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BackgroundWarmblood Fragile Foal Syndrome Type 1 (WFFS) is an autosomal recessive disorder reported previously only in warmbloods and thought to be caused by a variant in the gene procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1, c.2032G>A, p.Gly678Arg). Given the presentation of this Thoroughbred case, we hypothesised that a similar genetic mechanism caused this phenotype.ObjectivesTo describe the pathological and genetic findings on a foal presenting to a veterinary practice in the UK with skin lesions similar to other Ehlers-Danlos Syndromes, including those documented for warmbloods with WFFS.Study designA single case report describing a genetic investigation.MethodsA Thoroughbred foal presenting as dystocia was euthanised for multiple skin lesions and developmental abnormalities. DNA extracted from the foal was tested for the PLOD1 variant (c.2032G>A, p.Gly678Arg) using the commercially available assay. To confirm causality and further interrogate potential novel causes of Ehlers-Danlos Syndrome, 1799 functional candidate genes, including PLOD1, were analysed using whole genome sequencing data generated from DNA extracted from the foal's muscle. These data were compared to 34 control samples from at least 11 other breeds. Variants were prioritised for further evaluation based on predicted impact on protein function.ResultsPost-mortem evaluation concluded that this foal suffered from a condition of collagen dysplasia. The foal was homozygous for the c.2032G>A PLOD1 variant. Only two other missense variants identified from whole genome sequencing data were also computationally predicted to be deleterious to protein function, (NPHP3 c.1253T>C, p.Leu418Pro, EPDR1 c.154G>C, p.Glu52Gln). Neither of these genes have been linked to similar phenotypes, or Ehlers-Danlos Syndrome in humans or other species and thus further investigation of these variants as the cause of EDS was not warranted.Main limitationsThis study is a single case report in the Thoroughbred with no additional cases from this breed yet identified to replicate this finding.ConclusionsGiven the clinical presentation similar to WFFS, homozygosity for the PLOD1 variant, and absence of another more plausible causal variant from the WGS experiment, we conclude that PLOD1 c.2032G>A is the likely cause of this foal's condition. This is the first documented evidence of fragile foal syndrome caused by the PLOD1 variant in a breed outside of warmbloods, the Thoroughbred. We therefore recommend a change in the name of this disorder to fragile foal syndrome type 1 (FFS) and utilisation of genetic testing in Thoroughbreds to avoid producing affected foals.

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Chromosomal abnormalities are a common cause of human miscarriage but rarely reported in any other species. As a result, there are currently inadequate animal models available to study this condition. Horses present one potential model since mares receive intense gynecological care. This allowed us to investigate the prevalence of chromosomal copy number aberrations in 256 products of conception (POC) in a naturally occurring model of pregnancy loss (PL). Triploidy (three haploid sets of chromosomes) was the most common aberration, found in 42% of POCs following PL over the embryonic period. Over the same period, trisomies and monosomies were identified in 11.6% of POCs and subchromosomal aberrations in 4.2%. Whole and subchromosomal aberrations involved 17 autosomes, with chromosomes 3, 4, and 20 having the highest number of aberrations. Triploid fetuses had clear gross developmental anomalies of the brain. Collectively, data demonstrate that alterations in chromosome number contribute to PL similarly in women and mares, with triploidy the dominant ploidy type over the key period of organogenesis. These findings, along with highly conserved synteny between human and horse chromosomes, similar gestation lengths, and the shared single greatest risk for PL being advancing maternal age, provide strong evidence for the first animal model to truly recapitulate many key features of human miscarriage arising due to chromosomal aberrations, with shared benefits for humans and equids. [ABSTRACT FROM AUTHOR]

Background: Excessive umbilical cord length (UCL) is associated with equine pregnancy loss. However, a lack of UCL reference values makes it difficult to define excessive UCL. Further, factors associated with differences in UCL are poorly understood. Objectives: To (i) report the total, allantoic and amniotic UCL in healthy term pregnancies in Thoroughbreds, (ii) describe the relationship between gestational age and UCL, fetal weight and crown rump length (CRL) using clinically normal pregnancies (CNPs) from mares dying during gestation, and (iii) identify associations between UCL and maternal age and parity, paternal age, and fetal sex. Study design: Cross‐sectional. Methods: Data including UCLs, fetal weight, CRL and maternal age, parity, paternal age and fetal sex were taken from CNPs from Thoroughbred mares dying during gestation (n = 32), and placentas from HTPs (n = 34) in England. Correlations were assessed using Spearman's rank with significant correlations estimated by locally weighted scatter plot smoothing (LOWESS). Regression plots were fitted to highly correlated variables to further assess and quantify relationships. Differences in UCL between categorical variables were assessed using Kruskall Wallis and Mann–Whitney U tests. Results: The median total, amniotic and allantoic HTP UCLs were 53.5 cm (interquartile range [IQR] 16), 29.5 cm (IQR 7) and 25.0 cm (IQR 8) respectively. Gestational age and amniotic UCL were moderately correlated (rho = 0.53, p = 0.04), with LOWESS estimating an exponential increase followed by plateauing at around Day 200. Nonlinear associations were observed between fetal weight and gestational age and CRL (adjusted r2 = 0.98 and 0.95 respectively). A linear association was observed between gestational age and CRL: predicted CRL = −17.60 + 0.38 × gestational age, p < 0.001. Main limitations: Limited availability of CNPs from mares dying during gestation. Estimated relationships can only approximate growth. Conclusions: This study provides important UCL and fetal size reference values, which may aid in assessing abnormalities. For the first time, associations between UCL and gestational age have been described. [ABSTRACT FROM AUTHOR]

