The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive mitochondrial disease caused by mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene. ...DCMA or 3‐methylglutaconic aciduria type V is globally rare, but the largest number of patients in the world is found in the Hutterite population of southern Alberta in Canada. We provide an update on phenotypic findings, natural history, pathological findings, and our clinical experience. We analyzed all available records for 43 patients diagnosed with DCMA between 2005 and 2015 at the Alberta Children's Hospital. All patients studied were Hutterite and homozygous for the causative DNAJC19 variant (c.130‐1G>C, IVS3‐1G>C) and had elevated levels of 3‐methyglutaconic acid. We calculated a birth prevalence of 1.54 cases per 1000 total births in the Hutterite community. Children were small for gestational age at birth and frequently required supplemental nutrition (63%) or surgical placement of a gastrostomy tube (35%). Early mortality in this cohort was high (40%) at a median age of 13 months (range 4‐294 months). Congenital anomalies were common as was dilated cardiomyopathy (50%), QT interval prolongation (83%), and developmental delay (95%). Tissue pathology was analyzed in a limited number of patients and demonstrated subendocardial fibrosis in the heart, macrovesicular steatosis and fibrosis in the liver, and structural abnormalities in mitochondria. This report provides clinical details for a cohort of children with DCMA and the first presentation of tissue pathology for this disorder. Despite sharing common genetic etiology and environment, the disease is highly heterogeneous for reasons that are not understood. DCMA is a clinically heterogeneous systemic mitochondrial disease with significant morbidity and mortality that is common in the Hutterite population of southern Alberta.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in ...sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next‐generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin‐C (FLNC), an actin‐cross‐linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal‐dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin‐C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin‐C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal‐dominant RCM and broadens the phenotype spectrum of filaminopathies.
The article describes for the first time FLNC as a disease gene for familial restrictive cardiomyopathy (RCM). RCM is a heart muscle disease leading to heart failure at young ages often resulting in early heart transplantation. Two novel variants in FLNC have been discovered by next‐generation sequencing and show co‐segregation in two independent families. In addition, cytoplasmic protein aggregates were present in cardiac tissue of mutation carriers and in muscle cell lines expressing mutant filamin‐C.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
To evaluate aneuploidy rate, prognostic factors, and perinatal outcomes following a diagnosis of fetal megacystis at 11–14 week's gestation.
Methods
A retrospective study of first ...trimester fetal megacystis from 2010 to 2020 was performed, including ultrasound finding, perinatal outcomes, pathology reports, genetic tests, and neonatal investigations.
Results
A total of 98 cases of first trimester fetal megacystis was identified with an overall aneuploidy rate of 12%. There were 54% live births and 46% fetal losses including spontaneous fetal demise and elective termination. Among the 45 fetal losses, 64% had additional structural abnormalities at index ultrasound and final diagnoses were achievable in 64% cases. Among the 53 livebirths, additional ultrasound abnormalities were detected in only 1 fetus and spontaneous resolution of megacystis was detected in 96% of cases. The two cases where fetal megacystis persisted had major postnatal diagnoses: cloacal malformation and megacystis‐microcolon‐intestinal hypoperistalsis syndrome, respectively. Our data showed LBD ≥ 12 mm was the best individual predictor of adverse perinatal outcome and all 11 cases of lower urinary tract obstruction (LUTO) were diagnosed in fetuses with LBD ≥ 12 mm.
Conclusions
First trimester ultrasound provides important prognostic factors and isolated megacystis <12 mm is associated with a positive outcome.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
-The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories.
-To establish an agreed-upon ...protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community.
-Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible.
-The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous maturation, patterns of ascending intrauterine infection, and villitis of unknown etiology were agreed upon. Topics requiring further discussion were highlighted. Ongoing developments in our understanding of the pathology of the placenta, scientific bases of the maternofetoplacental triad, and evolution of the clinical significance of defined lesions may necessitate further refinements of these consensus guidelines. The proposed structure will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The objective of this study is to assess the effect of the lockdown measures during the coronavirus disease 2019 (COVID-19) pandemic on pregnancy outcomes of women who were not affected by severe ...acute respiratory syndrome coronavirus 2 infection.
We used data from the perinatal health program and neonatal databases to conduct a cohort analysis of pregnancy outcomes during the COVID-19 lockdown in the Calgary region, Canada. Rates of preterm birth were compared between the lockdown period (March 16 to June 15, 2020) and the corresponding pre-COVID period of 2015 to 2019. We also compared maternal and neonatal characteristics of preterm infants admitted to neonatal intensive care units (NICUs) in Calgary between the two periods.
