ANIMAL MODEL OF HUMAN DISEASE
Acrodermatitis Enteropathica, Zinc Malabsorption
Animal Model: Lethal Trait A 46 in Cattle (Hereditary Parakeratosis, Hereditary Thvmic Hypoplasia, Hereditary Zinc Deficiency) Contributed by: E. Brummerstedt, DVM, PhD, Department of Veterinary Virology and Immunology, A. Basse, DVM, Department of General Pathology and Pathological Anatomy, T. Flagstad, DVM, Institute of Internal Medicine, and E. Andresen, DVM, PhD, Department of Animal Genetics, Royal Veterinary and Agricultural University, Copenhagen, Denmark.
Biobogic Features
The lethal trait A 46 in Friesian cattle 1,2 has been observed in Scotland since the beginning of the early 1950s.3 Several names have been used for the syndrome, e.g., hereditary parakeratosis,4 hereditary thvmus hvpoplasia,5 and hereditary zinc deficiency.6 The disease has been reported from Scotland,3 Italv,7 The Netherlands,8 The Federal Republic of Germany,4 and Denmark.2 Clinically, the svndrome is characterized by exanthema with loss of hair on the legs and certain parts of the body and parakeratosis around mouth, eves, and under the jaw (Figure 1). Several animals suffer from conjunctivitis, rhinitis, bronchopneumonia, and diarrhea. The animals appear normal at birth, but the characteristic skin lesions commence at the age of 4 to 8 weeks. If left untreated the calves die within 4 to 8 weeks after clinical outbreak of the disease. Spontaneous recoverv has never been observed. Postmortem examination reveals a marked hvpoplasia of thvmus (Figure 2A and B), the average weight of thymus of the 15 animals examined being 18 g, compared with the normal weight of thymus of 250 to 400 g. Histologically, the thvmus is characterized by a severe depletion of small lymphocytes, particularly in the cortical region (Figure 3). Besides hvpoplasia of thvmus, hypoplasia of spleen, some regional lymph nodes, Peyer's patches, and the lvmphoid tissue along the gut is a constant feature. Publication sponsored by the Registry of Comparative
Pathology of the Armed Forces Institute of
Pathology and supported by Public Health Service Grant RR 00:301 from the Division of Research Resources. US Department of Health. Education and Welfare. under the auspices of Universities Xssociated for Research and Education in Pathology. Inc This swork supported by Grant 51:3 319
from the Danish Agricultural and Veterinary Research Council
725
726
BRUMMERSTEDT ET AL.
American Journal of Pathology
Figure 1-Calf with typical late lesions.
The clinical and pathologic findings indicate that dysfunction of the immune system may be expected. Examinations carried out so far support this interpretation.9 A decreased humoral immune response to tetanus toxoid has been found in affected animals, as has a decreased cell-mediated immune reaction against Mycobacteriunl tuberculosis and dinitrochlorobenzene. In all clinical descriptions of the syndrome a remarkable similarity to spontaneous zinc deficiency in cattle is obvious; this was the motive for supplying affected animals with zinc ions orally (e.g., ZnO or ZnSO4). This leads to an apparently complete recovery, including restoration of thymus morphology.56 Discontinuation of the zinc treatment causes a relapse after a couple of weeks. Initial experiments indicate that the key defect of the syndrome is an intestinal malabsorption."0 Acrodermatitis enteropathica in man corresponds closely to lethal trait A 46.11 Genetic examinations provide evidence for the hypothesis that the lethal trait is due to autosomal recessive inheritance and that the lethal factor has complete penetrance in homozygous individuals.2'12 Potential Usefulness of the Model
Lethal trait A 46 in calves may be a useful model for investigation of immune deficiencies, zinc absorption, the effect of zinc ion on the immune system, and for investigation of acrodermatitis enterophatica in man.
ACRODERMATITIS ENTEROPATHICA
Vol. 87, No. 3 June1977
---V
727
~~~~~~~~~~A
_ S ,
..,
tj".~~.
.~~~~~~~~~~~ ~~~~~.....
B
Flm 2A-Hypoplastic thymus (9.5 g) from affected calf. B-Normal sized thymus (372 g)
from a reconstited calf.
A biit
The affected animals examined so far by the authors have all appeared spontaneously. Since the genetic investigations of the disease indicate that the lethal trait is due to autosomal recessive inheritance with complete penetrance in homozygous calves, it is possible to obtain affected progeny following planned mating. Further, it is possible by supplying zinc ions to reconstitute affected animals and raise them until sexual maturity. It has been described 6 that 9 pregnant heifers and 1 fertile bull have been obtained after ZnSO4 reconstitution. The heifers gave birth to 9 calves, 1 of which died of Escherichia coli sepsis. The remaining 8 calves developed typical symptoms when from 7 to 16 weeks old. Thus it is possible to establish a pure breeding colony of fertile individuals homozygous for the recessive trait.
728
American Journal of Pathology
BRUMMERSTEDT ET AL.
