SAM domain variants of EPHB4 associated with aberrant signaling are linked to lymphatic-related fetal hydrops and facial dysmorphology.

Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation-Arteriovenous Malformation syndrome 2 and lymphatic-related (non-immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine-kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development.

RASopathies are the most common set of monogenic syndromes identified by exome sequencing for nonimmune hydrops fetalis: A systematic review and meta-analysis.

RASopathies are a group of malformation syndromes known to lead to nonimmune hydrops fetalis (NIHF) in severe presentations. Pathogenic variants can be de novo or parentally inherited. Despite being a known frequent presentation, the fraction of monogenic NIHF cases due to RASopathies is limited in the literature. Also, the specific parental contribution of RASopathies to NIHF is not well described. Our objective was to review pooled exome sequencing (ES) diagnostic yield of RASopathies for NIHF and to determine the parental contribution of RASopathy to NIHF. We performed a systematic review of prenatal ES studies from January 1, 2000 to August 1, 2022. Thirty-six studies met inclusion criteria. Cases with RASopathy gene variants were reviewed. NIHF cases were further classified as isolated or non-isolated. Thirty-six ES studies including 46 pregnancies with NIHF and a diagnosed RASopathy were reviewed. Forty-four diagnostic variants and 2 variants of uncertain significance in 12 RASopathy genes were identified. Expanding on what was previously published, a total of 506 NIHF cases were extracted with 191 cases yielding a positive diagnosis by ES. The overall rate of RASopathy diagnosis in clinically diagnosed NIHF cases was 9% (44/506). The rate of RASopathy diagnosis among NIHF cases with positive genetic diagnosis by ES was 23% (44/191). Of the 46 cases identified, 13 (28%) variants were parentally inherited; specifically, 5/13 (38%) maternal, 3/13 (23%) paternal, 2/13 (15%) biparental, and 3/13 (23%) unspecified. Majority of NIHF cases 29/46 (63%) were isolated. Among NIHF cases with positive ES diagnoses, RASopathy diagnostic yield by ES was 23%. NIHF secondary to RASopathies was parentally inherited in 28% of cases. Most cases of NIHF due to RASopathy were isolated, with no prenatal detection of associated anomalies.

Expansion of the prenatal phenotype of Baraitser-Winter syndrome: Presentation of two cases of multiple congenital anomaly syndrome.

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a variable multiple congenital anomaly condition, typically presenting postnatally with neurocognitive delays, distinctive facial features, cortical brain malformations, and in some, a variety of additional congenital malformations. However, only a few cases have reported the prenatal presentation of this syndrome. Here, we report two cases of BWCFF and their associated prenatal findings. One case presented with non-immune hydrops fetalis and a horseshoe kidney and was found to have a de novo heterozygous variant in ACTB (c.158A>G). The second case presented with gastroschisis, bilateral cleft lip and palate, and oligohydramnios, and was found to harbor a different de novo variant in ACTB (c.826G>A). Limited reports exist describing prenatally identified anomalies that include fetal growth restriction, increased nuchal fold, bilateral hydronephrosis, rocker bottom foot, talipes, cystic hygroma, omphalocele, and hydrops fetalis. In addition, only three of these cases have included detailed prenatal imaging findings. The two prenatal cases presented here demonstrate an expansion of the prenatal phenotype of BWCFF to include gastroschisis, lymphatic involvement, and oligohydramnios, which should each warrant consideration of this diagnosis in the setting of additional anomalies.

Homozygous SPTA1-associated hereditary pyropoikilocytosis presenting as hydrops fetalis.

INTRODUCTION: Hereditary pyropoikilocytosis (HPP) is a heterogeneous inherited disorder of red blood cell (RBC) membrane and cytoskeletal proteins that leads to hemolytic anemia. HPP is characterized by marked poikilocytosis, microspherocytes, RBC fragmentation, and elliptocytes on peripheral blood smear. Mutations in SPTA1 can cause HPP due to a quantitative defect in α-spectrin and can lead to profound fetal anemia and nonimmune hydrops fetalis, which can be managed with intrauterine transfusion. CASE PRESENTATION: We present a case of a 26-year-old G4P2102 woman of Amish-Mennonite ancestry with a pregnancy complicated by fetal homozygosity for an SPTA1 gene variant (SPTA1c.6154delG) as well as severe fetal anemia and hydrops fetalis, which was managed with four intrauterine transfusions between 26 and 30 weeks gestation. Pre-transfusion peripheral smears from fetal blood samples showed RBC morphology consistent with HPP. The neonate had severe hyperbilirubinemia at birth, which has resolved, but remains transfusion-dependent at 6 months of life. DISCUSSION/CONCLUSION: To our knowledge, this is the first report that correlates homozygosity of the SPTA1c.6154delG gene variant with RBC dysmorphology and establishes the diagnosis of HPP.

