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Congenital Ichthyosis in 14 Great Dane Puppies With a New Presentation

Article in Veterinary Pathology · August 2015

DOI: 10.1177/0300985815595516

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Original Article

Congenital Ichthyosis in 14 Great Dane Puppies With a New Presentation

• A. Hoffmann1, J. Metzger2, A. Wo

¨hlke2, M. Peters3, J. Junginger1,

• R. Mischke4, O. Distl2, and M. Hewicker-Trautwein1

Abstract The present study describes a generalized congenital skin condition in 14 Great Dane puppies. Macroscopically, all dogs showed generalized gray to yellow scaling and skin wrinkles on the head and all 4 extremities. Skin sections were histologically examined using hematoxylin and eosin, Heidenhain’s Azan, and Sudan red III staining methods and by conducting the alcian blue/periodic acid Schiff (AB/PAS) reaction technique on sections. Furthermore, incubation with hyaluronidase was performed. Skin samples were ultrastructurally analyzed using transmission electron microscopy. All affected Great Dane puppies had epidermal and follicular

• rthokeratotic hyperkeratosis, enlarged keratohyaline granules, vacuolated keratinocytes, and accumulations of an eosinophilic

and alcianophilic, lipid-rich material within dilated hair follicular lumina and the cytoplasm of sebocytes. The macroscopic, histopathologic, and ultrastructural skin changes in all 14 Great Dane puppies indicate a new variant of a primary disorder of cornification with congenital, non-epidermolytic, lamellar ichthyosiform appearance. Keywords canine, Great Dane, congenital, hyperkeratosis, ichthyosis, sebaceous glands

Introduction

Ichthyoses are a heterogenous group of rare congenital disor- ders of cornification that are characterized by hyperkeratosis and scales. This condition has been reported in cattle, dogs, pigs, chickens, laboratory mice, and a llama.3,11,20 Based on histologic findings, ichthyoses can be subdivided into epider- molytic and non-epidermolytic forms. In epidermolytic ichthyosis, vacuolization and lysis of keratinocytes together with hypergranulosis and hyperkeratosis occur within the spi- nous and granular cell layers.7,22 Non-epidermolytic ichthyosis is mainly characterized by marked, lamellar, orthokeratotic hyperkeratosis and mild acanthosis.19 Ichthyosiform disorders in dogs have strong breed predilections although they can occur in mixed-breed dogs as well.1,10,14,19,21 Syndromic ichthyoses, characterized by extracutaneous lesions, have been described in dogs, such as in the Cavalier King Charles spaniel with keratoconjunctivitis.4,15,16 Congenital, non-epidermolytic forms of ichthyosis with clinical and histomorphological fea- tures resembling autosomal recessive congenital ichthyosis in humans (ARCI) have been described in several purebred dog breeds, such as Golden Retriever, American Bulldog, and Jack Russell Terrier.11,12,14,20,21 The aim of this study was to describe the macroscopic, his- topathologic, and ultrastructural features of a new variant of a non-epidermolytic, congenital ichthyosis observed in Great Dane puppies associated with accumulations of an alcianophi- lic and lipid-rich material within sebaceous glands and dilated hair follicle lumina.

Materials and Methods Animals and Clinical Findings

Fourteen Great Dane puppies, 6 female and 8 male, aged from a few days to 5 weeks and originating from 6 different litters (Table 1) had been submitted for necropsy between 2006 and 2014 to the Department of Pathology, University of Veterinary Medicine Hannover (dog Nos. 1–11, 13, and 14) or to the CVUA-Westfalia in Arnsberg (dog No. 12). Dog Nos. 1 through 12, after clinical examination, were euthanized at veterinary practices with the consent of the owners. Two puppies (dog Nos. 13and 14), which were referred to the Small Animal Clinic, Uni- versity of Veterinary Medicine Hannover in 2014, were exam- ined clinically by 1 of the investigators (R.M.) and were euthanized with the consent of the owners. All animals had

1Department of Pathology, University of Veterinary Medicine Hannover,

Hannover, Germany

2Institute for Animal Breeding and Genetics, University of Veterinary Medicine

Hannover, Germany

3Chemical and Veterinary Investigation Office (CVUA) Westfalia, Arnsberg,

Germany

4Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover,

Germany Corresponding Author: Marion Hewicker-Trautwein, Department of Pathology, University of Veterinary Medicine Hannover, Bu ¨nteweg 17, D-30559 Hannover, Germany. Email: marion.hewicker-trautwein@tiho-hannover.de

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marked skin wrinkles on the head and legs since birth. The skin

• f the head and legs and other regions showed moderate to

severe scaling with fine white to yellow scales. Furthermore, the skin was covered with a yellow, greasy material, especially on the skin of the head and legs. Glabrous skin regions, such as axil- lar and inguinal areas, were dry and had a leathery appearance.

