LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function.

Long QT syndrome (LQTS), a rare congenital cardiac condition associated with life-threatening ventricular arrhythmias is characterized by a prolonged QT interval on electrocardiograph corrected for heart rate [corrected QT (QTc)]. LQTS has been historically categorized into the autosomal dominant Romano-Ward syndrome (RWS) and the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). JLNS is associated with prelingual sensorineural deafness. Both types of LQTS can be caused by mutations in channel genes (e.g. KCNQ1) responsible for potassium homeostasis in cardiac myocytes and cochlea. Autosomal dominant mutations often cause the RWS phenotype and homozygous or compound heterozygous mutations contribute to JLNS. Two First Nations communities in northern British Columbia are affected disproportionately with LQTS largely due to the V205M mutation in KCNQ1, however, the pathology and phenotypic expression for those V205M homozygous has been unknown. Here, we show that four V205M homozygous individuals have a significantly higher 'peak' QTc, and a more severe cardiac phenotype compared with 41 V205M heterozygous carriers and 57 first to third degree relatives without mutations. Given the lack of prelingual deafness the homozygous V205M LQTS patients present with a phenotype more typical of RWS than JLNS.

Radiological features of Gorham's disease.

AIM: To describe the key findings on plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI) of Gorham's disease. MATERIALS AND METHODS: Eight children diagnosed with Gorham's disease between 1999 and 2009 were included. All imaging studies performed on each patient were reviewed with special attention to the extent of bone, soft tissue, and visceral involvement. RESULTS: All patients had bone lesions at diagnosis, most commonly in the vertebrae. CT showed generalized osteopenia, multiple lytic lesions, and heterogeneous bone density. MRI demonstrated altered signal intensity in bone marrow that was hyperintense on T1 imaging. Seven patients had soft-tissue lymphangiomatous lesions adjacent to identified osseous lesions. Four patients had chylous pleural effusions: three with bilateral and one with unilateral involvement. The spleen was involved in six patients. CONCLUSION: Splenic lesions and soft-tissue involvement are common in patients with Gorham's disease. The presence of extra-osseous lesions along with characteristic bone lesions on plain radiography may be pathognomonic of Gorham's disease.

In utero eye development documented by fetal MR imaging.

BACKGROUND AND PURPOSE: To date, very limited attention has been given to ocular abnormalities or growth parameters detected by fetal MR imaging. Our objective was to retrospectively determine the relationship between different parameters of eye development and estimated gestational age in the human fetus by use of fetal MR imaging. MATERIALS AND METHODS: A retrospective study was performed to measure the transverse diameter, interocular distance, and lens diameter of the globes of 127 fetuses who had a morphologically normal central nervous system. Multiple single-shot T2 fast spin-echo images were obtained with a 1.5T magnet by use of contiguous 3-mm intervals in at least 2 orthogonal planes. Loess curves were fitted to explore the relationship between gestational age and each of the 3 measurements of interest. Different models were compared statistically to determine the model of best fit. RESULTS: For each variable of interest, the "best" model of eye growth was a quadratic function. Specifically, lens growth seems to plateau after 36 weeks of gestation, interocular distance plateaus after 36 weeks of gestation, and globe growth plateaus after 42 weeks of gestation. CONCLUSIONS: The lens, orbit, and interocular distance growth of the fetus can be demonstrated on fetal MR imaging. All 3 measurements suggest a quadratic model of growth, which indicates slowing of growth toward the end of gestation.