Disease severity in subsequent pregnancies with RhD immunization: A nationwide cohort.

BACKGROUND AND OBJECTIVES: To evaluate the severity of haemolytic disease of the foetus and newborn (HDFN) in subsequent pregnancies with RhD immunization and to identify predictive factors for severe disease. MATERIALS AND METHODS: Nationwide prospective cohort study, including all pregnant women with RhD antibodies. All women with at least two pregnancies with RhD antibodies and RhD-positive foetuses were selected. The main outcome measure was the severity of HDFN in the first and subsequent pregnancy at risk. A subgroup analysis was performed for the group of women where RhD antibodies developed after giving birth to an RhD-positive child and thus after receiving anti-D at least twice (group A) or during the first pregnancy at risk for immunization (group B). RESULTS: Sixty-two RhD immunized women with a total of 150 RhD-positive children were included. The severity of HDFN increased for the whole group significantly in the subsequent pregnancy (p < 0.001), although it remained equal or even decreased in 44% of women. When antibodies were already detected at first trimester screening in the first immunized pregnancy, after giving birth to an RhD-positive child (group A), severe HDFN in the next pregnancy was uncommon (22%). Especially when no therapy or only non-intensive phototherapy was indicated during the first immunized pregnancy (6%) or if the antibody-dependent cell-mediated cytotoxicity result remained <10%. Contrarily, women with a negative first trimester screening and RhD antibodies detected later during the first pregnancy of an RhD-positive child (group B), often before they had ever received anti-D prophylaxis, were most prone for severe disease in a subsequent pregnancy (48%). CONCLUSION: RhD-mediated HDFN in a subsequent pregnancy is generally more severe than in the first pregnancy at risk and can be estimated using moment of antibody detection and severity in the first immunized pregnancy. Women developing antibodies in their first pregnancy of an RhD-positive child are at highest risk of severe disease in the next pregnancy.

Correlation of endolymphatic hydrops and perilymphatic enhancement with the clinical features of Ménière's disease.

OBJECTIVES: To use three-dimensional real inversion recovery (3D-real IR) MRI to investigate correlations between endolymphatic hydrops (EH) grades or the degree of perilymphatic enhancement (PE) and clinical features of Ménière's disease (MD), as previous findings have been inconsistent. METHODS: A total of 273 consecutive patients with definite unilateral MD were retrospectively enrolled from September 2020 to October 2021. All patients underwent 3D-real IR and 3D-T2WI 6 h after intravenous gadolinium injection. MD-related symptom duration and vertigo frequency were recorded. EH grades were evaluated, the signal intensity ratio (SIR) was measured, and correlations between clinical features and EH, PE were assessed respectively. RESULTS: The study included 123 males and 150 females, with a mean age of 53.0 years. A longer duration of vertigo was associated with higher cochlear EH grades, whereas the opposite was true for the duration of aural fullness. A longer time since vertigo onset was associated with higher vestibular EH grades; the opposite was true for the duration of individual vertigo attacks. The multiple regression analysis revealed that age, tinnitus duration, and vestibular EH were risk factors for SIR. Furthermore, the low-frequency hearing threshold (HT) was a risk factor for cochlear and vestibular EH, and the SIR. CONCLUSION: The EH grade and SIR (an indicator for the quantitative evaluation of PE) were correlated with clinical features and HT of MD; thus, imaging can be a valuable tool in planning individualised treatment. CLINICAL RELEVANCE STATEMENT: This study revealed that the grade of endolymphatic hydrops and degree of perilymphatic enhancement positively correlates with the length of time since onset of clinical symptoms and hearing thresholds in patients with Ménière's disease, facilitating the tailored treatment. KEY POINTS: • Relationships between 3-dimensional real inversion recovery features and clinical symptoms in Ménière's disease are unknown. • Symptom duration and hearing thresholds correlated with endolymphatic hydrops grades and degree of perilymphatic enhancement. • MRI features correlate with MD severity; thus, imaging is valuable for planning tailored treatment.

