Lethal Acrodermatitis in Bull Terriers: A Problem of Defective Zinc Metabolism

Abstract— Three bull terrier pups from a litter of six developed exfoliative, crusty areas of alopecia, particularly affecting the feet and head, by the time they were seven weeks of age. Biopsies from two of the affected pups revealed parakeratotic hyperkeratosis consistent with zinc deficiency, but the dogs did not respond to oral zinc supplements. The breed, history and dermatopathology were considered consistent with lethal acrodermatitis of bull terriers, a condition that appears to be familial and autosomally recessive. Whereas similar acrodermatitic conditions in humans (acrodermatitis enteropathica) and cattle (lethal trait A46 of Black Pied Danish cattle) respond to oral zinc supplements, this condition in bull terriers may be due to an error in zinc metabolism at the cellular level. Attempts to treat one of the pups parenterally with zinc resulted in death after the fourth injection. Résumé— 3 choits d'une portée de 6 Bull Terriers ont développéà l'âge de 7 semaines une dermite podale et faciale exfoliative, crouteuse et alopécique. Les biopsies cutanées pratiquées sur 2 chiots ont révélé une hyperkératose parakératosique compatible avec une carence en zinc, mais les animaux n'ont pas répondu à une supplémentation en zinc. La race, l'anamnèse et l'aspect histologique, sont compatibles avec une acrondermatite léthale du Bull Terrier, maladie familiale, transmise sur un mode autosomal récessif. Des acrodermatites similaires chez l'homme (acrodermatitis enteropatica) et les bovins (anomalie léthale A46 de la Pie Noire Danoise) répondant à une supplémentation en zinc, cette affection chez le Bull Terrier pourrait êtro à une erreur dans le métabolisme du zinc au niveau cellulaire. Un essai de traitement d'un des chiots par vole parcutérale avec du zinc a abouti à sa mort après la quatrième injection. Zusammenfassung— Drei von sechs Bullterrierwelpen aus einem Wurf entwickelten im Alter von 7 Wochen exfoliative, krustige und haarlose Bezirke, besonders an Pfoten und Kopf. Biopsien von zwei der betroffenen Welpen zeigten eine Parakeratose, die bei Zinkmangel auftritt. Die Tiere sprachen jedoch nicht auf orale Zinksubstitution an. Rasse, Anamnese und Befunde der Hautuntersuchung stimmen mit der letalen Akrodermatitis der Bullterrier überein, einem familiären, autosomal rezessiv erblichen Leiden. Während ähnliche akrodermatitische Erkrankungen beim Menschen (Akrodermatitis enteropathica) und beim Rind (Letalfaktor A46 beim schwarzgefleckten Dänischen Rind) auf orale Zinkgaben ansprechen, ist diese Krankheit beim Bullterrier wahrscheinlich auf eine Störung im Zinkmetabolismus auf zellulärer Ebene zurückzuführen. Der Versuch, einen der Welpen parenteral mit Zink zu behandeln, führte zum Tod des Tieres nach der vierten Injektion. Resumen Tres cachorros de Bull Terrier de una camada de seis desarrollaron areas de alopecia exfoliativa, particularmente afectando a los pies y la cabeza, para el momento en que tenian siete semanas de edad. Biopsias de dos de los cachorros afectados revelaron hiperqueratosis paraqueratótica con deficiencia de zinc, pero los perros no respondían a los suplementos de zinc oral. La raza, historia y dermatopatología se consideraron consistentes en acrodermatitis letal de Bull Terriers, una condición que parece ser familial y autosómica recesiva. Mientras que condiciones de acrodermatitis similares en humanos (acrodermatitis enteropética) y ganado (rasgo letal A46 del ganado Black Pied Danish) respondían a los suplementos de zinc oral, esta condición en los Bull Terriers puede ser debida a un error en el metabolismo del zinc a nivel celular. Intentos de trater uno de los cachorros, por vía parenteral con zinc resultaron con la muerte después de la cuarta inyección.     

GROWTH OF THE RADIUS AND ULNA IN LABRADOR RETRIEVER DOGS WITH OCULAR AND SKELETAL DYSPLASIA

An associated ocular and skeletal dysplasia in Labrador Retrievers is caused by one abnormal gene which has recessive effects on the skeleton and incompletely dominant effects on the eye. The forelimbs of normal and affected pups were radiographed between birth and 156 days of age and the length of the radius and ulna measured. There was a significant difference in the mean length of these bones in normal and affected pups at birth and this difference was maintained over the period of observation. Similar differences were observed in purebred Labrador Retrievers and in Labrador Retriever-Beagle crosses. The results of this study suggest that the length of the radius and ulna could be used to identify pups affected by this syndrome if test matings with affected animals were done to identify carrier animals. Abnormal shape of the radius and ulna, which is seen in animals affected with this syndrome, should be used to augment the accuracy of identification of puppies affected by this syndrome.     

