Sodium Channel Gene Variants in Fetuses with Abnormal Sonographic Findings: Expanding the Prenatal Phenotypic Spectrum of Sodium Channelopathies.

Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of action potentials in the brain and muscle. Pathogenic variants in genes encoding VGSCs have been associated with severe disorders including epileptic encephalopathies and congenital myopathies. In this study, we identified pathogenic variants in genes encoding the α subunit of VGSCs in the fetuses of two unrelated families with the use of trio-based whole exome sequencing, as part of a larger cohort study. Sanger sequencing was performed for variant confirmation as well as parental phasing. The fetus of the first family carried a known de novo heterozygous missense variant in the SCN2A gene (NM_001040143.2:c.751G>A p.(Val251Ile)) and presented intrauterine growth retardation, hand clenching and ventriculomegaly. Neonatally, the proband also exhibited refractory epilepsy, spasms and MRI abnormalities. The fetus of the second family was a compound heterozygote for two parentally inherited novel missense variants in the SCN4A gene (NM_000334.4:c.4340T>C, p.(Phe1447Ser), NM_000334.4:c.3798G>C, p.(Glu1266Asp)) and presented a severe prenatal phenotype including talipes, fetal hypokinesia, hypoplastic lungs, polyhydramnios, ear abnormalities and others. Both probands died soon after birth. In a subsequent pregnancy of the latter family, the fetus was also a compound heterozygote for the same parentally inherited variants. This pregnancy was terminated due to multiple ultrasound abnormalities similar to the first pregnancy. Our results suggest a potentially crucial role of the VGSC gene family in fetal development and early lethality.

Suspected twin anemia polycythemia sequence in a dichorionic, diamniotic twin pregnancy: a case report.

BACKGROUND: Twin anemia polycythemia sequence is a rare complication in monochorionic twin pregnancy. CASE PRESENTATION: We describe a case of dichorionic twin pregnancy presenting with suspected twin anemia polycythemia sequence. A 31-year-old White female, on her third pregnancy, had a routine ultrasound scan at 12 weeks gestation, which demonstrated a dichorionic twin pregnancy with one placenta located in the anterior wall and the other in the posterior wall of the uterus. At 21 weeks, a scan demonstrated a 24% growth discordance between the two fetuses with normal Doppler studies and amniotic fluid. At 27 weeks, one twin showed signs of anemia and the other polycythemia; the fetal middle cerebral artery peak systolic velocity was high in the anemic fetus and low in the polycythemic twin (1.8 and 0.5 multiples of the median). An intrauterine blood transfusion was carried out and this increased the fetal hemoglobin concentration in the anemic twin from 3.5 to 12.5 g/dL. At 29 weeks, delivery by cesarean section was carried out because of evidence from middle cerebral artery peak systolic velocity of recurrence of anemia in one twin and worsening polycythemia in the co-twin; at birth the hemoglobin concentrations were 5.6 and 24.9 g/dL, respectively. Histopathological examination confirmed dichorionicity with no communicating vessels between the two placentas. CONCLUSIONS: This is the first case of twin anemia polycythemia sequence in a dichorionic, diamniotic twin pregnancy where intrauterine blood transfusion was used to prolong the pregnancy by almost 2 weeks in a "twin anemia polycythemia sequence-like" setting.

Chronic histiocytic intervillositis (CHI): current treatments and perinatal outcomes, a systematic review and a meta-analysis.

Background: Chronic histiocytic intervillositis (CHI) is a rare placental lesion with a high recurrence rate and poor perinatal outcomes. There are currently limited guidelines regarding the diagnosis of this condition in the index pregnancy and treatment where recurrence is suspected. Objective: The primary objective of this systematic review and meta-analysis was to determine the perinatal outcomes of pregnancies affected by chronic histiocytic intervillositis and to what extent they can be improved with treatment. The secondary objective was to assess the relationship between CHI lesion severity and pregnancy loss. Methods: A systematic search of Ovid Embase, Web of Science, Science Direct, PubMed, Ovid Medline, Google Scholar and CINAHL was carried out. Case reports, cohort, case-control and randomised controlled trials (RCT) detailing the perinatal outcomes of CHI pregnancies, both treated and untreated, were included. Results: No RCTs were identified. However, in a review population of 659 pregnancies, with additional 7 in case reports, CHI treatments included aspirin, prednisone, prednisolone, low molecular weight heparin (LMWH), hydroxychloroquine and adalimumab. A descriptive synthesis of data found mixed results for treatments in relation to live birth, miscarriage and fetal growth restriction outcomes. Furthermore, quantitative synthesis of 38 pregnancies revealed a non-significant improvement in live birth rate with CHI targeted treatment (OR 1.79 [95% CI 0.33-9.61] (p=0.50), while meta-analysis of CHI severity in line with pregnancy loss, in a sample of 231 pregnancies, revealed lower odds of pregnancy loss with less severe lesions (OR: 0.17 [0.03-0.80], p=0.03). Conclusions: This systematic review and meta-analysis reinforce notions surrounding the insufficient evidence for CHI treatment. It also strengthens previous hypotheses detailing the positive association between CHI lesion severity and odds of pregnancy loss. Aspirin, LMWH, prednisolone, hydroxychloroquine and adalimumab are candidates with varying levels of weak to moderate evidence supporting their use. Further prospective research is required to obtain robust evidence pertaining to treatment safety and efficacy and optimal drug regimes. Systematic Review Registration: [website], identifier CRD42021237604.

