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Journal of Veterinary Diagnostic Investigation Vol. 18 Issue 6, 573-579
Copyright © 2006 by the American Association of Veterinary Laboratory Diagnosticians
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Aplasia cutis congenita (epitheliogenesis imperfecta) in swine: observations from a large breeding herd

Marie-Odile Benoit-Biancamano1, Richard Drolet and Sylvie D'Allaire

Correspondence: 1Corresponding Author: Marie-Odile Benoit-Biancamano, Department of Pathology and Microbiology, Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, Saint-Hyacinthe, Québec, J2S 2M2, Canada, e-mail: marie-odile.benoit-biancamano{at}umontreal.ca


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Epitheliogenesis imperfecta has been reported in several animal species, and its inheritance is suspected to be autosomal recessive. This term has been used to describe two different diseases, namely epidermolysis bullosa and aplasia cutis congenita, which are both grossly characterized by an absence of epidermis or mucosal epithelium and are most frequently reported on the distal limbs and oral cavity. Epitheliogenesis imperfecta has been described in swine, but the literature on the subject is scarce. To better characterize this condition, 70 piglets with congenital skin defects macroscopically compatible with epitheliogenesis imperfecta were examined. In all but 1 case, only 1 piglet per litter was affected. Of the affected piglets, 65 (93%) were male, suggesting a sex-related problem. More than half of the piglets had multiple skin lesions. All defects were located on the caudal half of the body, and none was found in the oral cavity. Most lesions were characterized by an absence of epidermis and part of the dermis and adnexae. Adnexal dysplasia was also observed at several sites, both with and without epitheliogenesis imperfecta, suggesting a developmental problem. Fluid-filled, congenital subcutaneous bullae were noted grossly on 7 piglets; their relationship, if any, with epitheliogenesis imperfecta remains unknown. As the term epitheliogenesis imperfecta has been used in cases of epidermolysis bullosa, the term aplasia cutis congenita seems to be more appropriate to describe these lesions in swine.

Key Words: Aplasia cutis congenita • dysplasia • epitheliogenesis imperfecta • skin • swine


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Epitheliogenesis imperfecta refers to a condition in which discrete areas of the body are devoid of skin at the time of birth. It has been reported in several domestic and wild animal species1,7,9 and has been used to describe 2 different conditions with a similar clinical presentation, namely epidermolysis bullosa and aplasia cutis congenita.4,11,12,18–20

In swine, epitheliogenesis imperfecta is a sporadic congenital defect that occurs on many farms. Lesions have been described mainly on the trunk, but also on the distal limbs.3,9,15,16,19,22,24 Some authors have reported similar epithelial defects in the oral cavity as well as frequent concomitant hydronephrosis and hydroureter.8,9,13 This condition has been described in both white and colored breeds.4,19 Although one author suggested that it may represent a sex-linked defect,3 a simple, autosomal recessive mode of inheritance is more widely suspected.4,8,9,14,18,22

Detailed descriptions of this disease in pigs are lacking in the contemporary literature, and some of the reported characteristics seem to have been extrapolated from other species. The aim of the present study was to more accurately describe this congenital condition in swine based on observations in a large breeding herd.


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Animals
A total of 70 piglets with gross lesions compatible with epitheliogenesis imperfecta were included in this study. They originated from a 1,500-sow commercial breeding herd over a period of 3.5 years. The farm personnel did not systematically record and submit all affected piglets during that period. Collected data included the date of birth, sex of the affected piglets, number of affected animals per litter, parity of the dam, and identification of both sire and dam. Sows on this farm were artificially inseminated using semen from 1 to 3 boars. Sows were F1 Landrace x Yorkshire, and sires were from 3 different synthetic lines with Pietrain genetic background.

Diagnostic Procedures
A complete necropsy was performed on 68 pigs. Skin defects were photographed and measured, and concomitant abnormalities were noted. Samples of skin were fixed in 10% buffered formalin, embedded in paraffin, and 1 to 4 sections per lesion were cut at 3 µm and stained with hematoxylin-eosin-phloxine-saffron (HEPS) for routine light microscopic examination. Immunohistochemistry for cytokeratina and vimentinb was performed on subcutaneous bullae (6 pigs) as well as on sudoriparous cysts (3 pigs). Samples of liver, lung, and kidney from 5 weak pigs with extensive cutaneous lesions were submitted for routine bacteriology. Liquid contents from 6 subcutaneous bullae were submitted for cytologic and biochemical analysis, and 2 were also sent for routine bacterial culture. Of the 2 animals on which a complete necropsy was not performed, 1 was observed on the farm for a month to assess the evolution of the lesions, and the body of the other was kept for teaching purposes.