Skin Samples From Affected and Control Dogs

At necropsy, skin samples were collected from different wrinkled locations (head and fore and hind limbs), non- wrinkled locations (back, abdomen, sides, shoulders, navel), and various other organs and tissues. The samples were fixed in 10% formalin within approximately 24 to 36 hours after death and embedded in paraffin. Paraffin sections, 3 to 5 mm in thickness, were routinely stained with hematoxylin and eosin (HE). From 2 dogs (dog Nos. 13 and 14), 8-mm punch samples

• f skin were taken approximately 2 hours postmortem, and

either processed as above, embedded in Tissue-Tek O.C.T. compound (Sakura Finetek, Alphen aan den Rijn, the Nether- lands) and snap frozen in 2-methylbutane, or fixed in 2.5% glu- taraldehyde in 0.1M cacodylate buffer (pH 7.2) for 24 hours before processing for transmission electron microscopy. As normal control tissue, skin samples from the head, fore and hind limbs, back, and navel were obtained from 7 Great Dane puppies that were unrelated to the diseased dogs and had died after Caesarian section. Samples were obtained within 24 hours after death, histologic sections were prepared as above, and skin samples from 1 of the puppies were prepared for trans- mission electron microscopy as described above.

Histochemistry and Transmission Electron Microscopy

On skin sections from all diseased and control puppies, the com- binedalcianblue(pH2.5)/periodicacidSchiff(AB/PAS)reaction was performed. Furthermore, to evaluate hyaluronan, sections were digested with 80 ml/mL hyaluronate lyase from Strepto- myces hyalurolyticus (Sigma-Aldrich, St Louis, MO, USA) in 50 mM sodium acetate, 0.15 M NaCl, pH 6.7, at 37C, for 3 hours followedbystainingwithAB/PASatpH2.5(modified,according to Zanna et al29). Control sections were incubated in parallel with thesamesolution without theenzyme. On representativeskin sec- tions from several diseased dogs and control dogs, a Heidenhain’s Azan stain was performed. Frozen and previously formalin-fixed skin sections (5 mm in thickness) from dog Nos. 13 and 14 were routinely stained with Sudan red III.

Transmission Electron Microscopy

Electron microscopic examination of skin samples from dog

• Nos. 1, 2, 8, 9, 10, and 12 was performed using the pop-off

technique.17 From skin samples obtained from dog Nos. 13 and 14 and from the control dog, first semi thin sections were cut (1-2 mm) and stained with 0.1% toluidine blue. Subsequently, ultrathin sections were cut at 60 to 90 nm and stained with uranyl acetate and lead citrate. These were then examined with a Zeiss EM 10 A transmission electron microscope (Zeiss, Oberkochen, Germany).

Results Pathologic Findings

All 14 Great Dane puppies had markedly wrinkled skin on the head and on the distal extremities (Figs. 1–3). The skin surface had moderate to severe fine, dry, white to yellow scales. Furthermore, the skin had a greasy appearance, especially affecting the head and legs. In 1 puppy (dog No. 12), glabrous skin was noted on the muzzle (Fig. 1). In 2 puppies (dog Nos. 10 and 11), bilateral, mild to moderate hydronephrosis was

• found. Except for agonal changes, no other gross abnormalities

were seen in any of the dogs. HE-stained paraffin sections from wrinkled and non- wrinkled skin of all 14 puppies had similar histopathologic changes of moderate to marked, diffuse, orthokeratotic, lamel- lar, epidermal, and follicular hyperkeratosis and mild, regular acanthosis (Figs. 4, 5). In all 14 cases, vacuolated keratinocytes with occasionally slightly shrunken nuclei were present within the stratum granulosum, the stratum spinosum, and the hair fol- licle epithelium. Some keratinocytes had empty perinuclear vacuoles, while others had vacuoles with slightly eosinophilic homogenous material (Fig. 5). The keratohyaline granules of the stratum granulosum of the epidermis and of the hair follicle epithelium were normal in number and distribution. However,

• ften enlarged, spherical keratohyaline granules were noted

(Fig. 5). There was marked, orthokeratotic hyperkeratosis of dilated hair follicle infundibula with frequent keratotic plug- ging (Fig. 4). In all 14 dogs, some sebaceous gland appeared normal with mature sebocytes surrounded by a peripheral layer

• f basal cells, while other sebaceous glands were enlarged and

had numerous degenerating sebocytes with shrunken nuclei and homogenous unstained cytoplasmic material. Large amounts of such material were also found within dilated hair follicle lumina (Fig. 6).