:
_~~~~~~~~~~y
Figure 3-Depletion of lymphocytes in the hypoplastic thymus (H&E, x 40). References 1. Wiesner E, Willer S: Veterinarmedizinische Pathogenetik. Jena, VEB Gustav Fischer Verlag, 1974, p 458 2. Andresen E, Flagstad T, Basse A, Brummerstedt E: Evidence of a lethal trait, A 46, in Black Pied Danish cattle of Friesian descent. Nord Vet Med 22:473-485, 1970 3. Mc Pherson EA, Beattis IS, Young GB: An inherited defect in Friesian calves. Nord Vet Med 16 (Suppl 1):533-540, 1964 4. Stober M: Parakeratose beim schwarzbunten Niederungskalb. I. Klinisches Bild und .Atiologie. [Parakeratosis in Friesian calves. I. Clinical picture and etiology.] Dtsch Tieraerztl Wochenschr 78:257-284, 1971 5. Brummerstedt E, Flagstad T, Basse A, Andresen E: The effect of zinc on calves with hereditary thymus hypoplasia (lethal trait A 46). Acta Pathol Microbiol Scand [A] 79:686-687, 1971 6. Kroneman J, Mey GJWvD, Helder A: Hereditary zinc deficiency in Dutch Friesian cattle. Zentralbl Veterinaermed [A] 22:201-208, 1975 7. Gentile S: Suliper-paracheratosi dei bovini. [On hyper- and parakeratosis of the skin in cattle.] Nuova Vet 45:113-130, 1969 8. van Adrichem PMW, van Leeuwen JM, Leeuwen JM, van Kluyve JJ: Parakeratose van de huidbij kalveren. [Parakeratosis of the skin in calves.] Tijdschr Diergeneesk 95:1170-1176, 1970 9. Brummerstedt E, Andresen E, Basse A, Flagstad T: Lethal trait A 46 in cattle: Immunological investigations. Nord Vet Med 26:279-293, 1974 10. Flagstad T: Lethal trait A 46 in cattle: Intestinal zinc absorption. Nord Vet Med 28:160-169, 1976 11. Weismann K, Flagstad T: Hereditary zinc deficiencv (adema disease) in cattle, an animal parallel to acrodermatitis enteropatica. Acta Derm Venereol (Stockh) 56:151-154, 1976 12. Andresen E, Basse A, Brummerstedt E, Flagstad T: Lethal trait A 46 in cattle: Additional genetic investigations. Nord Vet Med 26:275-278, 1974
Acrodermatitis Enteropathica, Zinc Malabsorption
Animal Model: Lethal Trait A 46 in Cattle (Hereditary Parakeratosis, Hereditary Thvmic Hypoplasia, Hereditary Zinc Deficiency) Contributed by: E. Brummerstedt, DVM, PhD, Department of Veterinary Virology and Immunology, A. Basse, DVM, Department of General Pathology and Pathological Anatomy, T. Flagstad, DVM, Institute of Internal Medicine, and E. Andresen, DVM, PhD, Department of Animal Genetics, Royal Veterinary and Agricultural University, Copenhagen, Denmark.
Biobogic Features
The lethal trait A 46 in Friesian cattle 1,2 has been observed in Scotland since the beginning of the early 1950s.3 Several names have been used for the syndrome, e.g., hereditary parakeratosis,4 hereditary thvmus hvpoplasia,5 and hereditary zinc deficiency.6 The disease has been reported from Scotland,3 Italv,7 The Netherlands,8 The Federal Republic of Germany,4 and Denmark.2 Clinically, the svndrome is characterized by exanthema with loss of hair on the legs and certain parts of the body and parakeratosis around mouth, eves, and under the jaw (Figure 1). Several animals suffer from conjunctivitis, rhinitis, bronchopneumonia, and diarrhea. The animals appear normal at birth, but the characteristic skin lesions commence at the age of 4 to 8 weeks. If left untreated the calves die within 4 to 8 weeks after clinical outbreak of the disease. Spontaneous recoverv has never been observed. Postmortem examination reveals a marked hvpoplasia of thvmus (Figure 2A and B), the average weight of thymus of the 15 animals examined being 18 g, compared with the normal weight of thymus of 250 to 400 g. Histologically, the thvmus is characterized by a severe depletion of small lymphocytes, particularly in the cortical region (Figure 3). Besides hvpoplasia of thvmus, hypoplasia of spleen, some regional lymph nodes, Peyer's patches, and the lvmphoid tissue along the gut is a constant feature. Publication sponsored by the Registry of Comparative
Pathology of the Armed Forces Institute of
Pathology and supported by Public Health Service Grant RR 00:301 from the Division of Research Resources. US Department of Health. Education and Welfare. under the auspices of Universities Xssociated for Research and Education in Pathology. Inc This swork supported by Grant 51:3 319
from the Danish Agricultural and Veterinary Research Council
725
726
BRUMMERSTEDT ET AL.
