genetic test (www.antagen.com) in breeding animals to assess carrier state is
recommended.
American Bullterier ichthyosis
American bulldogs typically have a more
severe phenotype (then Golden retrievers) with lesions evident before weaning
(sometimes shortly after birth). The scaling is generalized (also in the coat) with
large, light brown adherent scale on the ventral thorax and abdomen, the skin
is often erythematous. The abdominal skin of adult dogs may be reddish-brown. The
animals may show otitis, pododermatitis and intertrigo. Secondary Malassezia infections may develop and be
associated with a significant pruritus. Pedigree analyses are highly suggestive
of an autosomal recessive trait and the responsible gene is coding for the
protein ICHTHYN. The test can be performed at The University of Pennsylvania
USA (dogderm@vet.upenn.edu)
Jack (Parson) Russel Icthyosis
The clinical lesions are characterized
by thick, adherent scales (0,5 -2 cm large) predominantly on ventral skin areas
(abdomen, ventral neck). The skin of the food pads and nose may be thickened
and greasy. The dogs may develop severe secondary yeast and/or bacterial
infections with corresponding inflammation and pruritus. Nonepidermolytic
ichthyosis in Jack Russell terriers (JRT) is caused by a loss of function
mutation in transglutaminase 1 (TGM1). TGM1 mediates calcium dependent
cross-linking of peptides (e.g. involucrin, loricrin) to form the cornified
envelope- the strong exterior of the corneocyte.
Non-determined cornification disorders
Some
other breeds are described with clinical signs of ichthyosis, but the molecular
characterization is not available yet. The following breeds are mentioned: Cavalier King Charles spaniel dogs (keratoconjunctivitis starting
from eyelid opening age, a roughened/curly haircoat, scaling with abdominal hyperpigmentation,
footpad hyperkeratosis, and nail dystrophy), West Highland White terriers,
soft-coated Wheaton terrier.
Unconfirmed cornification disorders
For some diseases, there is lack of
sufficient evidence that they are a primary cornification disorders. Vitamin A
– responsive dermatosis, generalized sebaceous gland hyperplasia and primary
seborrhea are in this moment controversial diseases.
References
- Mauldin
E. Proceedings of the 27th Annual congress of the ESVD-ECVD
2014, p.124-127
- Mauldin EA. Canine ichthyosis and related disorders of
cornification. Vet Clin North Am Small Anim Pract. 2013
;43(1):89-97
- Mauldin EA et al. The clinical and morphologic features of
nonepidermolytic ichthyosis in
the golden retriever. Vet Pathol. 2008;45(2):174-80.