Table 1. Signalment of 14 Great Dane Puppies With Congenital Ichthyosis. Dog No. Litter Age Sex 1 I Neonatal Male 2 II 15 days Male 3 II 15 days Male 4 II Neonatal Female 5 III Neonatal Male 6 III Neonatal Male 7 III Neonatal Male 8 III Neonatal Male 9 III Neonatal Female 10 IV 8 days Female 11 IV 8 days Female 12 V 28 days Male 13 VI 62 days Female 14 VI 62 days Female

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Except for 3 cases (dog Nos. 1, 12, and 13), inflammatory skin lesions were absent. In the skin of dog No. 1, few scattered lymphocytes and plasma cells were found within the superficial

• dermis. Dog No. 12 focally had bacterial colonies within

dilated hair follicle lumina and in the stratum corneum, in sam- ples of the muzzle and of the deep pyogranulomatous dermati- tis on the lip. This dog also had a mild focal intracorneal infiltration of neutrophils together with bacterial colonies. A moderate focal pyogranulomatous furunculosis including the sebaceous gland tissue as well as a mild focal intracorneal infil- tration with neutrophilic granulocytes and few intralesional bacteria were seen in a section from the muzzle of dog No. 13. Dermal collagen and subcutaneous tissues were within normal limits for all 14 dogs. Additional findings were restricted to a diffuse mild lymphohistiocytic interstitial pneumonia in dog

• Nos. 10 and 13, with a marked alveolar histiocytosis and edema

in the latter. The 2 dogs with bilateral hydronephrosis (dog

• Nos. 10 and 11) had focal, mild fibrosis of the renal medulla

and mild dilation of tubules. In the remaining organs and tis- sues of the 14 dogs, no histologic abnormalities were seen. In the skin of the control dogs, only few individual vacuo- lated keratinocytes were present both in the epidermis and the hair follicle epithelium. Otherwise, no histologic abnormalities were present.

Histochemical Findings and Results of Special Stains

In skin sections of all 14 dogs, the AB/PAS reaction revealed that the homogenous material within the deep portion of hair fol- licles and the sebaceous gland epithelium was strongly alciano- philic (Fig. 7). Furthermore, in sections from all puppies, accumulations of such alcianophilic material were present within and on the surface of the stratum corneum directly located at the hair follicle infundibula (Fig. 8). In all 14 cases, small amounts of slightly alcianophilic material were seen within peri- and interfollicular areas of the deeper der- mis and in the subcutis. In sections treated with hyaluroni- dase, the alcianophilic material was absent in peri- and interfollicular dermal areas while the material within sebac- eous glands and hair canals was still present. Small amounts

• f alcianophilic material digestable with hyaluronidase were

also found in skin samples from the 6 control puppies, but in none of them was such material seen within the sebac- eous glands or within the hair follicle lumina or infundibula. In sections from all 14 dogs, the homogenous material within hair follicle infundibula was intensely stained by Sudan red III. In histologically normal appearing sebaceous glands, the Sudan red III stain revealed accumulations of lipids show- ing a droplet-like staining pattern in the cytoplasm of mature

Figures 1–3. Ichthyosis, dog. Figure 1. Head, dog No. 12. The skin of the muzzle is covered with yellow, greasy material predominantly located between the skin folds. Figure 2. Body, dog No. 12. Marked skin wrinkles on the head and distal parts of the legs. Figure 3. Head, dog No. 13. The head has marked skin wrinkles and intense fine, yellow scaling.

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sebocytes while the sebocytes in enlarged sebaceous gland lobules exhibited a homogenous staining pattern. On sections stained by the Heidenhain’s Azan method, differences in qual- ity and distribution of collagen fibers were not seen between affected and control dogs.

Transmission Electron Microscopic Findings

Ultrastructurally, in all 8 affected dogs examined (dog Nos. 1, 2, 8, 9, 10, 12, 13, and 14), marked orthokeratotic epidermal and infundibular hyperkeratosis was present. In the epidermis and infundibulum, the superficial layer of the stratum corneum was structurally normal, while the deeper layers contained large accumulations of a fine granular, amorphous material between the layers (Fig. 9). The thickened epidermis and the hair follicle epithelium had numerous vacuolated keratinocytes, which were mainly located within the stratum granulosum and were also present in the superficial stratum spinosum. The affected kerati- nocytes had single or multiple, variably-sized, cytoplasmic, membrane-bound vacuoles, which sometimes contained smaller

• vesicles. The keratinocytic vacuoles often displaced the nucleus

and contained varying amounts of an amorphous, fine granular

• material. The stratum granulosum contained prominent kerato-

hyalingranulesvaryinginsizeandshape (Fig.10).Thesebaceous glands,besidesnormalappearingsebocytes,hadgroupsofdegen- erating and lysed sebocytes, which showed accumulations of an amorphous, electron-lucent material. Such material was also present within dilated hair follicle lumina. In skin samples of the control dog, only few keratinocytes of the epidermis had single, empty, cytoplasmic, perinuclear vacuoles.

