PC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M08

Signalment (JPC# 2017878):  One-day-old Angus-cross calf

HISTORY:  The entire skin had a thick horny epidermis that was divided into large plates by deep fissures.

HISTOPATHOLOGIC DESCRIPTION:  Haired skin:  Diffusely the stratum corneum is severely thickened (up to 2 mm) by laminated anuclear keratin (orthokeratotic hyperkeratosis), which entraps hair shafts; the follicular epithelium is also mildly hyperkeratotic.  The subcorneal epidermis is mildly hyperplastic forming projections that interdigitate with the corneal layer (papillated hyperplasia).  Keratinocytes in the stratum granulosum and spinosum are occasionally degenerate with indistinct cell borders and a prominent perinuclear clear vacuole.  Several follicles are mildly ectatic with loss of hair shafts, while hair follicles within the deeper dermis are haphazardly arranged with lack of/or irregular arrangement of sebaceous and apocrine glands (dysplasia).  The superficial dermis is mildly expanded by increased clear space (edema) and contains low numbers of neutrophils, lymphocytes, and plasma cells.  Diffusely, there is sebaceous gland atrophy and ectatic apocrine glands that are lined by attenuated epithelium. 

MORPHOLOGIC DIAGNOSIS:  Haired skin, epidermis and follicular epithelium:  Hyperkeratosis, orthokeratotic, diffuse, severe, with sebaceous gland atrophy, Angus‑cross, bovine.

ETIOLOGIC DIAGNOSIS:  Hereditary congenital hyperkeratosis

CAUSE:  Autosomal recessive genetic defect (presumed)

CONDITION:  Ichthyosis fetalis

SYNONYM:  Fish scale disease

GENERAL DISCUSSION: 

• Heterogeneous group of rare congenital, often autosomal recessive, dermatoses reported in cattle, dogs, humans, cats, mice, chickens, pigs, llamas, alpacas, and greater kudus
• Congenital and/or hereditary defect in the formation of the stratum corneum
• Hallmark lesion is marked lamellar hyperkeratosis (scales)
• Classification is complex with four major and several minor types described in humans
  • Epidermolytic: Vacuolation and lysis of keratinocytes together with hypergranulosis and hyperkeratosis within the spinous and granular cell layers
  • Non-epidermolytic subtype is gaining favor in veterinary medicine in that most ichthyoses in veterinary species are nonepidermolytic: Marked lamellar orthokeratotic hyperkeratosis and mild acanthosis

PATHOGENESIS: 

• The underlying biochemical defect in most cases is unknown and probably varies among different forms of the disease
• Pathogenesis involves either increased cohesion or defective dishesion (retention hyperkeratosis) of keratinocytes associated with either a short epidermal turnover time and/or disruption of the normal desquamative process or possibly alteration of lipid metabolism
• In severe forms of the disease, fissuring leads to exudation of protein and secondary bacterial and/or fungal infections which may lead to death
• Some icthyoses with lamellar cornification patterns associated with filaggrin intermediate protein processing
• ABCA12 mutation in Chianina cattle, Polled Herefords and Shorthorns

TYPICAL CLINICAL FINDINGS: 

Cattle (both forms inherited as simple autosomal recessive traits):

• Ichthyosis fetalis:
  • Most severe form; incompatible with life, and affected animals are aborted or survive only a few days after birth
  • Most analogous to harlequin ichthyosis in man, a rare fatal autosomal recessive disorder
  • Norwegian red poll, Friesian, and brown Swiss calves
  • Skin is covered by large horny plates separated by deep fissures corresponding to normal cutaneous cleavage lines
  • Hair is either absent or present as short stubble trapped in the thick hyperkeratotic plaques or lining the bottom of the fissures
  • Skin is tight and inelastic causing tension and eversion of eyelids (ectropion), lips (eclabium), and/or other mucocutaneous junctions
  • Ear pinnae are often small (microtia)

