Three-month-old, Pinzgauer-cross, steer, (Bos taurus).Since birth, the
calf failed to grow hair and maintained a thickened crusty skin. Shortly
before death, the calf became anorexic and lethargic. The calf had developed
disseminated pocks, sub-cutaneous nodules, and interdigital ulcers. This calf
was the first on this farm with this presentation.
three-month-old Pinzgauer-cross steer calf presented with severe generalized
hypotrichosis with the exception of the preputial skin. Large areas of the
skin, especially the trunk, were covered with thick layers of keratin resulting
in a fish scale or elephant skin appearance. The thickened keratin layer had
criss-crossed, deep fissures that extended into the dermis. There were
scattered dermal, up to 7mm in diameter nodules over the trunk, thigh, and
shoulder. Over the carpal and tarsal joints, the skin was smooth. The
interdigital skin had multiple small (up to 5 mm) areas of ulceration. All
subcutaneous and internal lymph nodes were moderately to severely enlarged
(e.g., right prescapular lymph node measured 7 x 3 x 2). The oral mucosa had
extensive erosions and the tongue had a focal area of hyperkeratosis over the
fossa linguae. There were a few small areas of epithelial hyperplasia and
hyperkeratosis in the esophagus and forestomachs. No significant gross lesions
were present in other organs and tissues including bone marrow, eye, and liver.
section contains skin lesions of increasing severity along the length of tissue
with one end much more affected and distorted than the other. In the section
of skin, there is mild to moderate epidermal hyperplasia with mild to severe
compact orthokeratotic hyperkeratosis and segmental parakeratosis. In severely
affected areas, hair follicles are rare and small for the follicles that are
present. Some affected follicles contain clumps of keratin with no discrete
hair shafts whereas other contains hair shafts that are angled, thin, and
fragmented. Multifocally, the epidermis has severe ballooning degeneration with
cytoplasmic eosinophilic inclusions in degenerate keratinocytes. This is
associated with suppurative folliculitis and pustular epidermitis. Areas of
hyperkeratosis are colonized by small numbers of Malassezia sp.
Severe epidermal compact hyperkeratosis. Severe
follicular dysplasia and hyper-keratosis. Severe chronic
ulcerative and pustular dermatitis with epithelial ballooning degeneration and
intracytoplasmic viral inclusion bodies.
microscopic examination of the skin identified poxviral particles in areas of
ballooning degeneration. Immunohistochemistry on a section the skin did not
identify bovine viral diarrhea virus.
Congenital hypotrichosis and pox
Pinzgauer-cross calf suffered from a combination of ichthyosis and follicular
dysplasia, which was complicated by surface Malassezia sp. infection,
suppurative folliculitis, and changes compatible with a poxviral dermatitis.
This constellation of maladies has not, to the best of the authors knowledge,
yet been described. Autosomal recessive ichthyosis with hypotrichosis syndrome
has been described in humans, but not well established in the veterinary
literature. The skin of this calf tested negative for bovine viral diarrhea
virus by immunohistochemistry and an underlying virus induced immune deficiency
was excluded in this case.
There are at least 36 types of ichthyosis described in humans.14 Ichthyosis in animals has not been well correlated with human forms. However, there are five human ichthyosis correlates described in animals, which include ichthyosis vulgaris, x-linked ichthyosis, epidermolytic hyperkeratosis, lamellar ichthyosis and harlequin ichthyosis.9 Ichthyosis is a rare skin condition that has been shown to affect cattle, dogs, pigs, chickens, mice and llamas9, among others. Two inherited forms of ichthyosis, both through autosomal recessive genes, have been reported in cattle: ichthyosis fetalis and ichthyosis congenita. Ichthyosis fetalis is generally fatal and affected animals usually survive for only a few days after birth. This disease has been described in Norwegian red poll, Friesian, and brown Swiss calves, and this entity most closely resembles human harlequin ichthyosis.2 Hairless skin is associated with ichthyosis fetalis and is characterized by large, horny, plates separated by deep clefts. Microtia, cataracts, thyroid hypoplasia, and eversion of mucocutaneous junctions are common features of this type of ichthyosis. These manifestations were not apparent in this case.
Ichthyosis congenita, a milder variant of ichthyosis, has been reported in Jerseys, Pinzgauer, Chianina, and Holstein-Friesian breeds.9 The lesions of ichthyosis congenita are similar to those of ichthyosis fetalis, but less severe and often localized to the skin over the abdomen, inguinal region, joints and the muzzle. Ichthyosis congenita most closely resembles human lamellar ichthyosis. Due to the older age of this calf and clinical presentation, ichthyosis congenita is suspected in this case. Eight genes have been linked to congenital ichthyosis: TGM1 (in people and Jack Russell terriers, but shown to not be the case in cattle 3, ABCA121, ABHD5(CG158)7, 2 lipoxygenases (ALOXE3 and ALOX12B5, NIPAL4 (ICTHYIN, Golden retrievers10), LIPN4, CYP4F2213, and PNPLA-1(American bulldogs16). The listed mutations result in disruption of the normal protective barrier that the skin provides while ichthyosis represents the local response to restore that barrier4. For example, TGM deficiency results in the abnormal cross-linking of the cornified envelope. Lipoxygenase deficiency in ALOXE3 and ALOX12B mutations are directly associated with abnormal lipid metabolism, impairing the structural integrity of the lipid bilayers. GJB2 mutations affect gap-junction integrity. Accumulation of large amounts of keratin and impairment of the permeability barrier promote the colonization and subsequent infection of skin. The surface Malassezia sp. infection, suppurative folliculitis, and poxviral dermatosis likely represent secondary lesions to the ichthyosis.
