Primary cornification disorders

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

- Barnhart KF et al. A heritable keratinization defect of the superficial epidermis in norfolk terriers. J Comp Pathol. 2004 May;130(4):246-54.

- Credille KM. Transglutaminase 1-deficient recessive lamellar ichthyosis associated with a LINE-1 insertion in Jack Russell terrier dogs. Br J Dermatol. 2009;161(2):265-72.
- Credille KM et al.  Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs. Br J Dermatol. 2005 Jul;153(1):51-8.
- Grall A et al. PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans. Nat Genet. 2012;44(2):140-7
- Guaguere E et al. Clinical, histopathological and genetic data of ichthyosis in the golden retriever: a prospective study. J Small Anim Pract. 2009;50(5):227-35
- Lewis et al. Characterization and management of a Jack Russell terrier with congenital ichthyosis. Vet Dermatol 1998; 9(2) pages 111–118.

- 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.