An unenhanced 3D-FLAIR sequence using long repetition time and constant flip angle to image endolymphatic hydrops.

OBJECTIVES: To evaluate a three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequence using a long repetition time (TR) and constant flip angle (CFA) in differentiating between perilymph and endolymph in a phantom study, and unenhanced endolymphatic hydrops (EH) imaging in a patient study. METHODS: Three solutions in similar ion and protein concentrations with endolymph, perilymph, and cerebrospinal fluid were prepared for variable flip angle (VFA) 3D-FLAIR (TR 10,000 ms) and CFA (120°) 3D-FLAIR using different TR (10,000, 16,000, and 20,000 ms). Fifty-two patients with probable or definite Meniere's disease received unenhanced CFA (120°) 3D-FLAIR using a long TR (20,000 ms) and 4-h-delay enhanced CFA (120°) 3D-FLAIR (TR 16,000 ms). Image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of them were compared. Agreement in the evaluation of the EH degree between them was analyzed. RESULTS: In the phantom study, CNRs between perilymphatic and endolymphatic samples of VFA 3D-FLAIR (TR 10,000 ms) and CFA 3D-FLAIR (TR 10,000, 16,000, and 20,000 ms) were 6.66 ± 1.30, 17.90 ± 2.76, 23.87 ± 3.09, and 28.22 ± 3.15 (p < 0.001). In patient study, average score (3.65 ± 0.48 vs. 4.19 ± 0.40), SNR (34.56 ± 9.80 vs. 51.40 ± 11.27), and CNR (30.66 ± 10.55 vs. 45.08 ± 12.27) of unenhanced 3D-FLAIR were lower than enhanced 3D-FLAIR (p < 0.001). Evaluations of the two sequences showed excellent agreement in the cochlear and vestibule (Kappa value: 0.898 and 0.909). CONCLUSIONS: The CFA 3D-FLAIR sequence using a long TR could be used in unenhanced EH imaging with high accuracy. CLINICAL RELEVANCE STATEMENT: Unenhanced imaging of endolymphatic hydrops is valuable in the diagnosis and follow-up of patients, especially those who cannot receive contrast-enhanced MRI. KEY POINTS: Ion and protein concentration differences can be utilized in differentiating endolymph and perilymph on MRI. Endolymphatic and perilymphatic samples could be differentiated in vitro on this 3D-FLAIR sequence. This unenhanced 3D-FLAIR sequence is in excellent agreement with the enhanced constant flip angle 3D-FLAIR sequence.

A novel radiomics nomogram based on T2-sampling perfection with application-optimized contrasts using different flip-angle evolutions (SPACE) images for predicting cochlear and vestibular endolymphatic hydrops in Meniere's disease patients.

OBJECTIVES: To construct and validate a radiomics nomogram based on T2-sampling perfection with application-optimized contrasts using different flip-angle evolutions (SPACE) images for predicting cochlear and vestibular endolymphatic hydrops (EH) in Meniere's disease patients. METHODS: A total of 156 patients (312 affected ears) with bilateral definite Meniere's disease who underwent delayed enhancement MRI scans were enrolled in this study. All ears of the patients were divided into a training set (n = 218) and an internal validation set (n = 94). A radiomics nomogram was constructed from radiomics features extracted from the T2-SPACE images, and a radiomics score was calculated. Performance of the radiomics nomogram was assessed using receiver operating characteristics analysis. RESULTS: Five features were selected for the construction of the cochlear radiomics nomogram, and seven features for the vestibular radiomics nomogram. The radiomics nomograms exhibited robust performance in differentiating between EH-positive and EH-negative statuses in both training and validation cohorts, with the area under the receiver operating characteristics curve values for cochlear and vestibular radiomic nomograms being 0.703 and 0.728 in the training set, and 0.718 and 0.701 in the validation set, respectively. CONCLUSION: The novel radiomics nomograms based on T2-SPACE images were successfully constructed to predict cochlear and vestibular EH in Meniere's disease. The models showed a solid and superior performance and may play an important role in the EH prediction. CLINICAL RELEVANCE STATEMENT: We constructed a novel radiomics nomogram, which can be a very useful tool for predicting cochlear and vestibular endolymphatic hydrops in Meniere's disease patients. KEY POINTS: • This is the first T2-SPACE-based nomogram to predict cochlear and vestibular endolymphatic hydrops. • The nomogram is of great value to patients who are unable to undergo delayed enhancement MRI scans.