A hemizygous mutation in the FOXP3 gene (IPEX syndrome) resulting in recurrent X-linked fetal hydrops: a case report.

BACKGROUND: Fetal hydrops is excessive extravasation of fluid into the third space in a fetus, which could be due to a wide differential of underlying pathology. IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome primarily affects males. It is a monogenic primary immunodeficiency syndrome of X-linked recessive inheritance due to FOXP3 gene variants. It is characterised by the development of multiple autoimmune disorders in affected individuals. CASE PRESENTATION: We present a rare cause of male fetal hydrops in the context of IPEX syndrome and discuss FOXP3 gene variants as a differential for 'unexplained' fetal hydrops that may present after the first trimester. DISCUSSION AND CONCLUSIONS: In all similar cases, the pathological process begins during intrauterine life. Furthermore, there are no survivors described. Consequently, this variant should be considered as a severe one, associated with intrauterine life onset and fatal course, i.e., the most severe IPEX phenotype.

Placental magnetic resonance imaging in chronic hypertension: A case-control study.

INTRODUCTION: We aimed to explore the use of magnetic resonance imaging (MRI) in vivo as a tool to elucidate the placental phenotype in women with chronic hypertension. METHODS: In case-control study, women with chronic hypertension and those with uncomplicated pregnancies were imaged using either a 3T Achieva or 1.5T Ingenia scanner. T2-weighted images, diffusion weighted and T1/T2* relaxometry data was acquired. Placental T2*, T1 and apparent diffusion coefficient (ADC) maps were calculated. RESULTS: 129 women (43 with chronic hypertension and 86 uncomplicated pregnancies) were imaged at a median of 27.7 weeks' gestation (interquartile range (IQR) 23.9-32.1) and 28.9 (IQR 26.1-32.9) respectively. Visual analysis of T2-weighted imaging demonstrated placentae to be either appropriate for gestation or to have advanced lobulation in women with chronic hypertension, resulting in a greater range of placental mean T2* values for a given gestation, compared to gestation-matched controls. Both skew and kurtosis (derived from histograms of T2* values across the whole placenta) increased with advancing gestational age at imaging in healthy pregnancies; women with chronic hypertension had values overlapping those in the control group range. Upon visual assessment, the mean ADC declined in the third trimester, with a corresponding decline in placental mean T2* values and showed an overlap of values between women with chronic hypertension and the control group. DISCUSSION: A combined placental MR examination including T2 weighted imaging, T2*, T1 mapping and diffusion imaging demonstrates varying placental phenotypes in a cohort of women with chronic hypertension, showing overlap with the control group.

T2* Placental Magnetic Resonance Imaging in Preterm Preeclampsia: An Observational Cohort Study.

Placental dysfunction underlies the cause of pregnancies complicated by preeclampsia. The use of placental magnetic resonance imaging to provide an insight into the pathophysiology of preeclampsia and thus assess its potential use to inform prognosis and clinical management was explored. In this prospective observational cohort study, 14 women with preterm preeclampsia and 48 gestation-matched controls using 3-Tesla magnetic resonance imaging at median of 31.6 weeks (interquartile range [IQR], 28.6-34.6) and 32.2 weeks (IQR, 28.6-33.8), respectively, were imaged. The acquired data included T2-weighted images and T2* maps of the placenta, the latter an indicative measure of placental oxygenation. Placentae in women with preeclampsia demonstrated advanced lobulation, varied lobule sizes, high granularity, and substantial areas of low-signal intensity on T2-weighted imaging, with reduced entire placental mean T2* values for gestational age (2 sample t test, t=7.49) correlating with a reduction in maternal PlGF (placental growth factor) concentrations (Spearman rank correlation coefficient 0.76) and increased lacunarity values (t=3.26). Median mean T2* reduced from 67 ms (IQR, 54-73) at 26.0 to 29.8 weeks' gestation to 38 ms (IQR, 28-40) at 34.0 to 37.9 weeks' gestation in the control group. In women with preeclampsia, median T2* was 23 ms (IQR, 20-23) at 26.0 to 29.8 weeks' gestation and remained low (22 ms [IQR, 20-26] at 34.0-37.8 weeks' gestation). Histological features of maternal vascular malperfusion were only found in placentae from women with preeclampsia. Placental volume did not differ between the control group and women with preeclampsia. Placental magnetic resonance imaging allows both objective quantification of placental function in vivo and elucidation of the complex mechanisms underlying preeclampsia development.