Figure 4–7. Ichthyosis, skin, dog. Figure 4. Skin of the left distal forelimb, dog No. 13. Severe epidermal and follicular hyperkeratosis with keratin plugging. Sebaceous glands and hair follicles contain amorphous material (asterisks). Hematoxylin and eosin (HE). Figure 5. Skin of the right distal forelimb, dog No. 1. Severe epidermal hyperkeratosis. The granular layer has enlarged keratohyalin granules. Keratinocytes of the stratum spinosum show vacuoles containing slightly eosinophilic material (arrows). HE. Figure 6.Skin of the nose, dog No. 8. Slightly eosino- philic amorphous material in sebaceous glands and the dilated deep portion of the hair follicle (asterisks). HE. Figure 7. Skin of the nose, dog

• No. 8. Alcianophilic substance within the pilosebaceous unit, namely, in the dilated isthmus and the deeper lumen of the hair follicle (asterisks)

and in the sebaceous gland epithelium (arrows). AB/PAS.

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Pedigree Analysis

Thirteen dogs of this study were shown to be related (Fig. 11). Dog No. 1 was of unknown parentage and could not be assigned to the pedigree.

Discussion

The 14 Great Dane puppies examined in this study had identical macroscopic, histopathologic, and ultrastructural skin changes, which based on morphological features are compatible with a primary disorder of cornification. The early onset as well as clin- ical presentation and histopathologic appearance of the lesions are suggestive of a congenital, non-epidermolytic, lamellar ichthyosis as described in Golden Retrievers. Macroscopically, all 14 Great Dane puppies had moderate to severe, generalized scaling with fine, dry, and white to yellow scales and a greasy and leathery appearance of the axillary and inguinal skin regions. The histopathologic findings in all dogs were characterized by diffuse, orthokeratotic hyperkeratosis, folli- cular keratosis, focal keratin plugging, and acanthosis with vacuo- lization of keratinocytes without epidermolysis. These skin changes are compatible with lamellar ichthyosis as has been described in other purebred dog breeds such as the Golden Retrie- ver,6,12,13,20 American Bulldog,19,21 American Pit Bull,28 and Jack Russell Terriers.8 Similar findings of abnormal and enlarged ker- atohyalin granules in canine ichthyosiform dermatoses were pres- ent in Norfolk Terriers, a Labrador Retriever, and a mixed-breed dog affected by epidermolytic ichthyosis.2,5,21 The significance and pathogenesis of the findings in these dogs remain unclear. Changes in the folliculosebaceous unit containing accumula- tions of an amorphous material found in Great Danes of this investigation have not been described in other canine ichthyosi- form dermatoses. In all cases, prominent sebaceous glands with enlarged glandular lobes were present, in which several sebocytes contained an amorphous, lipid-rich material as revealed by the Sudan red III stain. Such material was also pres- ent within dilated hair follicle lumina and on the surface of and within the thickened, hyperkeratotic layers of the epidermal and infundibular stratum corneum. The material within the sebac- eous glands and in the infundibula, in addition to lipid staining by Sudan red III, also had alcianophilic staining characteristics. Alcian blue at a pH of 2.5 as used in this study stains all types of glycosaminoglycans including sulfated and carboxylated muco- substances such as mucin.24 The lipid-rich and alcianophilic material seen in the folliculosebaceous unit of Great Dane pup- pies was not digestable with hyaluronate lyase, therefore ruling

• ut the presence of mucinous substances, although the presence
• f non-sulfated glycosaminoglycans cannot be ruled out. The

exact composition of this material is unclear. Further investiga- tions to identify the material are planned. Such findings, to the best of our knowledge, have not yet been described in dogs with congenital ichthyosis. Sebaceous glands produce and release sebum, a complex mixture of lipids, through an excretory duct into the follicular canal, finally being extruded to the skin surface.25,26 During sebum production, mature holocrine- secreting sebocytes undergo degeneration and lysis and are renewed by division of basal cells.25,26 The histologic findings in the folliculosebaceous unit of the Great Dane puppies of this study indicate excess production of lipid-rich sebum in hyper- plastic sebaceous glands with possible increased turnover of proliferating sebocytes. The ultrastructural findings in 8 of 14 examined dogs were characterized by accumulations of material between the corneocytes of the epidermal and infundibular stra- tum corneum, perinuclear vacuoles within keratinocytes, as well as the presence of enlarged keratohyalin granules. The material found in the stratum corneum correlated focally with Sudan red III- and AB/PAS-positive reactions, indicating a lipid- and glycosaminoglycan-rich material. Membrane-bound, cytoplas- mic vacuoles in keratinocytes were described in other breeds