American Journal of Pathology
Figure 1-Calf with typical late lesions.
The clinical and pathologic findings indicate that dysfunction of the immune system may be expected. Examinations carried out so far support this interpretation.9 A decreased humoral immune response to tetanus toxoid has been found in affected animals, as has a decreased cell-mediated immune reaction against Mycobacteriunl tuberculosis and dinitrochlorobenzene. In all clinical descriptions of the syndrome a remarkable similarity to spontaneous zinc deficiency in cattle is obvious; this was the motive for supplying affected animals with zinc ions orally (e.g., ZnO or ZnSO4). This leads to an apparently complete recovery, including restoration of thymus morphology.56 Discontinuation of the zinc treatment causes a relapse after a couple of weeks. Initial experiments indicate that the key defect of the syndrome is an intestinal malabsorption."0 Acrodermatitis enteropathica in man corresponds closely to lethal trait A 46.11 Genetic examinations provide evidence for the hypothesis that the lethal trait is due to autosomal recessive inheritance and that the lethal factor has complete penetrance in homozygous individuals.2'12 Potential Usefulness of the Model
Lethal trait A 46 in calves may be a useful model for investigation of immune deficiencies, zinc absorption, the effect of zinc ion on the immune system, and for investigation of acrodermatitis enterophatica in man.
ACRODERMATITIS ENTEROPATHICA
Vol. 87, No. 3 June1977
---V
727
~~~~~~~~~~A
_ S ,
..,
tj".~~.
.~~~~~~~~~~~ ~~~~~.....
B
Flm 2A-Hypoplastic thymus (9.5 g) from affected calf. B-Normal sized thymus (372 g)
from a reconstited calf.
A biit
The affected animals examined so far by the authors have all appeared spontaneously. Since the genetic investigations of the disease indicate that the lethal trait is due to autosomal recessive inheritance with complete penetrance in homozygous calves, it is possible to obtain affected progeny following planned mating. Further, it is possible by supplying zinc ions to reconstitute affected animals and raise them until sexual maturity. It has been described 6 that 9 pregnant heifers and 1 fertile bull have been obtained after ZnSO4 reconstitution. The heifers gave birth to 9 calves, 1 of which died of Escherichia coli sepsis. The remaining 8 calves developed typical symptoms when from 7 to 16 weeks old. Thus it is possible to establish a pure breeding colony of fertile individuals homozygous for the recessive trait.
728
American Journal of Pathology
BRUMMERSTEDT ET AL.
:
_~~~~~~~~~~y
Figure 3-Depletion of lymphocytes in the hypoplastic thymus (H&E, x 40). References 1. Wiesner E, Willer S: Veterinarmedizinische Pathogenetik. Jena, VEB Gustav Fischer Verlag, 1974, p 458 2. Andresen E, Flagstad T, Basse A, Brummerstedt E: Evidence of a lethal trait, A 46, in Black Pied Danish cattle of Friesian descent. Nord Vet Med 22:473-485, 1970 3. Mc Pherson EA, Beattis IS, Young GB: An inherited defect in Friesian calves. Nord Vet Med 16 (Suppl 1):533-540, 1964 4. Stober M: Parakeratose beim schwarzbunten Niederungskalb. I. Klinisches Bild und .Atiologie. [Parakeratosis in Friesian calves. I. Clinical picture and etiology.] Dtsch Tieraerztl Wochenschr 78:257-284, 1971 5. Brummerstedt E, Flagstad T, Basse A, Andresen E: The effect of zinc on calves with hereditary thymus hypoplasia (lethal trait A 46). Acta Pathol Microbiol Scand [A] 79:686-687, 1971 6. Kroneman J, Mey GJWvD, Helder A: Hereditary zinc deficiency in Dutch Friesian cattle. Zentralbl Veterinaermed [A] 22:201-208, 1975 7. Gentile S: Suliper-paracheratosi dei bovini. [On hyper- and parakeratosis of the skin in cattle.] Nuova Vet 45:113-130, 1969 8. van Adrichem PMW, van Leeuwen JM, Leeuwen JM, van Kluyve JJ: Parakeratose van de huidbij kalveren. [Parakeratosis of the skin in calves.] Tijdschr Diergeneesk 95:1170-1176, 1970 9. Brummerstedt E, Andresen E, Basse A, Flagstad T: Lethal trait A 46 in cattle: Immunological investigations. Nord Vet Med 26:279-293, 1974 10. Flagstad T: Lethal trait A 46 in cattle: Intestinal zinc absorption. Nord Vet Med 28:160-169, 1976 11. Weismann K, Flagstad T: Hereditary zinc deficiencv (adema disease) in cattle, an animal parallel to acrodermatitis enteropatica. Acta Derm Venereol (Stockh) 56:151-154, 1976 12. Andresen E, Basse A, Brummerstedt E, Flagstad T: Lethal trait A 46 in cattle: Additional genetic investigations. Nord Vet Med 26:275-278, 1974