Canine bone shape analysis by use of a radiographic image-classification system.

A radiographic image-classification system was developed to analyze and compare the shape of the humerus of neonatal Labrador Retriever and Labrador Retriever x Beagle pups that were either phenotypically normal or affected with an ocular-skeletal dysplasia syndrome. The system consistently defined the shape of the humerus within the groups of pups studied and indicated a difference in the shape of the humerus between normal and affected pups. Results indicated that the radiographic image-classification system may be able to identify Labrador Retriever pups affected by the ocular-skeletal dysplasia syndrome at or shortly after birth.     

Neonatal cerebellar ataxia in Coton de Tulear dogs

A neonatal ataxia syndrome was observed in Coton de Tulear dogs. Seven affected pups (32%; 7/22) of both genders came from 5 different litters with phenotypically normal parents. Neurologic examination revealed normal mental status, head titubation, intention tremors, and severe gait, stance, and ocular ataxia beginning at 2 weeks of age. One of the pups was able to walk with assistance, but most of the affected pups were unable to stand and used propulsive movements ("swimming") for goal-oriented activities. They frequently would fall to lateral recumbency with subsequent decerebellate posturing and paddling. Ocular motor abnormalities included fine vertical tremors at rest and saccadic dysmetria. The condition was nonprogressive at least until 4 months of age. No specific abnormalities were identified in routine laboratory screening of blood and urine. Cerebrospinal fluid (CSF) analysis was normal in 1 dog, and a mild increase in protein concentration was observed in a second dog. CSF organic and amino acid concentrations were within normal limits. Magnetic resonance imaging and computed tomography of the brain, electromyography, motor nerve conduction studies, and brain stem auditory-evoked potentials were within normal limits. Postmortem examinations were performed on 5 affected dogs between 2 and 4 months of age. Routine light microscopic and immunocytochemical examination of brain, spinal cord, peripheral nerve, and muscle did not disclose any gross or histologic lesions. Compared with the cerebellum from an age-matched normal dog, the cerebellum from an affected dog showed synaptic abnormalities, including loss of presynaptic terminals and organelles associated with parallel fiber varicosities within the molecular layer and increased numbers of lamellar bodies in Purkinje cells. An autosomal recessive trait affecting development of the cerebellum is suspected.     

Lymphocyte alterations in zinc-deficient calves with lethal trait A46

Lymphocyte numbers and activities were evaluated at 2, 4, 8 and 12 weeks of age in two calves with lethal trait A46 (A46), a genetic disorder affecting intestinal zinc absorption. Plasma zinc concentrations declined to subnormal by 3 weeks of age, after which anorexia, diarrhea, alopecia and hyperkeratosis occurred. Lymphocyte response to phytohemagglutinin-P (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) stimulation was variably reduced. CD4+ T-lymphocytes were subnormal on at least one observation period following onset of zinc deficiency, and relative numbers of B lymphocytes were decreased at 8 weeks. Secondary antibody responses to bacteriophage phi X 174 were significantly reduced. The results demonstrate that calves homozygous for the A46 trait have normal numbers of functional lymphocyte subpopulations at birth, and that the activity of their lymphocytes is altered once the calves become zinc deficient.     

Sister chromatid exchanges in calves with hereditary zinc deficiency (lethal trait A 46)

Frequencies of sister chromatid exchanges (SCEs) in cultured blood lymphocytes are rather lower than higher in calves with hereditary zinc deficiency (lethal trait A 46) than in healthy, normal cows.     

Chromosome studies in cattle with hereditary zinc deficiency (lethal trait A 46)

Summary Blood lymphocyte and skin fibroblast cultures from cattle with hereditary zinc deficiency (lethal trait A 46) have not revealed unusually large numbers of cells with chromosomal aberrations as reported by Herzog and H?hn (6).     

Sister chromatid exchanges in calves with hereditary zinc deficiency (lethal trait A 46)

Summary

Frequencies of sister chromatid exchanges (SCEs) in cultured blood lymphocytes are rather lower than higher in calves with hereditary zinc deficiency (lethal trait A 46) than in healthy, normal cows.     

Inherited epidermal dysplasia in Holstein-Friesian calves

Inherited epidermal dysplasia (IED), formerly called baldy calf syndrome, is a lethal disease of calves of Holstein-Friesian ancestry. The disease causes progressive illthrift and skin, horn and hoof lesions, which can be confused with inherited zinc deficiency. The clinicopathological features and ancestry of 10 affected calves in Gippsland, Victoria are described.     