Assessing the optimal MRI descriptors to diagnose Ménière's disease and the added value of analysing the vestibular aqueduct.

OBJECTIVES: To evaluate the diagnostic performance and reliability of MRI descriptors used for the detection of Ménière's disease (MD) on delayed post-gadolinium MRI. To determine which combination of descriptors should be optimally applied and whether analysis of the vestibular aqueduct (VA) contributes to the diagnosis. MATERIALS AND METHODS: This retrospective single centre case-control study evaluated delayed post-gadolinium MRI of patients with Ménièriform symptoms examined consecutively between Dec 2017 and March 2023. Two observers evaluated 17 MRI descriptors of MD and quantified perilymphatic enhancement (PLE) in the cochlea. Definite MD ears according to the 2015 Barany Society criteria were compared to control ears. Cohen's kappa and diagnostic odds ratio (DORs) were calculated for each descriptor. Forward stepwise logistic regression determined which combination of MRI descriptors would best predict MD ears, and the area under the receiver operating characteristic curve for this model was measured. RESULTS: A total of 227 patients (mean age 48.3 ± 14.6, 99 men) with 96 definite MD and 78 control ears were evaluated. The presence of saccular abnormality (absent, as large as or confluent with the utricle) performed best with a DOR of 292.6 (95% confidence interval (CI), 38.305-2235.058). All VA descriptors demonstrated excellent reliability and with DORs of 7.761 (95% CI, 3.517-17.125) to 18.1 (95% CI, 8.445-39.170). Combining these saccular abnormalities with asymmetric cochlear PLE and an incompletely visualised VA correctly classified 90.2% of cases (sensitivity 84.4%, specificity 97.4%, AUC 0.938). CONCLUSION: Either absent, enlarged or confluent saccules are the best predictors of MD. Incomplete visualisation of the VA adds value to the diagnosis. CLINICAL RELEVANCE STATEMENT: A number of different MRI descriptors have been proposed for the diagnosis of Ménière's disease, but by establishing the optimally performing MRI features and highlighting new useful descriptors, there is an opportunity to improve the diagnostic performance of Ménière's disease imaging. KEY POINTS: • A comprehensive range of existing and novel vestibular aqueduct delayed post-gadolinium MRI descriptors were compared for their diagnostic performance in Ménière's disease. • Saccular abnormality (absent, confluent with or larger than the utricle) is a reliable descriptor and is the optimal individual MRI predictor of Ménière's disease. • The presence of this saccule descriptor or asymmetric perilymphatic enhancement and incomplete vestibular aqueduct visualisation will optimise the MRI diagnosis of Ménière's disease.

Novel Clinical Algorithm for Prenatal Monitoring of Congenital Lung Malformations.

INTRODUCTION: Congenital lung malformations (CLMs) are readily identified early in pregnancy with a variable natural history. Monitoring for lesion size and mediastinal shift (MS) is recommended following diagnosis. The purpose of this study is to propose a risk-stratified clinical algorithm for prenatal monitoring of CLM. METHODS: After ethical approval, all fetuses with CLMs evaluated at our fetal center from January 2015 to June 2022 were retrospectively reviewed. Patient demographics, imaging characteristics, and fetal interventions were collected. Lesions were stratified by congenital lung malformation volume ratio (CVR) and the presence of MS. Descriptive statistics and receiver operating characteristic curves were employed in the analysis. RESULTS: We analyzed 111 patients with a mean of 23.4 wk gestational age, a median CVR of 0.5 (interquartile range, 0.3-1.2), and MS in 76 of 111(68%) patients on initial evaluation. Among low-risk patients (CVR ≤1.1), 96% remained low-risk on final evaluation. No patients transitioned from low to high risk during the growth period. Patients with CVR >1.1 often had persistent MS (P < 0.001). Hydrops (5/111, 5%) and fetal intervention (4/111, 4%) only occurred in patients with CVR >1.1 (P < 0.001, P = 0.002) and MS (P = 0.144, P = 0.214). On receiver operating characteristic curve analysis, initial CVR >1.1 had 100% sensitivity and negative predictive value for hydrops and fetal intervention. CONCLUSIONS: CLMs with initial CVR ≤1.1 are low risk for hydrops and fetal intervention. We propose a risk-stratified algorithm for the monitoring of CLM during the growth period based on CVR. While our experience suggests that patients with CLM and MS are at higher risk, the current subjective assessment of MS is not adequately predictive. Incorporating an MS grading system may further refine risk stratification in the management of CLM.

Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.

OBJECTIVE: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. METHODS: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. RESULTS: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. CONCLUSIONS: Mitochondrial complex-I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

The Connection Between Anatomical Substrate and Clinical Severity in Fetal Ebstein Anomaly.

Ebstein anomaly (EA) is a rare congenital heart defect characterized by abnormal development of the tricuspid valve (TV) and right ventricular myocardium. This study documents 2 dramatic cases of fetal EA characterized by hydrops and cardiomegaly, leading to intrauterine or early neonatal death. These clinical outcomes were associated with morphological abnormalities including severe tricuspid regurgitation, unguarded TV orifice, pulmonary atresia, and flattened right ventricular myocardium. This study highlights that these adverse anatomical features may result in unfavorable clinical outcomes in fetal EA. While timely identification of such features by prenatal ultrasound is crucial for providing accurate prognostic stratification and guiding treatment decisions, fetopsy may be necessary to discern EA among the spectrum of right-heart anomalies.

Hydrops fetalis caused by a complex congenital heart defect with concurrent hypoplasia of pulmonary blood vessels and lungs visualized by micro-CT in a French Bulldog.

BACKGROUND: Hydrops fetalis (HF) is fluid accumulation in fetus body cavities and subcutaneous tissue. The condition has been described in various farm and companion animal species, including dogs. Most of cases result from a heart defect. Exact nature of this defect is rarely clarified. CASE PRESENTATION: A newborn, male French bulldog puppy with severe HF underwent a full anatomopathological examination to diagnose the primary cause of HF. Based on the anatomopathological examination, fetal ultrasound, and micro-computed tomography, transposition of the great arteries with hypoplasia of the ascending aorta, aortic arch interruption, ostium secundum atrial septal defect, severe tricuspid valve dysplasia, as well as hypoplasia of pulmonary vessels and lungs were diagnosed. CONCLUSIONS: This is the first report of HF caused by severe, complex congenital heart defects with concurrent pulmonary vessel and lung hypoplasia.

A singleton pregnancy with placental chorioangioma and hydrops fetalis complicated with mirror syndrome and ritodrine-induced side effects: a case report.

BACKGROUND: Ritodrine hydrochloride is a widely used beta-adrenergic agonist used to stop preterm labor in Taiwan. Many side effects causing maternal morbidity and mortality have been reported. We report a case complicated with ritodrine-induced side effects and mirror syndrome that was associated with placental chorioangioma. CASE PRESENTATION: A 36-year-old singleton pregnant woman at 25 6/7 weeks of gestation, with an undiagnosed placental chorioangioma, underwent tocolysis due to preterm uterine contractions. Her clinical condition deteriorated, attributed to mirror syndrome and adverse events induced by ritodrine. An emergency cesarean section was performed at 27 1/7 weeks of gestation, delivering an infant with generalized subcutaneous edema. A placental tumor measuring 8.5 cm was discovered during the operation, and pathology confirmed chorioangioma. Gradual improvement in her symptoms and laboratory data was observed during the postpartum period. Identifying mirror syndrome and ritodrine-induced side effects poses challenges. Therefore, this case is educational and warrants discussion. CONCLUSION: Our case demonstrates mirror syndrome induced by chorioangioma, which is rare, and ritodrine-induced side effects. The cessation of intravenous ritodrine and delivery are the best methods to treat maternal critical status due to fluid overload.

Fetal bradyarrhythmias: classification, monitoring and outcomes of 40 cases at a single center.