Epicutaneous sensitization with Dermatophagoides farinae induces generalized allergic dermatitis and elevated mite-specific immunoglobulin E levels in a canine model of atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a cutaneous hypersensitivity associated with elevated levels of antigen-specific IgE, commonly to house dust mites (HDMs). It remains controversial as to whether sensitization and clinical disease are induced by cutaneous exposure to HDM. OBJECTIVES: The objectives of this study were to determine whether repeated applications of Dermatophagoides farinae slurry to intact skin of Maltese-Beagle atopic (MAB) dogs would result in the development of clinical signs or lesions resembling spontaneous canine AD, to determine whether repeated slurry applications would induce elevations in mite-specific IgE and/or IgG, and to determine whether mite antigens could be demonstrated within the dermis of application sites. METHODS: Dogs received weekly slurry applications to the axilla and groin, and were patch tested at 120 days, or were patch tested at days 1, 60 and 120, but did not receive further slurry applications. Skin biopsies and serum samples were obtained on days 1, 60 and 120. RESULTS: Pruritic dermatitis was seen in all dogs by day 60. D. farinae-specific IgE was elevated by day 60. Histologic examination of early application sites revealed mild, mononuclear perivascular dermatitis. Later application sites were characterized by a dense inflammatory infiltrate and oedema in both the dermis and the epidermis. Immunofluorescent staining confirmed the presence of D. farinae antigens in the dermis. CONCLUSIONS: This study demonstrated that epicutaneous application of HDM slurry to MAB dogs results in elevations of HDM-specific IgE, localized and generalized pruritic dermatitis resembling spontaneous canine AD, and histologic changes typical of IgE-driven inflammation. We feel that these results suggest that epicutaneous exposure to allergen may play an important role during both the sensitization and the perpetuation of AD, and provide support for the use of a canine model in the investigation of the pathogenesis of AD.

Iron loading and morbidity among relatives of HFE C282Y homozygotes identified either by population genetic testing or presenting as patients.

BACKGROUND AND AIMS: Although most cases of hereditary haemochromatosis are associated with homozygosity for the C282Y mutation of the HFE gene, clinical penetrance varies and other genes may modify disease expression. If so, relatives from clinically affected families, by inheriting such genes, may accumulate more iron. To seek evidence for this, we compared iron status and morbidity in unselected first degree relatives of two groups of index cases from South Wales, namely asymptomatic C282Y homozygotes identified by genetic screening of blood donors (n = 56) and C282Y homozygous haemochromatosis patients presenting clinically (n = 60). METHODS: All participating relatives had a structured interview, clinical assessment, and laboratory investigations. Health related quality of life was measured (SF-36 version 2). RESULTS: In total, 92% of 180 eligible first degree relatives were interviewed in the "screened" family group and 85% of 143 eligible relatives in the "patient" group. Of 59 relatives homozygous for C282Y, 76% of men and 32% of women had the "iron phenotype" (raised transferrin saturation and serum ferritin). Logistic regression modelling of the iron phenotype risk showed that 42% of the initial model deviance could be explained by homozygosity for C282Y, another 6% by lifestyle factors, and 6% by being male. Family group membership was not a significant risk factor. Morbidity and SF-36 scores did not differ significantly either between C282Y homozygotes and relatives lacking C282Y, or between C282Y homozygotes from the "screened" and "patient" groups. Serious morbidity (including cirrhosis) was low in both groups of relatives. CONCLUSIONS: HFE C282Y homozygosity has a high penetrance for iron accumulation but a low clinical penetrance. Lack of excess morbidity among C282Y homozygous relatives of index cases who presented clinically suggests that residual unknown genetic or environmental factors do not greatly influence clinical outcome among C282Y homozygotes.

Eleven cases of vesicular cutaneous lupus erythematosus in Shetland sheepdogs and rough collies: clinical management and prognosis.

A cutaneous ulcerative disease is recognized to affect the adult Shetland sheepdog and rough collie. This has a distinct clinical and histological appearance consistent with a vesicular variant of cutaneous lupus erythematosus (VCLE). Retrospective information on the clinical outcome and response to therapy was collected from 11 cases of histologically confirmed VCLE. In 8/11 dogs the onset of disease was in the summer; in three dogs recrudescence occurred in subsequent summers. In eight dogs the skin disease was judged to be 75-100% controlled with therapy after a minimum follow-up of 9 months. Successful treatment in seven of these cases comprised immunosuppressive doses of oral glucocorticoids, alone (one dog), in combination with azathioprine (five dogs) and doxycycline (one dog). One case responded to topical fluocinolone. Three dogs were euthanised for reasons directly related to the disease, one prior to initiating any therapy. Vesicular cutaneous lupus erythematosus in the rough collie and Shetland sheepdog can be a debilitating skin disease which is best managed with aggressive immunosuppressive therapy. Sun avoidance or the use of sunscreens is an important additional management recommendation.