Chromosome studies in cattle with hereditary zinc deficiency (lethal trait A 46)

Summary

Blood lymphocyte and skin fibroblast cultures from cattle with hereditary zinc deficiency (lethal trait A 46) have not revealed unusually large numbers of cells with chromosomal aberrations as reported by Herzog and Höhn (6).     

An epizootic of peroneal and tibial neuropathy in Walker Hound pups

Early in life, Walker Hound pups from several litters, later determined to have peroneal and tibial neuropathy, had been given supplements of either evaporated milk and corn syrup mixed with well water or powdered bitch milk formula mixed with well water. Other pups not given supplements were not affected. Pelvic limb monoparesis, areflexia, analgesia, and muscular atrophy developed by 2 weeks of age. Abnormalities detected by light and electron microscopy included scattered swollen axons containing increased organelles and whorled neurofilaments. The clear association between clinical signs of disease and dietary supplementation of pups among healthy dogs in a kennel, as well as lack of an obvious pattern of inheritance, suggested an environmentally acquired toxin, specifically the well water. Attempts to reproduce neuropathy in a litter of Beagle pups 2 years after initial evaluation of the disease syndrome were unsuccessful. Atomic absorption studies performed on the well water to detect heavy metals did not reveal toxic concentrations. Toxins that may have been responsible for the neuropathy in these pups were not identified.     

Evidence of Inheritance of Intrahepatic Portosystemic Shunts in Irish Wolfhounds

Background: The etiogenesis of congenital portosystemic shunt in dogs is not understood. In Irish Wolfhounds, intrahepatic portosystemic shunt (IHPSS) is thought to be hereditary, but the mode of inheritance is unknown.
Objectives: To document the genetic background and investigate the potential mode of inheritance of IHPSS in Irish Wolfhounds.
Animals: Three mature, privately owned, affected siblings and their progeny produced in 2 litters.
Methods: Prospective, observational study. Two test matings of 1 affected sire with 2 of his affected sisters were used to determine the inheritance pattern. Affection status was determined by measuring venous blood ammonia concentrations, detection of the shunt by ultrasonography and confirmation during surgical attenuation of the intrahepatic shunting vessel.
Results: In 1 litter of 5 pups all had an IHPSS. In the other litter 5 of 11 pups were affected. Both left- and right-sided shunts occurred in both litters. No sex predisposition was evident among affected dogs.
Conclusions and Clinical Importance: Our results show that IHPSS in Irish Wolfhounds is a familial disorder that is likely genetic. It is unlikely that the mode of inheritance is monogenic. A digenic, triallelic trait could explain the observed occurrence of IHPSS but other modes of inheritance cannot be excluded.     

An autosomal recessive, lethal, neurologic disease of Gordon Setter puppies.

This report details clinical, necropsy, and pedigree data on an inherited, lethal, neurologic disease of young Gordon Setters. This disorder is characterized by an early age of onset, gait and postural abnormalities, progressive weakness, and recumbency by 5-6 weeks of age. Although clinically distinctive, postmortem changes in affected pups were minimal. Gross lesions were not observed. Microscopic changes were subtle and consisted of astrocyte swelling, primarily in the cerebrocortical and cerebellar white matter, and white matter tracts of the brainstem. Immunohistochemistry for glial fibrillary acidic protein revealed a marked increase in the number and staining intensity of astrocyte cytoplasmic processes in affected pups compared with age-matched controls. Neither cerebral inflammation nor neuronal necrosis was identified. Pedigree analysis of affected litters demonstrated an autosomal recessive mode of inheritance. A diagnosis of this heritable disease should be based on the early age of onset (3-4 weeks of age), characteristic clinical signs, rapid progression to recumbency by 5-6 weeks of age, identification of swollen astrocytes primarily in the cerebellar and cerebrocortical white matter and white matter tracts of the brainstem, and the exclusion of other disease processes.     

Congenital hypothyroidism with goiter in toy fox terriers

Congenital hypothyroidism with goiter was observed to segregate as a simple autosomal recessive trait in Toy Fox Terriers (TFTs). Neonatal affected pups exhibited inactivity, abnormal hair coat, stenotic ear canals, and delayed eye opening. Palpable ventrolateral cervical swellings were evident by 1 week of age. Serum thyroid hormone and thyroid-stimulating hormone concentrations were low and high, respectively. Histologic examination of the cervical masses disclosed cuboidal to columnar follicular epithelial cell hyperplasia with widely varying follicular size, shape, and amount of colloid. Oral thyroid hormone replacement therapy restored near-normal growth and development. At 8 weeks of age, radioiodine uptake and perchlorate discharge testing indicated an iodine organification defect. Biochemical analysis of thyroid tissue from affected dogs demonstrated enzymatic iodine oxidation deficiency and lack of sodium dodecyl sulfate-resistant thyroglobulin dimers, suggesting thyroid peroxidase deficiency. A nonsense mutation in the thyroid peroxidase gene of affected dogs was discovered and demonstrated to segregate with the disease. A DNA-based carrier test was developed and currently is used by TFT breeders to prevent this disorder.     