Post-mortem Characterisation of a Case With an ACTG1 Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia.

Cytoplasmic Actin Gamma 1 (ACTG1) gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). ACTG1 anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an ACTG1 gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with ACTG1 variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the ACTG1 variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the ACTG1 variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the ACTG1 variant. The caudal ganglionic eminence and the PVWM regions in the ACTG1 variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the ACTG1 gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.

Complete Bilateral Agenesis of the Diaphragm.

Bilateral agenesis of the diaphragm is a very rare congenital diaphragmatic defect. Bilateral congenital diaphragmatic hernia (CDH) is much more frequently associated with other anomalies compared with unilateral CDH (70% vs 30%-40%). These include cardiovascular, respiratory (other than lung hypoplasia), gastrointestinal, renal, and genital malformations. We report a case of complete bilateral agenesis of the diaphragm associated with a horseshoe kidney and an imperforate anus. These additional malformations have not previously been reported in association with complete bilateral agenesis of the diaphragm. We also present a review of previous cases of total diaphragm agenesis published in the English language and provide some insights about pathogenesis.

"Delayed Villous Maturation" in Placental Reporting: Concordance among Consultant Pediatric Pathologists at a Single Specialist Center.

Delayed villous maturation (DVM) has been associated with an increased risk of adverse pregnancy outcome, including stillbirth, in the late third trimester, but there are limited published data. Moreover, it is recognized that the assessment of villous maturation is subjective and hampered by both intraobserver and interobserver variability. This audit aims to assess concordance in the reporting of DVM among pediatric pathologists at a single specialist center to improve reproducibility of this potentially important diagnosis. This is a retrospective review of singleton placentas from pregnancies at 35 weeks gestation or greater submitted for histopathologic examination between June 2013 and December 2013. Placental slides were reviewed independently by 4 pediatric pathologists, blinded to the original report, apart from gestational age; villous maturation was assessed as appropriate, accelerated, or delayed for the stated gestational age. A total of 464 placental histopathology reports were reviewed, of which 164 were greater than 35 weeks gestation; of those, 42 (26%) were originally reported as DVM. Following the audit slide review, 38 cases (23%) were assessed to show DVM by at least 1 pathologist. Consensus, with at least 3 pathologists agreeing to a diagnosis of DVM, was achieved in only 14 cases (9% of all cases reviewed; 37% of all cases called DVM). However, the proportion of overall agreement between 2 of the pathologists was 0.92. Concordance for DVM is poor among pathologists and subject to much interobserver variability. Consistency may be improved by consensus histologic review of all the placentas in which the diagnosis of DVM is being considered and stringent application of the published diagnostic criteria.

Fetal calcifications are associated with chromosomal abnormalities.

OBJECTIVE: The biological importance of calcifications occasionally noted in fetal tissues (mainly liver) at autopsy or ultrasound is largely unexplored. Previous reports hint at an association to infection, circulatory compromise, malformations or chromosomal abnormalities. To identify factors associated with calcifications, we have performed a case-control study on the largest cohort of fetuses with calcifications described thus far. METHODS: One-hundred and fifty-one fetuses with calcifications and 302 matched controls were selected from the archives of the Department of Pathology, Karolinska University Hospital. Chromosome analysis by karyotyping or quantitative fluorescence-polymerase chain reaction was performed. Autopsy and placenta reports were scrutinized for presence of malformations and signs of infection. RESULTS: Calcifications were mainly located in the liver, but also in heart, bowel, and other tissues. Fetuses with calcifications showed a significantly higher proportion of chromosomal abnormalities than controls; 50% vs. 20% (p<0.001). The most frequent aberrations among cases included trisomy 21 (33%), trisomy 18 (22%), and monosomy X (18%). A similar distribution was seen among controls. When comparing cases and controls with chromosomal abnormalities, the cases had a significantly higher prevalence of malformations (95% vs. 77%, p=0.004). Analyzed the other way around, cases with malformations had a significantly higher proportion of chromosomal abnormalities compared with controls, (66% vs. 31%, p<0.001). CONCLUSION: The presence of fetal calcifications is associated with high risk of chromosomal abnormality in combination with malformations. Identification of a calcification together with a malformation at autopsy more than doubles the probability of detecting a chromosomal abnormality, compared with identification of a malformation only. We propose that identification of a fetal tissue calcification at autopsy, and potentially also at ultrasound examination, should infer special attention towards co-existence of malformations, as this would be a strong indicator for a chromosomal abnormality.