Background: Dorsoproximal osteochondral defects commonly affect the proximal phalanx, but information about diagnosis on computed tomography (CT) and magnetic resonance imaging (MRI) is limited. Objectives: To assess CT and MRI diagnoses of osteochondral defects, describe the lesions and compare sensitivity and specificity of the modalities using macroscopic pathology as gold standard. Study design: Cross‐sectional study. Methods: Thirty‐five equine cadaver limbs underwent standing cone‐beam CT (CBCT), fan‐beam CT (FBCT), low‐field MRI and pathological examination. CT and MR images were examined for proximal phalanx dorsomedial and dorsolateral eminence osteochondral defects. Defect dimensions were measured. Imaging diagnoses and measurements were compared with macroscopic examination. Results: Fifty‐six defects were seen over 70 potential locations. On CBCT and FBCT, osteochondral defects appeared as subchondral irregularity/saucer‐shaped defects. On MRI, osteochondral defects were a combination of articular cartilage defect on dorsal images and subchondral flattening/irregularity on sagittal images. Subchondral thickening and osseous short tau inversion recovery hyperintensity were found concurrent with osteochondral defects. Compared with pathological examination, the sensitivity and specificity of diagnosis were 86% (95% confidence interval [95% CI] 75%–93%) and 64% (95% CI 38%–85%) for FBCT; 64% (95% CI 51%–76%) and 71% (95% CI 46%–90%) for CBCT; and 52% (95% CI 39%–65%) and 71% (95% CI 46%–90%) for MRI. Sensitivity of all modalities increased with defect size. Macroscopic defect dimensions were strongly correlated with CBCT (r = 0.76, p < 0.001) and moderately correlated with FBCT and MRI (r = 0.65, p < 0.001). Macroscopic measurements were significantly greater than all imaging modality dimensions (p < 0.001), potentially because macroscopy included articular cartilage pathology. Main limitations: Influence of motion artefact could not be assessed. Conclusions: Osteochondral defects could be visualised using both CT and MRI with sensitivity increasing with defect size. Diagnostic performance was best using FBCT, followed by CBCT then MRI, but CBCT‐measured defect size best correlated with macroscopic examination. MRI provided useful information on fluid signal associated with defects, which could represent active pathology. [ABSTRACT FROM AUTHOR]

Background: Pregnancy loss after Day 70 of gestation manifests as abortion, stillbirth or perinatal death. While previous studies have reported the diagnoses of laboratory submissions, none have quantified the incidence and causes of abortions, stillbirths and perinatal mortality at a population level. Objectives: To report the incidence and causes of pregnancy loss after Day 70 of gestation in a cohort of Thoroughbreds. Study design: Retrospective cohort study. Methods: Outcomes of Day 70 pregnancies were collected from eight Thoroughbred farms over the 2013‐2017 breeding seasons. Stud, veterinary and laboratory records were supplemented with publicly available data. Cause of loss was categorised using custom criteria. Results: Data were collected on 3,586 pregnancies from 1,802 mares. The incidence risk of a pregnancy failing to produce a live foal at 24 hours post parturition was 7.3% (95% confidence interval (CI) 6.5‐8.2, equating to 7.3 cases per 100 Day‐70 pregnancies). The incidence of pregnancy loss between Day 70 and 300 of gestation, Day 301‐315 and stillbirth/perinatal death was 4.0% (95% CI 3.4‐4.7), 0.3% (95% CI 0.2‐0.6) and 1.4% (95% CI 1.1‐1.9) respectively. Of the pregnancy losses where tissue was available, 61.1% were submitted for post‐mortem examination. The incidence risk of loss due to umbilical cord‐related pathologies was 1.5% (95% CI 1.1‐1.9), 0.4% (95% CI 0.2‐0.6) for noninfectious placental disease and 0.3% (95% CI 0.2‐0.6) for both infectious placentitis and Equine Herpesvirus infection. No primary diagnosis was made in 11.2% of the cases which underwent full post‐mortem examination. Main limitations: It was not possible to differentiate between intra‐partum stillbirth and early post‐partum death. Conclusion: Pregnancy loss after Day 70 of gestation is a significant source of loss in the Thoroughbred with umbilical cord‐related pathologies being the most commonly diagnosed cause. Reporting the incidence of pregnancy loss at a population level with clear case definitions will allow for accurate global comparisons. [ABSTRACT FROM AUTHOR]