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Clinical Findings
All the affected piglets were born with the skin defect. The age of the piglets at the time of necropsy ranged from a few hours up to 13 days, with more than 51 piglets (70%) being younger than 2 days old. All pigs were bright and alert, except for 5 weak pigs, 2 of which had an Escherichia coli septicemia, as evidenced by detection of E. coli in multiple organs; 2 others had empty stomachs.

Of the 70 affected piglets, 65 (93%) were males. The parity of the dams that had produced affected piglets ranged from 1 to 13; there was no relationship between the parity and the frequency of epitheliogenesis imperfecta in piglets. Only 3 dams had affected piglets on 2 distinct farrowings. Among these, 1 sow had a litter with 2 affected piglets, which represented the only case with more than 1 affected piglet within a litter. Sixty different sires were involved in the affected litters, with only 17 litters from homospermic insemination, in which 14 different boars were involved.

Gross Pathology
Of the 70 piglets, 33 had a single skin defect, whereas 37 had multiple skin lesions, with up to 7 lesions present on the same piglet. Lesions were always located in the caudal half of the body, restricted to the back, thighs, and abdomen (Fig. 1). None were seen on the distal limbs or in the oral cavity.


Figure 18060801
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  		Figure 1 Simple (a) and multiple (b) skin lesions of epitheliogenesis imperfecta, all located in the caudal half of the body. Lesions in newborns are moist and glistening (a). Figure 2. The lesion focally extends deeper within the dermis.

Figure 3. Evolution of a lesion in an affected piglet at 3 (a), 10 (b), and 31 days (c) of age.

 
In newborns, the lesions were bright red, glistening, and depressed. Within a few hours, they became covered with reddish to brownish crusts, especially when pigs were older than a day. Scarring was most evident in week-old pigs. Most lesions appeared as clear-cut, punched-out areas devoid of skin and hair and varying in size and shape. The depth of the skin defects was variable even within a single lesion (Fig. 2).

In the single piglet observed over a period of time, progressive scarring and reduction in size of the lesion were noted. Almost complete resolution was noted after 1 month (Fig. 3).

Clefts, varying in length from a few millimeters to 2–3 cm, were located at the periphery of some lesions. All were in continuity with the skin defects.

Whorls or simple collarettes of abnormally oriented hair were found in the skin surrounding some defects. In a few cases, a narrow band of normal-appearing skin separated 2 adjacent lesions (Fig. 1b). Two piglets (1 male and 1 female) had a single cutaneous lesion that appeared grossly as an area devoid of epidermis but that was still covered with hair (Fig. 4).


Figure 18060802
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  		Figure 4 A lesion located in an area typical of epitheliogenesis imperfecta is sparsely haired.

 
Subcutaneous bullae measuring up to 7 cm in diameter were observed in 7 newborn piglets. They were near or partially underneath epitheliogenesis imperfecta lesions or else not closely associated with them (Fig. 5). The content of the bullae was fluid, translucid and yellowish or blood-tinged. Cytologic and biochemical analyses of the fluid revealed that only 1 of the bullae was compatible with a seroma, and the contents of the others were neither compatible with lymph nor serum because of their low triglyceride and protein concentrations. Most contained a mild, chronic inflammatory infiltrate. Bacterial culture was negative in the 2 samples of fluid submitted for bacteriology.


Figure 18060803
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  		Figure 5 Congenital subcutaneous bullae were present in some piglets; 1 was located under an epitheliogenesis imperfecta lesion (a) whereas others occurred near (b) or distant (c) from such defects.

 
Markedly dilated sweat glands (sudoriparous cysts) were noted in 7 piglets, mainly on the abdomen, in the vicinity of lesions of epitheliogenesis imperfecta. Most were 1 to 5 mm in diameter, but 2 were 1.5 cm in diameter.

A localized thinning of the abdominal wall, characterized by a focal absence of abdominal muscle (abdominal pseudohernia), was present in 3 piglets. Three cases of unilateral hydronephrosis and hydroureter were observed among the examined piglets.

Histopathology
Most cutaneous lesions observed grossly and considered compatible with epitheliogenesis imperfecta were characterized by an absence of the epidermis, superficial to mid-dermis and adnexae. In the few lesions in which the adnexae were still present, they were scattered and the hair follicles were sometimes abnormally shaped and oriented.

Various changes were noted at the junction between the normal and affected skin. In 43 animals, the epidermis and superficial to mid-dermis surrounding parts of the lesions were multifocally detached from the underlying tissue, forming a cleft that often contained cellular and vegetal debris and inflammatory cells (Fig. 6). The appearance of hair follicles at the junction between the normal skin and the lesion was variable, and 3 groups of equal size could be defined: 1) normal (Fig. 7), 2) multifocally increased in number or size (Fig. 8), and 3) abnormally shaped and variably sized with an abnormal orientation (dysplasia). The dysplastic area could form a raised plateau and was often eroded and covered with a serocellular crust (Fig. 9).