Unusual concurrence of heterotopic glial nodule of the scalp and congenital herpes simplex virus type-2 infection.

Heterotopic glial nodules are rare congenital cutaneous lesions; only 13 cases of scalp localized lesions of this kind are reported in the English medical literature. Herpes simplex virus is a rare cause of neonatal morbidity and mortality and is a rare cause of intrauterine infection. We report the first case of concurrent presence of a heterotopic glial nodule of the scalp and neonatal, in utero-acquired, fatal herpes simplex virus type-2 infection.

An unusual case of multiple-gunshot suicide of an alcohol-intoxicated cancer sufferer with prolonged physical activity.

Multishot firearm suicides are relatively rare and suggest the possibility of homicide. Physical activity following gunshots to the head, the neck, and the thorax does occur, and immediate incapacitation does not occur in every fatal gunshot wound that penetrates the head or perforates the heart. Cancer patients appear to be at increased suicide risk, but alcohol intoxication is less common in such cases. We present-to the best of our knowledge for the first time-a case of a 54-year old, male, liver cancer sufferer, who under the influence of alcohol, discharged his revolver three times, suffered, among other wounds, a heart-perforating wound, and died after c. 1.5 h, being able to talk until just before he died. Our case underlines the importance of keeping an open critical mind when dealing with multiple-gunshot fatalities, especially when posttraumatic physical activity might be crucial in differentiating homicide from suicide.

Fetal mediastinal tumor of neuroepithelial origin in a case of missed abortion.

We report a rare case of a primitive embryonal tumor discovered in the upper anterior mediastinum during routine autopsy of a macerated fetus at the 18th week of gestation. Our diagnosis was based on autopsy findings and histologic examination, which showed neuroepithelial differentiation of the tumor with frequent ependymal-type rosette formation; no structures of other germ cell layer origin were revealed. Additional positive immunohistochemical staining for CD56, CD57, and neurofilament protein confirmed the neural origin of the tumor, whereas the genetic analysis showed no MYCN gene amplification and no 11q23 deletion or rearrangement of EWS locus (22q12). Our findings exclude the possibility of teratoma and support the diagnosis of undifferentiated primitive tumor of neuroepithelial origin uncommonly located in the anterior mediastinum at the early 2nd trimester of gestation in a case of missed abortion.

Development of fetal intestinal length during 2nd-trimester in normal and pathologic pregnancies.

Linear growth of the human fetal gastrointestinal tract is not often discussed in the literature, and little is known about the effects of chromosomal abnormalities and intrauterine growth restriction (IUGR) on intestinal length, especially during the 2nd trimester. Accurate evaluation of intestinal length and knowledge of normal and reference values are of clinical importance. For example, intestinal resection may be necessary in preterm infants with necrotizing enterocolitis or mid-gut volvulus, and the surgeon should use data to be judicious in the amount removed. Linear measurements are essential in evaluating fetal development ultrasonographically and are an integral part of the postmortem examination. The intestinal lengths of 203 2nd-trimester fetuses and premature infants were measured. Small intestine length (SIL), colon length (CL), total bowel length (TBL; TBL  =  SIL + CL), and the length of the appendix (AL) increased with gestational age. No differences between the genders were observed. Colon length increased secondary to maceration, but no such effects were shown on SIL, TBL, or AL. No differences were shown in relation to IUGR. Small intestine length, CL, and TBL, but not AL, were shorter in fetuses with trisomy 21. Appendix length was not affected by any of the studied factors. We propose that the measurement of the length of the appendix may be used as an additional parameter for the postmortem evaluation of gestational age. Furthermore, its assessment may have potential as an ultrasonographic indicator of gestational age, particularly for the 2nd trimester.

Immunohistochemical expression and prognostic significance of CCND3, MCM2 and MCM7 in Hodgkin lymhoma.

BACKGROUND: Increased proliferation rate may be associated with inferior outcome in patients with Hodgkin lymphoma (HL). Minichromosome maintenance proteins (MCMs) and D-type cyclins are essential for DNA replication. PATIENTS AND METHODS: Lymph node sections from 138 HL patients were immunohistochemically stained for cyclin D3 (CCND3), MCM2 and MCM7 aiming to investigate clinical outcome. RESULTS: Higher MCM2 expression was observed in patients in early stage disease and normal albumin levels; higher MCM7 was found for asymptomatic patients, early stage disease, <5 involved sites, no anemia and normal albumin levels; higher CCND3 expression was found for older patients and normal lactate dehydrogenase (LDH). Univariate analysis revealed no correlation with failure-free (FFS) or overall survival (OS). Multivariate analysis revealed that high MCM7 expression was an adverse prognostic factor for OS, along with older age and advanced stage, while it was of borderline significance for FFS when adjusted for stage. CONCLUSION: These results suggest that MCM7 deserves further evaluation as a potential independent prognostic factor in larger patient series.