Evaluation of the clinical and allergen specific serum immunoglobulin E responses to oral challenge with cornstarch, corn, soy and a soy hydrolysate diet in dogs with spontaneous food allergy.

Fourteen dogs with known clinical hypersensitivity to soy and corn were maintained on a limited antigen duck and rice diet until cutaneous manifestations of pruritus were minimal (78 days). Sequential oral challenges with cornstarch, corn and soy were then performed. Subsequently, the dogs were fed a diet containing hydrolysed soy protein and cornstarch. Throughout the study period the dogs were examined for cutaneous manifestations of pruritus and, additionally, serum was collected for measurement of allergen-specific and total immunoglobulin (Ig)E concentrations. Intradermal testing with food antigens was performed prior to entry into the study and after 83 days. A statistically significant clinical improvement was measured between days 0 and 83. Significant pruritus was induced after oral challenge with cornstarch, corn and soy (P = 0.04, 0.002, 0.01, respectively) but not with the hydrolysed diet (P = 0.5). The positive predictive value of the skin test for soy and corn allergy was reduced after feeding a soy and corn free diet. Although increases in soy and corn-specific serum IgE concentrations were measured in individual dogs post challenge they were not statistically significant and could not be used to predict clinical hypersensitivity.

IgE is present on peripheral blood monocytes and B cells in normal dogs and dogs with atopic dermatitis but there is no correlation with serum IgE concentrations.

Blood was collected from 29 dogs, 14 with atopic dermatitis (AD) and 15 controls. Total serum IgE was quantitated. Peripheral blood monocytes were harvested and labeled with leucocyte markers and anti-canine IgE before analysis by flow cytometry. There was no statistically significant difference between the atopic and control groups when the mean number of cells in the monocyte (CD14), antigen presenting cell (CD1c) or B cell (CD21) populations were examined. However, the variation in cell numbers was significant and much greater in the atopic group for CD1c and CD14 labeled cells. The mean percentage of double labeled cells, CD1c/IgE and CD14/IgE was significantly lower in the atopic population compared with the controls. More variation was observed in the numbers of monocytes of atopic dogs (CD14/IgE) and antigen presenting cells (CD1c/IgE) of control dogs. The mean percentage of B cells expressing IgE was 65 and 51% in the atopic and control groups respectively which is greater than that reported in humans. There was no statistically significant difference. Total serum IgE concentrations were similar in each group and did not correlate with cell bound IgE in any of the leucocyte populations studied. Canine AD is associated with more variability in circulating monocyte numbers and lower numbers of monocytes expressing IgE than control dogs. Unlike in humans, there is no correlation between circulating and cell bound IgE. Furthermore, high levels of IgE in the dog may be related to a greater number of B cells in the circulation committed to IgE production.

HFE mutations, iron deficiency and overload in 10,500 blood donors.