Figure 18060804
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  		Figure 6 A cleft, filled with cellular and vegetal debris, is present at the junction between the normal and the affected skin. HEPS stain. Figure 7. The epidermis and adnexae adjacent to the epitheliogenesis imperfecta lesion appear normal. HEPS stain.

Figure 8. The hair follicles at the margin of the epitheliogenesis imperfecta lesion are increased in number. HEPS stain.

Figure 9. Dysplastic changes at the margins of some epitheliogenesis imperfecta lesions had a variable appearance. In some lesions, misshapen and haphazardly arranged hair follicles were at the junction between normal and affected skin (a) while the skin formed an ulcerated, raised plateau at the edge of other lesions (b). HEPS stain.

Figure 10. Two bullae are present in the subcutis. One bulla is surrounded by a thick fibrous capsule (right), whereas the capsule of the other is thin (left). HEPS stain.

 
In 14/68 (21%) of the piglets, lesions grossly resembling epitheliogenesis imperfecta were in fact solely dysplastic and were histologically similar to the dysplastic margins described above. At the same time, most of these piglets presented 1 or more lesions typical of epitheliogenesis imperfecta; however, in 2 piglets (1 male and 1 female) (Fig. 4), dysplastic lesions were the only defect observed on microscopic examination.

In newborns, inflammation was absent to minimal in the lesions; congested surface blood vessels and mild hemorrhages were often present in the exposed dermis. In piglets a few hours old, the superficial part of the lesions was infiltrated by nondegenerate neutrophils. In 1-day-old piglets, the defect was covered with a serocellular crust composed of serum, fibrin, degenerate neutrophils, and often, vegetal debris. The exposed dermis was infiltrated with neutrophils and macrophages. Mild epidermal hyperplasia, increasing in intensity with the age of the piglet, was often present at the periphery of the defect. By day 3, abundant, inflamed fibrovascular tissue (granulation tissue) was present in the crust-covered, exposed dermis. This tissue eventually evolved into abundant, mature, and dense collagen, partially covered by an often hyperplastic epidermis.

The congenital bullae observed in 7 animals were located in the subcutis and were surrounded by a fibrous capsule of variable thickness (Fig. 10). They were lined by vimentin-positive and cytokeratin-negative flattened cells. In 2 other piglets, similar histologic lesions were noted (subcutaneous clefts surrounded by a capsule of variable thickness), although no liquid-filled bullae were observed at necropsy.

The sudoriparous cysts, located in the mid to deep dermis of 7 piglets, were lined by cuboidal to flattened or sometimes polygonal cells. Although the epithelium was 1-cell thick in most cases, a few were lined by 2 to 4 layers of cells, resembling a stratified squamous epithelium. The lining cells were diffusely cytokeratin positive and vimentin negative.


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As all piglets born with epitheliogenesis imperfecta lesions on this farm were not systematically submitted for this study, the exact incidence of the disease in the herd could not be determined. However, based on personnel's observations, it was estimated at less than 0.1%. The low incidence of epitheliogenesis imperfecta that was observed within affected litters in this study would be compatible with an autosomal recessive disease. However, with this type of inheritance, a roughly equal proportion of affected males and females would be expected. Rather, the high ratio of affected males to females in this study suggests a sex-related defect, whether sex-linked (X-chromosome linked) or not. Because up to 3 sires were used per insemination, it was not possible with the small data set to relate this congenital skin defect to particular boars. A nonheritable congenital defect would also be compatible with a low incidence within a litter and within a herd. The frequency of some nonheritable defects can also be higher for males or females when the risk is modified by gender, as is seen, for example, with neural tube closure defects in human beings, to which females appear predisposed.10,21 Because the study was performed in only 1 herd, and the environmental conditions and genetic background vary between farms, the frequency and inheritance of this problem could be different in other herds. However, a higher prevalence of the lesions in male piglets was also reported in 1 other study, in which all affected animals were male.3 Sows of all parities gave birth to affected piglets, which precludes an age-related problem in the dam.

Cases of epidermolysis bullosa have long been described under the name of epitheliogenesis imperfecta. In epidermolysis bullosa, the ulcerated sites are those that are more prone to mechanical damage, namely the mouth and distal extremities. At the microscopic level, dermo-epidermal clefts can often be observed at the margins of the lesions, and the adnexae are usually present within the lesions. In this study, the sites and microscopic lesions were not compatible with epidermolysis bullosa. Indeed, dermo-epidermal clefts were not observed, and the cutaneous defects extended to the superficial to mid-dermis and were all restricted to the caudal half of the body.