A total of 4,357 and 24,160 live births occurred in the lockdown and corresponding pre-COVID period, respectively. There were 366 (84.0 per 1,000 live births) and 2,240 (92.7 per 1,000 live births) preterm births in the lockdown and corresponding pre-COVID period, respectively (
= 0.07). Rates of very preterm and very-low-birth-weight births were lower in the lockdown period compared with the corresponding pre-COVID period (11.0 vs. 15.6 and 9.0 vs. 14.4 per 1,000 live births,
= 0.02 and
= 0.005, respectively). There was no difference in spontaneous stillbirth between the two periods (3.7 vs. 4.1 per 1,000 live birth,
= 0.71). During the lockdown period, the likelihood of multiple births was lower (risk ratio RR 0.73, 95% confidence interval CI: 0.60-0.88), while gestational hypertension and clinical chorioamnionitis increased (RR 1.24, 95%CI: 1.10-1.40; RR 1.33, 95%CI 1.10-1.61, respectively).
Observed rates of very preterm and very-low-birth-weight births decreased during the COVID-19 lockdown. Pregnant women who delivered during the lockdown period were diagnosed with gestational hypertension and chorioamnionitis more frequently than mothers in the corresponding pre-COVID period.
· Lockdown measures to reduce COVID-19 transmission were associated with a lower rate of preterm birth.. · Mental and physical wellbeing of pregnant women were significantly affected by the lockdown measures.. · A comprehensive public health plan to relieve psychosocial stress during pregnancy is required..
Retinoblastoma is the most common cause of all intraocular pediatric malignancies. It is caused by the loss of
tumor suppressor gene function, although some tumors occur due to
oncogene amplification ...with normal
genes. Nearly half of all retinoblastomas occur due to a hereditary germline
pathogenic variant, most of which manifest with bilateral tumors. This germline
mutation also predisposes to intracranial midline embryonal tumors. Accurate staging of retinoblastoma is crucial in providing optimal vision-, eye-, and life-saving treatment. The
has undergone significant changes, resulting in a universally accepted system with a multidisciplinary approach for managing retinoblastoma. The authors discuss the role of MRI and other diagnostic imaging techniques in the pretreatment assessment and staging of retinoblastoma. A thorough overview of the prevailing imaging standards and evidence-based perspectives on the benefits and drawbacks of these techniques is provided. Published under a CC BY 4.0 license. Test Your Knowledge questions for this article are available in the supplemental material.
Hypoxic Ischemic Encephalopathy (HIE) can lead to devastating consequences for the affected infant. Although therapeutic cooling benefits infants with moderate and severe HIE, differentiating mild ...from moderate-severe HIE may be challenging. The placenta reflects the fetal intrauterine environment and may reveal underlying processes that affect brain injury.
To describe placental histopathology using the Amsterdam Placental Workshop Group Criteria in different grades of HIE.
Retrospective cohort.
Infants admitted to a tertiary care neonatal intensive care unit with a diagnosis of HIE between 2011 and 2016.
Maternal and neonatal clinical variables and placental histopathology using the Amsterdam Placental Workshop Group Criteria were compared between mild and moderate-severe HIE. Mann-Whitney or t-test or ꭓ2 were performed for bivariate associations as appropriate. To explain the relationship between placental pathology and severity of HIE odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using logistic regression models.
Of the 73 infants in the study, 23 had mild and 50 moderate-sever HIE. There was no difference in maternal and neonatal characteristics except for sentinel events which were higher in the moderate- severe group. On placental histopathology, acute inflammation, including fetal inflammatory reaction (FIR) were significantly higher in the moderate-severe group. After adjusting for confounders, FIR remained significantly associated with moderate-severe HIE, ORs 6.29, 95 % CI 1.5–25.
Our study demonstrates FIR in the placenta is associated with severity of HIE.
•Hypoxemic ischaemic encephalopathy (HIE) can have devastating effects on newborns.•Moderate-severe HIE, amenable to cooling, is difficult to differentiate from mild HIE.•Amsterdam classification was used to describe placental histopathology in HIE.•Placental fetal inflammatory reaction was associated with moderate-severe HIE.•The placenta should be examined in all cases of HIE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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