People with genetic haemochromatosis (GH) accumulate iron from excessive dietary absorption. In populations of northern European origin, over 90% of patients are homozygous for the C282Y mutation of the HFE gene. While about 1 in 200 people in the general population have this genotype the proportion who develop clinical haemochromatosis is not known. The influence of HFE genotype on iron status was investigated in 10 556 blood donors. The allele frequencies of the C282Y and H63D mutations were 8.23% and 15.3% respectively. Heterozygosity for C282Y occurred in 1 in 7.9 donors, for H63D in 1 in 4.2 donors, and 1 in 42 were compound heterozygotes. Homozygosity for H63D occurred in 1 in 42 donors and 1 in 147 (72) were homozygous for C282Y. Mean values increased for transferrin saturation (TS) and serum ferritin (sFn), and decreased for unsaturated iron binding capacity (UIBC) in the order: donors lacking the mutations, H63D heterozygotes, C282Y heterozygotes, H63D homozygotes, compound heterozygotes and C282Y homozygotes, but serum ferritin (sFn) concentrations were no higher in H63D heterozygotes and C282Y heterozygous women than in donors lacking mutations. The percentage of donors failing the screening test for anaemia or of those with sFn < 15 microg/l did not differ among the genotype groups. C282Y and H63D heterozygotes and donors homozygous for H63D were at no greater risk of iron accumulation than donors lacking mutations, of whom 1 in 1200 had both a raised TS and sFn. The risk was higher for compound heterozygotes (1 in 80, P = 0.003) and for C282Y homozygotes (1 in 5, P < 0.0001). There was no correlation between sFn and either age or donation frequency in C282Y homozygotes. None of the 63 C282Y homozygous donors interviewed showed physical signs of overload or were aware of relatives with haemochromatosis. The Welsh Blood Service collects blood from about 140 000 people each year including an estimated 950 who are homozygous for HFE C282Y. They are probably healthy and unaware of any family history of iron overload.

Ulcerative dermatosis of the Shetland sheepdog and rough collie dog may represent a novel vesicular variant of cutaneous lupus erythematosus.

A syndrome of ulcerative dermatitis (UDSSC) previously has been described as unique to the Shetland sheepdog and rough collie dog. The pathogenesis of this disease is poorly understood and it has been suggested that it may be a variant of canine dermatomyositis (DM) which is also seen in these breeds. Information on the clinical presentation and previous medical history was collected from five Shetland sheepdogs and three rough collie dogs previously diagnosed with UDSSC. Characteristic features of the disease were adult onset in the summer months with annular, polycyclic and serpiginous ulcerations distributed over sparsely haired areas of the body. Skin biopsies taken from active lesions were compared in a blinded fashion with histological sections from seven Shetland sheepdogs and one rough collie with DM. Dermatomyositis was characterized histologically as a cell poor interface dermatitis associated with follicular atrophy. In contrast, the lesional pattern of UDSSC is that of a lymphocyte-rich interface dermatitis and folliculitis with vesiculation at the dermal-epidermal junction. The authors conclude that these represent two distinct diseases and that UDSSC may be a vesicular form of cutaneous lupus erythematosus seen in the adult rough collie dog and Shetland sheepdog.

Diagnosing new autoimmune blistering skin diseases of dogs and cats.

Autoimmune blistering skin diseases have been recognized for decades in humans and dogs. In the dog, most of these diseases unfortunately were grouped under the generic denomination of bullous pemphigoid without any confirmation that the autoantibodies targeted bullous pemphigoid antigens. In recent years, advanced diagnostic methods have permitted the recognition of new autoimmune blistering skin diseases in humans and companion-animal species. At this time, the diagnosis of these entities is made by combining clinical signs and results of histopathology. Immunologic methods serve to establish the presence of skin-fixed and circulating autoantibodies that target various epidermal or basement membrane antigens. In this article, salient features of the most common canine and feline subepidermal blistering dermatoses (mucous membrane pemphigold, bullous pemphigold, epidermolysis bullosa acquisita) and new variants of cutaneous lupus (type I bullous systemic lupus erythematosus and vesicular cutaneous lupus erythematosus) are presented.

Diagnostic techniques in dermatology: the investigation and diagnosis of adverse food reactions in dogs and cats.

Most veterinary clinicians recognize a population of patients in which dermatologic and/or gastrointestinal signs are related to the feeding of particular dietary components. This article briefly reviews the clinical signs associated with adverse food reactions in dogs and cats, and discusses the practical issues associated with confirming a diagnosis.

Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda.