Etymologically, epitheliogenesis imperfecta refers to faulty epithelial formation, which adequately describes the lesions observed in piglets from this study, except for the involvement of the dermis. The term epitheliogenesis imperfecta also encompasses epidermolysis bullosa in veterinary medicine. Therefore, it seems more appropriate to use the term aplasia cutis congenita to describe the lesions observed in this study, as it refers to a partial absence of the skin, including the dermis. Aplasia cutis congenita is used in human medicine to describe lesions similar to those observed in these piglets. In human beings, such defects can be observed on the scalp as well as on other sites on the body. Hair whorls are sometimes seen around lesions on the scalp and are considered characteristic of neuroectodermal defects.5 In our cases, part of the dermis was also absent, suggesting either that the embryonic mesoderm was also involved, or that part of the dermis might in fact originate from the embryonic ectoderm, as proposed by Balinsky.2 However, most authors believe the dermis comes solely from the mesoderm.6,17 Further investigation of this problem could therefore provide a model for the study of skin embryogenesis. As observed in many of the piglets in this study, an increased number of hair follicles16 and abnormally oriented hair15 have been previously described in the margins surrounding the skin defects in swine. The presence of concomitant dysplastic lesions is also consistent with a developmental defect.

To the authors' knowledge, the peculiar congenital subcutaneous bullae observed in 7 piglets of this study have not been previously reported. Their precise origin has not been determined. The low protein and triglyceride content of the bullae was not compatible with lymph or serum (except in 1 case); however, their content could have changed with time, so these possibilities cannot be completely excluded. The presence of cytokeratin-negative and vimentin-positive cells lining these bullae did not help define their origin. These mesenchymal cells could simply represent normal resident fibroblasts. Despite the negative cytokeratin results, a different origin, such as markedly dilated sudoriparous glands, although unlikely, cannot completely be excluded. These bullae could have lost their epithelial lining, thereby explaining the negative results. Their relationship, if any, with lesions of epitheliogenesis imperfecta remains unknown. Theoretically, the rupture of these bullae, subsequently leaving punched-out lesions and "flaps" of skin at the margins, would be an attractive hypothesis for the development of lesions of epitheliogenesis imperfecta. However, the location of the bullae is hardly compatible with such a theory, because bullae were in the subcutis, whereas epitheliogenesis imperfecta lesions rarely extended deeper than the mid-dermis. The remainder of a capsule would also be expected at the margins of these lesions, as was found around some of the bullae. In addition, this hypothesis would not explain the presence of dysplastic edges and purely dysplastic lesions found in several piglets in this study.

Although lesions of epitheliogenesis imperfecta in piglets have been described previously in the oral cavity, namely on the tongue,9 none of the piglets studied presented such lesions. This alternative pattern or manifestation of the disease, which has not been reported in recent decades, might represent a different entity. Similarly, the concurrent congenital hydroureter and hydronephrosis reported to be frequent in these piglets were observed in only 3 animals in our study.

The isolation of E. coli from the internal organs of 2 sick piglets confirms that animals affected with epitheliogenesis imperfecta might have an increased susceptibility to septicemia,24 particularly when the cutaneous lesions are extensive. The weakness of 2 other piglets could be attributed to hypoglycemia, secondary to inanition. Another piglet was also very weak despite the absence of septicemia and the presence of milk in its stomach. A different cause, such as a loss of liquid or an electrolyte imbalance, could be responsible for some deaths, as suggested previously.23 It is also possible that large epithelial defects may render young piglets more susceptible to heat loss.

As this condition is sporadic and affects few animals within a litter, and because of the widespread use of heterospermic artificial insemination, it would be difficult and probably economically unsound to prevent this disease by removing breeding stock known to have produced affected progeny. However, defective offspring that survive should not be kept as future breeders. As shown in this study, lesions can heal when they are not too large and given time and care. Antibiotics or nonirritant topical disinfectants may be used to prevent secondary pyoderma that may potentially lead to septicemia.


   Acknowledgments
 
The authors gratefully acknowledge the farm employees (Brigitte McDonald, Johanne LeFrançois, Sandra Thibodeau, and Catherine L'Heureux) and attending veterinarian (Dr. Julie Ménard), without whom the realization of this project would not have been possible.


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From the Department of Pathology and Microbiology (Benoit- Biancamano, Drolet) and the Department of Clinical Sciences (D'Allaire), Faculty of Veterinary Medicine, University of Montreal, Saint-Hyacinthe, Québec, Canada. Back

a. Keratin, Pan Ab-1 (Clone AE1/AE3), NeoMarkers Inc, Fremont, CA. Back

b. Vimentin Ab-2 (Clone V9), NeoMarkers Inc, Fremont, CA. Back


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  1. Baker J.R., Lyon D.G.: 1983, Epitheliogenesis imperfecta and gonadal malformation in pumas (Felis concolor). Vet Rec 112:37 pp.[Medline]
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  6. Guidoni P.: 1968, Les téguments et leurs annexes. (Teguments and their adnexae.) In: Embryologie, ed. Guidoni P., pp. 393–397. Éditions Doin, Paris, France.
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