• Ichthyosis congenita:
  • Less severe form reported in Jerseys, Pinzgauer, Chianina, and Holstein‑Friesian calves which live longer
  • Most analogous to lamellar ichthyosis in man, an autosomal recessive ichthyosis thought to be caused by defective keratinocyte transglutaminase
  • Lesions similar to but less severe than those of ichthyosis fetalis; most severe on the limbs, abdomen, and muzzle
  • Alopecia is not an initial feature; may develop over time
  • Thick hyperkeratotic and curling scales in areas where hair is short, i.e. behind the muzzle and in the axilla
  • Skin is dry, hard, and inflexible like old leather, hair is entrapped in the plates of hyperkeratosis which are separated by shallow hyperemic fissures
  • Pinzgauer calves also have an associated microtia, cataracts and thyroid abnormalities

TYPICAL GROSS FINDINGS: 

• Lichenification and crusting; deep (ichthyosis fetalis) or shallow (ichthyosis congenita) fissures
• Alopecia, hyperpigmentation, and lymphadenopathy are possible

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• The stratum corneum is markedly thickened by laminated orthokeratotic and occasional parakeratotic hyperkeratosis affecting both surface and follicular epithelia
• Elongation of rete pegs and secondary bacterial infections
• Histologic changes in the subcorneal epidermis vary between different anatomic locations and different forms, but it may be thin, acanthotic, or edematous, and is often extremely folded on itself

DIFFERENTIAL DIAGNOSIS: 

• Cattle: Hyperkeratotic lesions in calves
  • Mycotic dermatitis: In fetal calves; observed with mycotic abortions (Aspergillus, Absidia, Mucor, Rhizopus); irregular, multifocal to coalescing elevated plaques about the periorbit, occiput, shoulders, back, and sides
  • Cutaneous dermatophytosis/ringworm (Trichophyton , Microsporum sp.): Well-circumscribed, alopecic, roughly circular lesions with a thick layer of gray-white scale-crust; periocular region and other parts of the head most common in calves
• Dogs: Most cornification disorders are secondary to other diseases; differential diagnosis for hyperkeratosis of the nasal planum or footpads
  • Immune-mediated: Pemphigus foliaceus, lupus erythematosus, drug reaction
  • Metabolic/endocrine: Hypothyroidism, hyperadrenocorticism, sex hormone imbalance/deficiency, superficial necrolytic dermatitis, zinc-responsive dermatosis, generic dog food dermatosis
  • Infectious: Canine distemper, leishmaniasis, papillomavirus, ectoparasites (demodicosis), dermatophytosis
  • Neoplastic: Exfoliative form of cutaneous lymphoma
  • Inherited: Familial footpad hyperkeratosis (KRT16 mutation in Dogue de Bordeaux; FAM83G in terriers), familial nasal hyperkeratosis, nasal parakeratosis of the Labrador retriever (SUV39H2), hyperplastic dermatosis of the West Highland white terrier
  • Idiopathic: Primary seborrhea, nasodigital hyperkeratosis, sebaceous adenitis

COMPARATIVE PATHOLOGY:

• Dogs:
  • Golden retriever: PNPLA1 gene defect; outer epidermal lipid metabolism gene
  • American bulldog: NIPAL4 (ICHTHYIN) gene defect; altered lipid metabolism
  • Great Dane: FATP4 gene defect; unique accumulations of eosinophilic lipid-rich material within dilated hair follicles and sebocyte cytoplasm
  • Jack Russell Terrier: TGM1 gene defect; mediates calcium dependent cross linking of peptides
  • German shepherd: ASPRV1 gene defect; affects filaggrin processing
  • Norfolk terrier: KRT10 gene defect
  • Cavalier King Charles spaniel: FAM83H gene defect
• Cattle:
  • Chianina: ABCA12 gene defect
• Equine:
  • Akhal-Teke horse: ST14 gene defect; affects filaggrin processing

REFERENCES: 

1. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Diseases of the epidermis. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA:Blackwell; 2005:174-179.
2. Hoffmann A, Metzger J, et al. Congenital ichthyosis in 14 Great Dane puppies with a new presentation. Vet Pathol. 2016; 53:614-620.
3. Lazar AJF, Murphy GF. The skin. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA:Saunders Elsevier; 2010:1186.
4. Mauldin E, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA:Elsevier; 2016:531-532.
5. O’Rourke BA, Kelly J, Spiers ZB, et al. Ichthyosis fetalis in Polled Hereford and Shorthorn calves. J Vet Diagn Invest. 2017;29(6):874-876.
6. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1167-1168.

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