Porphyria cutanea tarda is a skin disease caused by photosensitization by porphyrins whose accumulation is caused by deficiency of hepatic uroporphyrin- ogen decarboxylase activity. Mutations in the uroporphyrinogen decarboxylase gene are present in the low-penetrant, autosomal dominant familial form but not in the commoner sporadic form of porphyria cutanea tarda. We have investigated the relationship between age of onset of skin lesions and mutations (C282Y, H63D) in the hemochromatosis gene in familial (19 patients) and sporadic porphyria cutanea tarda (65 patients). Familial porphyria cutanea tarda was identified by mutational analysis of the uroporphyrinogen decarboxylase gene. Five previously described and eight novel mutations (A80S, R144P, L216Q, E218K, L282R, G303S, 402-403delGT, IVS2 + 2 delTAA) were identified. Homozygosity for the C282Y hemochromatosis mutation was associated with an earlier onset of skin lesions in both familial and sporadic porphyria cutanea tarda, the effect being more marked in familial porphyria cutanea tarda where anticipation was demonstrated in family studies. Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is an important susceptibility factor in both types but suggested that heterozygosity for this mutation has much less effect on the development of the disease.

Cardiac pheochromocytoma: resection after diagnosis by 111-indium octreotide scan.

Cardiac pheochromocytoma is an exceedingly rare and unusual clinical entity. Only 37 previous surgically treated adult patients were found in review of the surgical literature. We report the case of a 13-year-old boy who had a cardiac pheochromocytoma that was localized by the 111-indium diethylenetriamine pentaacetic acid octreotide scintigraphy scan and confirmed by magnetic resonance imaging after computed tomographic and B1-iodine-metaiodobenzylguanidine scans had failed. At operation, a 6-cm pheochromocytoma of the left atrium was found and successfully resected with reconstruction of the left atrium using autologous pericardium.

Methicillin-resistant Staphylococcus aureus infections in 11 dogs.

Methicillin-resistant Staphylococcus aureus infection was identified in 11 dogs. The infection was associated with surgical treatment especially orthopaedic surgery. Infection after traumatic wounding, and recurrent pyoderma was also seen. Oral antibiotic treatment improved or resolved the infection in nine of the 11 dogs, although the methicillin-resistant isolates were susceptible to relatively few antibiotics.

Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism.

A 10-year-old ovariohysterectomised domestic shorthaired cat was presented with multiple nodular calcifications of the footpads and interdigital spaces. Renal insufficiency was diagnosed by routine biochemistry and urinalysis. Additionally, the cat had a calcium and phosphorus solubility product greater than 70 mg/dl and elevated circulating parathyroid hormone. Dietary management of the renal disease resulted in a reduction in the mineral solubility product and normalisation of the concentration of parathyroid hormone accompanied by concurrent resolution of the pedal lesions.

Retrospective survey of allergen immunotherapy in canine atopy.

The clinical records of 277 cases of canine atopy treated with specific allergen immunotherapy were reviewed. A good response was defined as control with immunotherapy either alone or with topical agents, a partial response as control with immunotherapy and other systemic agents, and a poor response as no perceived benefit and the immunotherapy discontinued. The mean follow-up period was 29.2 months (range 10 to 85 months). Ninety-one cases (33 per cent) were lost to follow-up or failed to comply with the therapeutic protocol. Of the remaining 186 cases, 40 (21.5 per cent) had a good response to immunotherapy, 74 (39.8 per cent) had a partial response, and 72 (38.7 per cent) had a poor response. Immunotherapy was therefore of long-term benefit in 114 dogs (61.3 per cent). No significant differences in response rates were associated with the breed or sex of the dog, or the age of onset of the disease, or with the type or number of allergens included in a vaccine. Dogs which had clinical signs for more than 61 months before immunotherapy had a significantly poorer response rate (23.5 per cent, P < 0.05). In-house cases had a significantly better response rate (95.2 per cent, P < 0.05) than externally managed cases.