Hemangiosarcoma is an uncommon tumor in horses. We characterized 3 cases of equine renal hemangiosarcoma, focusing on clinical and pathologic features, and describe occurrence of the epithelioid variant of hemangiosarcoma in one of these cases. Nuclear expression of phosphorylated STAT3 (pSTAT3) was assessed to analyze potential inappropriate STAT3 activation as a component of tumor pathogenesis. Clinical signs in the 3 horses included insidious weight loss, followed in one case by serosanguineous nasal discharge and terminal epistaxis, and nonspecific signs of abdominal pain. Two of the hemangiosarcomas had a classical histopathologic appearance; in the other, neoplastic cells were polygonal and were arranged in densely packed sheets, resembling the epithelioid variant. Cross-reactivity of a pSTAT3 antibody was established by demonstration of pSTAT3 expression in the epithelium of glabrous skin by immunoblotting and immunohistochemistry. In the epithelioid hemangiosarcoma, ~40% of neoplastic cells exhibited nuclear pSTAT3 expression, but in the other 2 cases, expression was weak and variable in the neoplastic population, although stromal cell pSTAT3 activity was evident in pulmonary metastases in one case. [ABSTRACT FROM AUTHOR]

Equine pregnancy failure can occur throughout gestation, with causes varying by region. In the UK, umbilical cord torsion (UCT) accounted for 44.0% of pregnancy loss (PL) cases occurring after day 70 of gestation and submitted to a diagnostic laboratory. Limited reports on the features of UCT are available. This study aimed to compare the gross and histological features in PLs resulting from UCT to those with no UC pathology. Cases submitted to a UK diagnostic laboratory diagnosed with definitive or suspected UCT (n=81) were compared to PLs diagnosed as not associated with umbilical cord (UC) pathology (nUCT) (n=33). Logistic regression analysis was used for categorical data and Mann-Whitney U tests for non-parametric continuous data. Median gestation age at loss was significantly lower in the UCT (215 days, inter-quartile range (IQR) 32) group compared to nUCT (325 days, IQR 56), p<0.005, with 83.5% of the UCT abortions occurring prior to day 240 of gestation compared to 10.3% of the nUCT cases. The median fetal weight in the UCT group was significantly lighter than the nUCT group, 11.0kg (IQR 6.4) and 45.4kg (IQR 22.5) respectively, remaining after adjustment for gestational age (p<0.005). The UCT group had a significantly longer median total UC length (UCL) (79cm, IQR 19, p<0.001) and amniotic UCL (45cm, IQR 14, p<0.001) but not allantoic UCL (p=0.32) compared tothe nUCT group (total UCL 61cm, IQR 22 and amniotic UCL 27.5cm, IQR 13). A 7.3-fold (95% confidence interval (CI) 2.9-18.2) increase in the risk of UCT diagnosis was identified when the amniotic:allantoic UCL ratio was >1. There was no significant difference in the fetal sex ratio between the two groups (p=0.79). Seven gross features were associated with UCT diagnosis (p<0.05), with reddening of the chorioallantois leading to the greatest increase in the odds of UCT diagnosis (OR 17.4, 95% CI 5.7, 53.4). Histological assessment of the chorioallantois in a subset of cases (46 UCT and 31 nUCT) identified three features associated with UCT diagnosis: autolysis, villous mineralisation and villous karyorrhexis (p<0.001). No UCT cases (0/46) exhibited a significant inflammatory infiltrate in the chorioallantois, compared to 9/31 cases of nUCT. The presence of karyorrhexis and mineralisation likely reflects ischaemic injury resulting from malperfusion of the chorion, in the case of UCT, as a response to episodes of venous stasis following increased vascular resistance associated with the significant increase in UCL and/or vascular obstruction. Collectively, this suggests a more chronic pathophysiology involving lengthening of the amniotic, not allantoic, UC. Identification of these features enables evidence-based refinement of diagnostic criteria for UCT, which can now undergo consultation to reach a universally accepted consensus. [ABSTRACT FROM AUTHOR]

Information regarding the histopathology of the proximal phalanx (P1) sagittal groove in racehorses is limited. Twenty-nine cadaver limbs from nine Thoroughbred racehorses in racing/race-training underwent histological examination. Histological specimens of the third metacarpal/metatarsal (MC3/MT3) parasagittal grooves and P1 sagittal grooves were graded for histopathological findings in hyaline cartilage (HC), calcified cartilage (CC), and subchondral plate and trabecular bone (SCB/TB) regions. Histopathological grades were compared between (1) fissure and non-fissure locations observed in a previous study and (2) dorsal, middle, and palmar/plantar aspects. (1) HC, CC, and SCB/TB grades were more severe in fissure than non-fissure locations in the MC3/MT3 parasagittal groove ( p < 0.001). SCB/TB grades were more severe in fissure than non-fissure locations in the P1 sagittal groove ( p < 0.001). (2) HC, CC, and SCB/TB grades including SCB collapse were more severe in the palmar/plantar than the middle aspect of the MC3/MT3 parasagittal groove ( p < 0.001). SCB/TB grades including SCB collapse were more severe in the dorsal and middle than the palmar/plantar aspect of the P1 sagittal groove ( p < 0.001). Histopathology in the SCB/TB region including bone fatigue injury was related to fissure locations, the palmar/plantar MC3/MT3 parasagittal groove, and the dorsal P1 sagittal groove.