Follicular dysplasia or hypotrichosis is not an initial feature of ichthyosis congenita. However, hairlessness was present at birth in this calf, which suggests a primary rather than secondary process. Histologically, the follicular morphology is most consistent with follicular dysplasia. Based on genetic studies, an autosomal recessive component for follicular dysplasia has been described in cattle, such as for Herefords, Polled Herefords, Ayrshires, Guernseys, Jerseys, Holsteins and Black Angus.8,12,15
1. Haired skin: Epidermal dysplasia, diffuse, severe, with focally
extensive epidermal and follicular compact othokeratotic hyperkeratosis,
suppurative epidermitis and folliculitis, and marked follicular dysplasia,
Pinzgauer-cross, steer, Bos taurus.
Conference participants unanimously agreed that this is a
fascinating case and both a diagnostic and descriptive challenge. The
superimposition of the multiple processes in this case made it difficult to
identify the etiology of the inflammatory process. In fact, given the degree of
inflammation within the proliferative area, most participants did not initially
identify poxviral intracytoplasmic inclusion bodies within areas of epidermal
ballooning degeneration, confirmed by the contributors provided transmission
electron microscopy image. Readers are encouraged to review 2013. Participants
were struck by the diffusely malformed hair follicles numerous containing
shrunken, twisted, coiled, fragmented and densely packed hair shafts consistent
with follicular dysplasia. Follicular
dysplasia is the congenital abnormality of the morphogenesis of hair follicles
leading to changes in the quality and/or quantity of the hair shaft and
resulting in hypotrichosis.8,9,11 Congenital hypotrichosis has been
widely reported in all domestic veterinary species, but is most common in
calves. Various reported cases of congenital hypotrichosis in cattle have
either been associated with an X-chromosome linked ectodermal dysplasia,
autosomal dominant, or autosomal recessive hereditary conditions.9,11
Cattle affected by X-linked ectodermal dysplasia also have concurrent dental
disease characterized by incomplete dentition and lack of secondary tooth
development and is known as hypotrichosis and anodontia (HAD). In Holsteins,
this has been associated with an inherited defect in the ectodysplasin-1 (ED1)
Both lethal and viable variants of autosomal recessive and dominant forms of congenital hypotrichosis have been reported with generalized alopecia associated with excessive scaling, infundibular hyper-keratosis, easily broken and misshapen hair shafts, keratinocyte degeneration, and dilated apocrine glands. Other reported findings include subcapsular hepatic fibrosis, anemia, and neurologic deficits.8,11 Non-genetic causes of hypotrichosis in calves include iodine deficiency, adeno-hypophyseal hypoplasia, maternal ingestion of the toxic plant Veratrum album, and intrauterine infection with bovine pestivirus.9
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3. Dardano S, Gandolfi B, Parma P, et al. Characterization of bovine TGM1 and exclusion as candidate gene for ichthyosis in Chianina. J Hered. 2008;99(1):81-83.
4. Elias PM, Williams ML, Holleran WM, Jiang YJ, Schmuth M. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res. 2008;49(4):697-714.
5. Jobard F, Lefèvre C. Lipoxygenase-3 (ALOXE3) and 12 (R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome. Hum Mol Genet. 2002;11(1):107-113.
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10. "'>Mauldin EA, Wang P, Evans E, et al. Autosomal Recessive Congenital Ichthyosis in American Bulldogs Is Associated With NIPAL4 (ICHTHYIN) Deficiency. Vet Pathol. 2015;52(4):654-662.
11. Mecklenburg L. An overview on congenital alopecia in domestic animals. Vet Dermatol. 2006;17(6):393-410.
12. Miller WH, Scott DW. Black-hair follicular dysplasia in a Holstein cow. Cornell Vet. 1990;80(3):273-277.
13. Ohno Y, Nakamichi S, Ohkuni A, et al. Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. Proc Natl Acad Sci U S A. 2015;112(25):7707-7712.
14. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol. 2010;63(4):607-641.
15. Scott DW. Color Atlas of Farm Animal Dermatology. 1st ed.; 2008.
16. Tamamoto-Mochizuki C, Banovic F, Bizikova P, Laprais A, Linder KE, Olivry T. Autosomal recessive congenital ichthyosis due to PNPLA1 mutation in a golden retriever-poodle cross-bred dog and the effect of topical therapy. Vet Dermatol. May 2016.