Congenital deafness and vestibular deficit in the dobermann

A condition characterised by the early onset of vestibular deficit and hearing loss was investigated in the dobermann breed of dog. Affected pups showed behavioural signs of head tilt, circling and ataxia and there was a total absence of vestibular response to rotation or caloric stimulation. Severe deafness, as assessed by brainstem auditory evoked response testing, was present by three weeks of age in all affected animals. The inner ears showed a progressive neuroepithelial type of cochlear degeneration with loss of the auditory sensory cells. In the vestibular system, however, there was no equivalent sensory cell loss and the only abnormal feature was the absence or abnormality of the otoconia in some of the affected animals. Pedigree analysis suggested that the condition was inherited as an autosomal recessive trait.     

Anury in two Cairn terriers

Congenital anury (taillessness) was observed in 2 Cairn Terriers. Fecal staining of the hind limbs was evident in both dogs. A mating of the affected dogs produced a litter of 2 apparently normal pups. The small litter size may have been attributable to lethal gene combinations similar to those described in mice. The radiographic appearance of the caudal and sacral vertebrae was atypical in both tailless dogs. Results of myelography and electrodiagnostic testing of anal sphincter function were normal in one of the dogs. One of the tailless dogs was euthanatized and was found to lack specific muscles and muscle parts responsible for normal defecation, which resulted in fecal staining of the hind limbs. Pedigree analysis revealed the tailless dogs to be closely related and slightly inbred, suggesting a hereditary etiologic factor for anury.     

Spontaneous antenatal resolution of canine hydrops fetalis diagnosed by ultrasound

A previously unreported syndrome of transient mid-gestational hydrops fetalis identified by ultrasound was diagnosed in 16 litters of 16 different dogs between November 1999 and May 2002. During this study period, a total of 161 canine pregnancies were diagnosed by ultrasound. A 17th litter of eight fetuses developed similar ultrasonographic changes concurrently with maternal systemic mastocytosis and subsequently spontaneously aborted. No pups were born with clinical signs of hydrops fetalis. Fetal resorption in the affected litters was 7/95 (7.4 per cent) and 8/95 (8.4 per cent) aborted. Of the fetuses that survived to term, there were 7/88 (8 per cent) stillbirths. Neonatal mortality rate in the affected litters was 15 per cent (11/73) and the incidence of congenital abnormalities was 7/73 (9.6 per cent). Pugs were significantly (22.8 times) more likely to be affected than other breeds.     

Current prevalence of adult Uncinaria spp. in northern fur seal (Callorhinus ursinus) and California sea lion (Zalophus californianus) pups on San Miguel Island, California, with notes on the biology of these hookworms

A prevalence survey for hookworms (Uncinaria spp.) was done in northern fur seal (Callorhinus ursinus) and California sea lion (Zalophus californianus) pups on San Miguel Island, CA, in 2000. Intestines of dead pups were examined for adult hookworms in July. These parasites were found in 95% of 20 fur seal pups and 100% of 31 sea lion pups. The number of hookworms varied from 4 to 2142 (mean = 760) in fur seal pups and from 20 to 2634 (mean = 612) in sea lion pups. A direct relationship was evident between body condition and number of hookworms in the pups; that is, pups in poor condition had fewer hookworms than those in good condition. There was a decline in the number of hookworms in sea lion pups in 2000 compared to collections in 1996. Eggs of Uncinaria spp. were found in rectal feces (collected in late September and early October) of none of 35 (0%) live fur seal pups and 41 of 48 (85%) live sea lion pups. Packed cell volume values, determined for most of the same live pups, were essentially normal for C. ursinus but were much lower than normal for most Z. californianus. Hookworm larvae were not found in blubber of fur seal and sea lion pups or in rookery sand in July. Rookery sand, positive for live hookworm larvae when put in a refrigerator, was negative at removal 2.5 years later. The average number of eggs in utero of female hookworms was 285 for three specimens from a fur seal pup and 281 from three specimens from a sea lion pup. One hookworm larva was recovered from milk stripped from the teats of a stranded Z. californianus female at The Marine Mammal Center, Sausalito, CA.