• f dogs with different forms of ichthyotic skin disorders in pre-

vious studies.7,18,20,21 In some cases, these vacuoles were accompanied by epidermolysis, which was not seen in the pres- ent study on Great Danes.2,5,7,21 The specificity of perinuclear vacuoles seen in diseased dogs in our study, however, is ques- tionable as vacuoles were also found in skin sections of the con- trol dogs. Furthermore, such vacuoles can often be seen in skin sections as a fixation artefact. The pedigree analysis of 13 of 14 Great Danes showed that all dogs were related. The Great Dane ichthyosis does not fit in the classification seen in humans where many different forms

• f autosomal recessive, congenital ichthyoses (ARCI) are clas-

sified into subgroups.12,27 Based on the classification system, most similarities exist with the congenital, autosomal reces- sive, non-epidermolytic, lamellar ichthyosis described for Golden Retrievers, although differences were present.12,13,20 Histologic changes not yet observed in ichthyotic dogs include the accumulation of an amorphous material within hair canals and sebocytes found with different staining patterns. Primary ichthyosis is a non-inflammatory skin disease.19 Only in 3 dogs of this study were the skin changes

Figure 8. Ichthyosis, skin, distal forelimb, dog No. 12. Within the epi- dermal stratum corneum close to hair follicle infundibula, accumulations

• f alcianophilic material are present (arrow). AB/PAS.

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accompanied by mild, focal pyogranulomatous or lympho- plasmacytic inflammatory lesions with few intralesional bac-

• teria. These findings indicate that the disease, with advancing

age, may lead to secondary infections and inflammatory skin

• lesions. A predisposition for secondary skin changes such as

mycosis and bacterial infection has been described in

Figure 9. Ichthyosis, skin, dog. Skin of the head, dog No. 13. Thickened stratum corneum with accumulations of loosely structured material between the corneocytes (asterisk). Transmission electron microscopy. Figure 10. Skin of the head, dog No. 13. Keratinocyte of the stratum granulosum with multiple cytoplasmic perinuclear membrane-bound vacuoles containing varying amounts of loosely structured material. An almost empty vacuole has a marginal vesicle (arrow). Transmission electron microscopy. Figure 11. Pedigree, dogs Nos. 2 through 14 showing that 13 dogs are related.

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American Bulldogs with ichthyosis as well as in Shar Pei dogs, possibly due to the wrinkled skin.19,21 The etiology of the marked wrinkling of the skin seen in all 14 Great Dane puppies of this study remains unknown. This reflects previous reports of ichthyosis seen in American Bull- dogs.19,21 The leathery skin areas could be interpreted as early cutaneous signs for puppies affected by ichthyosis.13 In the Chinese Shar Pei, skin wrinkles are associated with the pres- ence of dermal accumulations of mucin within the interfollicu- lar dermis, a condition that was suggested to be associated with a mutation in the HAS2 gene.9,23,29 The alcianophilic material within the interfollicular dermis and subcutis both of Great Dane puppies with skin folds and in control dogs was digesta- ble with hyaluronidase and most likely represents normal amounts of mucin, which is often seen in normal canine skin.25 Also, the presence of a dermal mucinosis caused by a mutation was ruled out in the puppies of this study. Ichthyosis is a heterogenous group of congenital disorders

• f cornification, and the excessive scaling is due to a direct

defect in 1 or more steps involved in the formation of the stra- tum corneum.19 There are defects that are related to mutations in genes that encode the structural proteins that form the corneocyte, or enzymes involved in lipid formation or lipid transport.19 In conclusion, this study describes a congenital ichthyosis occurring in Great Dane puppies, which is asso- ciated with histologic changes within the folliculosebaceous

• unit. Based on histopathologic features, we suggest a conge-

nital, non-epidermolytic, lamellar form of ichthyosis with a pathogenesis involving a disturbance in sebum production and/or cellular turnover of sebocytes. Acknowledgements

We wish to thank Bettina Buck, Klaus-Peter Kuhlmann, and Kerstin Rohn for their excellent technical assistance.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author- ship, and/or publication of this article.

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