OBJECTIVES: To assess congenital fetal bradyarrhythmias with regard to etiological causes, features, risk factors, and prognosis. METHODS: This retrospective study involved fetuses with fetal bradyarrhythmias. All fetuses were evaluated by ultrasonography. Parental ECGs and family histories were obtained, and maternal autoantibodies were measured. Gestational age at diagnosis, fetal atrial and ventricular rates at presentation, type of bradyarrhythmias, the presence or absence of a congenital heart defect (CHD), fetal hydrops, fetal myocardial dysfunction, extra-cardiac abnormalities, maternal autoimmune diseases, maternal autoantibodies as well as prenatal treatment, and neonatal outcome were collected. RESULTS: Of the 40 fetuses included in the study, 11 had maternal rheumatologic disease, 16 had complex cardiac anomalies such as left and right isomerism. Fetuses with CHD significantly differed from those without CHD with increased rates of extra-cardiac anomalies, hydrops, fetal deaths and shorter survival after 28 days (p<0.05). Survival was significantly better in fetuses with maternal rheumatic disease as compared with those with no maternal rheumatic disease (p<0.05). Maternal anti-arrhythmic therapy was administered in 11 fetuses. In utero maternal treatment resulted in no significant difference in the course of arrhythmia or hydrops in fetuses with or without maternal rheumatic disease (p<0.05). In regression analysis, the absence of fetal hydrops was the only independent factor associated with survival (p=0.04). CONCLUSIONS: The course of bradyarrhythmias, along with survival, seems to be more favorable in fetuses with maternal rheumatic disease than in those with CHD, especially left and right isomerism. Hydrops was the sole independent factor associated with poor survival.

Congenital metastatic neuroblastoma with placental involvement as a rare cause of non-immune fetal hydrops.

Non-immune hydrops fetalis represents the end-stage status of a variety of diseases, including metastatic tumors. We report a case of non-immune hydrops fetalis associated with multiple disseminated echogenic nodular lesions detected by ultrasound and confirmed by magnetic resonance. Cordocentesis demonstrated anemia and thrombopenia. Differential diagnosis included histiocytosis X, acute leukemia or metastatic disease. A stillbirth was diagnosed at week 25 + 6. The autopsy revealed hydrops fetalis, a right adrenal gland mass, multiple disseminated nodules histologically composed of small round blue cells positive for synaptophysin, and placental involvement, concordant findings with congenital undifferentiated neuroblastoma Stage M. No chromosomal abnormalities were associated, nor amplification abnormalities in MYCN and ALK genes. Metastatic neuroblastoma should be considered in the differential diagnosis of non-immune hydrops fetalis associated with multiple nodular lesions.

Fetal NT-proBNP levels and their course in severe anemia during intrauterine treatment.

PURPOSE: In adults and fetuses, N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a marker of cardiac failure and myocardial remodelling. We examined the effect of anemia and intrauterine transfusion (IUT) on NT-proBNP concentrations in fetuses with anemia and established gestational age-dependent reference values of a control group. METHODS: We analyzed NT-proBNP levels in anemic fetuses that underwent serial intrauterine transfusions (IUT), focusing on different causes and severity of anemia and comparing the results to a non-anemic control group. RESULTS: In the control group, the average NT-proBNP concentration was 1339 ± 639 pg/ml, decreasing significantly with increasing gestational age (R = - 74.04, T = - 3.65, p = 0.001). Subjects had significantly higher NT-proBNP concentrations before initiation of IUT therapy (p < 0.001), showing fetuses with parvovirus B19 (PVB19) infection having the highest concentrations. Hydropic fetuses also showed an increased NT-proBNP concentration compared to non-hydropic fetuses (p < 0.001). During the course of therapy, NT-proBNP concentration before subsequent IUT decreased significantly from pathologically high levels, while MoM-Hb and MoM-MCA-PSV remained pathological. CONCLUSION: NT-pro BNP levels in non-anemic fetuses are higher than in postnatal life, decreasing with ongoing pregnancy. Anemia is a hyperdynamic state and its severity correlates with circulating NT-proBNP levels. Highest concentrations occur in fetuses with hydrops and with PVB19 infection, respectively. Treatment by IUT leads to a normalisation of NT-proBNP concentrations, so the measurement of its levels may be useful in therapy monitoring.

Perinatal outcomes following early prenatal diagnosis: insights from a single-center experience with Ebstein anomaly and tricuspid valve dysplasia.

PURPOSE: Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) represent uncommon congenital malformations of the tricuspid valve. The purpose of this study is to report on current perinatal outcomes of EA/TVD in our center and to investigate clinical and fetal echocardiographic predictors of perinatal mortality. METHODS AND RESULTS: We performed a retrospective study among fetuses diagnosed from January 2014 to December 2023. Clinical and echocardiographic data were obtained from hospital records of Research and Education Hospital. The primary outcome was perinatal mortality. Of 21 fetuses diagnosed, there were 1 lost to follow-up, 1 termination, and 7 demises. In the live-born cohort of 12 live-born patients, 2 died before discharge, yielding an overall perinatal mortality of 50%. The median gestational age at diagnosis was 23 for non-survivors and 24 weeks for survivors. Birth weight was lower in non-survivors (2430 g vs 2990 g). Tricuspid insufficiency severity varied insignificantly. Non-survivors exhibited higher rates of hydrops, functional atresia, and absent antegrade flow (p < 0.05). Two infants with severe tricuspid insufficiency and congenital abnormalities died postnatally. The limited dataset enables further analysis for a predictive model. Notably, all non-survivors displayed hydrops, functional atresia, and absent antegrade flow, hindering definitive determination of the most impactful parameter on survival estimation. CONCLUSION: Perinatal mortality remains notably elevated in fetuses with EA/TVD. The individuals at the highest risk are those with antegrade flow loss and functional atresia of pulmonary valve, this high-risk subgroup could benefit from targeted interventions, such as novel prenatal therapies or a more comprehensive perinatal approach involving optimized timing of delivery and postnatal interventional strategies.

Blood-labyrinth barrier breakdown in Meniere's disease.

OBJECTIVE: We compared the signal intensity ratio (SIR) of the cochlear basal turn between Meniere's disease and healthy controls to investigate potential damage of the blood-labyrinth barrier in Meniere's disease. METHODS: Thirty patients diagnosed with unilateral definite Meniere's disease and 24 healthy controls were enrolled. 3D-FLAIR scan was conducted to assess the grades of endolymphatic hydrops in Meniere's patients while measuring the SIR of cochlear basal turns in both groups. The differences of bilateral SIR between Meniere's disease and healthy control were compared, and the correlation between the SIR on affected ear in Meniere's disease and the grades of cochlear and vestibular hydrops were analyzed. RESULTS: SIR of affected ear in Meniere's disease exhibited significant increase compared to that of unaffected ear. No significant difference was observed in SIR between the two ears in the healthy control. Furthermore, the SIR of unaffected side in Meniere's disease was higher than that of both ears in healthy controls. The SIR in affected ear of Meniere's disease exhibited positive correlation with hydrops in both cochlea and vestibula. CONCLUSION: The permeability of blood-labyrinth barrier is increased in Meniere's disease, in combination with the typical criteria of Meniere's disease it may be a good biological marker. Destruction of blood-labyrinth barrier may be one of the causes of endolymphatic hydrops in Meniere's disease.

Impact of endolymphatic hydrops on the function of the horizontal canal during caloric stimulation in Ménière's disease.

PURPOSE: When a dizzy patient with episodic vertigo has an abnormal caloric and a normal video head impulse test (vHIT), this caloric-vHIT dissociation provides vital information for a diagnosis of Ménière's disease (MD). Endolymphatic hydrops (EH), a histological marker of MD, is hypothesized to be involved in the caloric-vHIT dissociation in MD through hydropic duct distension of the horizontal semicircular canal (SC). This study was designed to determine the impact of EH on the function of horizontal SC during caloric stimulation. METHODS: Caloric test and vHIT were used to evaluate the function of horizontal SC every six months, annual magnetic resonance imaging (MRI) was used to evaluate the degree of EH size in the vestibule, and monthly vertigo and hearing evaluation was done for 12 months. EH shrinkage was defined as the size change of vestibular EH from significant to none. RESULTS: Among 133 MD patients evaluated for eligibility, 67 patients with caloric-vHIT dissociation entered the study. Fifteen participants had EH shrinkage (G-I), while 52 participants had no remarkable EH change (G-II). Average values (IQR) of the maximum slow phase velocity in G-I and G-II were 29.6 (13.0-34.0) and 25.9 (17.3-31.3), respectively, at baseline, 26.1 (9.0-38.0) and 23.6 (18.0-28.3) at 12 months. Two-factor repeated-measures ANOVA showed no significant differences between the groups (P = 0.486). The values of vestibulo-ocular reflex gain of the horizontal SC in G-I and G-II remained above 0.8 during the study period. CONCLUSIONS: EH detected by MRI shows limited correlation with caloric stimulation results.