De novo heterozygous missense variants in CELSR1 as cause of fetal pleural effusions and progressive fetal hydrops.

Fetal hydrops as detected by prenatal ultrasound usually carries a poor prognosis depending on the underlying aetiology. We describe the prenatal and postnatal clinical course of two unrelated female probands in whom de novo heterozygous missense variants in the planar cell polarity gene CELSR1 were detected using exome sequencing. Using several in vitro assays, we show that the CELSR1 p.(Cys1318Tyr) variant disrupted the subcellular localisation, affected cell-cell junction, impaired planar cell polarity signalling and lowered proliferation rate. These observations suggest that deleterious rare CELSR1 variants could be a possible cause of fetal hydrops.

Prognostic accuracy of factors associated with poor outcome in prenatally diagnosed sacrococcygeal teratoma: A systematic review and meta-analysis.

Several factors associated with poor outcome in patients with prenatally diagnosed sacrococcygeal teratoma (SCT) have been found. However, the prognostic accuracy of these factors has not been well established. Therefore, we aimed to systematically review the prognostic accuracy of factors associated with poor outcome in these patients. We queried Search Premier, COCHRANE Library, EMCARE, EMBASE, PubMed, ScienceDirect, and Web of Science databases to identify studies regarding patients with prenatally diagnosed SCT. Poor outcome was defined as termination of pregnancy (TOP), intrauterine fetal death (IUFD), or perinatal death. We estimated the odds ratio of factors associated with poor outcome. Eleven studies (447 patients) were included. Overall mortality, including TOP, was 34.9%. Factors associated with poor outcome in fetuses with prenatally diagnosed SCT were cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, and placentomegaly. A tumor volume to fetal weight ratio (TFR) of >0.12 before a gestational age of 24 weeks is predictive of poor outcome. The prognostic accuracy of factors associated with poor outcome in fetuses prenatally diagnosed with SCT seems promising. Factors associated with cardiac failure such as cardiomegaly, hypervascular tumor, solid tumor morphology, fetal hydrops, placentomegaly, and TFR >0.12 were found to be predictive of poor outcome.

Mirror syndrome: a systematic literature review.

OBJECTIVE: This study aimed to review the diagnostic criteria for mirror syndrome and describe its clinical presentation. DATA SOURCES: Databases from PubMed, Scopus, Cochrane Library, ClinicalTrials.gov, and CINAHL were inquired for case series containing ≥2 cases of mirror syndrome from inception to February 2022. STUDY ELIGIBILITY CRITERIA: Studies were included if they reported ≥2 cases of mirror syndrome and included case reports, case series, cohort studies, and case-control studies. STUDY APPRAISAL AND SYNTHESIS METHODS: The studies' quality and risk of bias were independently assessed. Data were tabulated using Microsoft Excel and summarized using narrative review and descriptive statistics. This systematic review was conducted according to the Preferred Reporting Item for Systematic Reviews and Meta-Analyses statement. All eligible references were assessed. Screening of records and data extraction were independently performed, and a third author resolved disagreements. RESULTS: Of 13 citations, 12 studies (n=82) reported diagnostic criteria for mirror syndrome: maternal edema (11/12), fetal hydrops (9/12), placental edema (6/12), placentomegaly (5/12), and preeclampsia (2/12); 12 studies (n=82) described the clinical presentation of mirror syndrome as maternal edema (62.2%), hypoalbuminemia (54.9%), anemia (39.0%), and new-onset hypertension (39.0%); 4 studies (n=36) reported that hemodilution was present in all patients; 8 studies (n=36) reported the etiology of fetal hydrops, with the most common being structural cardiac malformations (19.4%), alpha thalassemia (19.4%), Rh isoimmunization (13.9%), and nonimmune hydrops fetalis (13.9%); and 6 studies (n=47) reported maternal complications, 89.4% of which were major: postpartum hemorrhage (44.7%), hemorrhage requiring blood transfusion (19.1%), intensive care unit admission (12.8%), heart failure (10.6%), pulmonary edema (8.5%), and renal dysfunction (8.5%). In 39 cases, the reported fetal outcomes were stillbirth (66.6%) and neonatal or infant death (25.6%). The overall survival rate among continued pregnancies was 7.7%. CONCLUSION: The diagnostic criteria of mirror syndrome differed considerably among studies. Mirror syndrome clinical presentation overlapped with preeclampsia. Only 4 studies discussed hemodilution. Significant maternal morbidity and fetal mortality were associated with mirror syndrome. Further research is warranted to elucidate the pathogenesis of mirror syndrome to better guide clinicians in identifying and managing the condition.

Diagnosis and clinical management of red cell membrane disorders.

Heterogeneous red blood cell (RBC) membrane disorders and hydration defects often present with the common clinical findings of hemolytic anemia, but they may require substantially different management, based on their pathophysiology. An accurate and timely diagnosis is essential to avoid inappropriate interventions and prevent complications. Advances in genetic testing availability within the last decade, combined with extensive foundational knowledge on RBC membrane structure and function, now facilitate the correct diagnosis in patients with a variety of hereditary hemolytic anemias (HHAs). Studies in patient cohorts with well-defined genetic diagnoses have revealed complications such as iron overload in hereditary xerocytosis, which is amenable to monitoring, prevention, and treatment, and demonstrated that splenectomy is not always an effective or safe treatment for any patient with HHA. However, a multitude of variants of unknown clinical significance have been discovered by genetic evaluation, requiring interpretation by thorough phenotypic assessment in clinical and/or research laboratories. Here we discuss genotype-phenotype correlations and corresponding clinical management in patients with RBC membranopathies and propose an algorithm for the laboratory workup of patients presenting with symptoms and signs of hemolytic anemia, with a clinical case that exemplifies such a workup.

An Atypical Case of Congenital Erythropoietic Porphyria.

Congenital erythropoietic porphyria (CEP, OMIM #606938) is a severe autosomal recessive inborn error of heme biosynthesis. This rare panethnic disease is due to a deficiency of uroporphyrinogen III synthase (or cosynthase). Subsequently, its substrate, the hydroxymethylbilane is subsequently converted into uroporphyrinogen I in a non-enzymatic manner. Of note, uroporphyrinogen I cannot be metabolized into heme and its accumulation in red blood cells results in intramedullary and intravascular hemolysis. The related clinical symptoms occur most frequently during antenatal or neonatal periods but may also appear in late adulthood. The main antenatal clinical presentation is a non-immune hydrops fetalis. We report here two cases of antenatal CEP deficiency and a review of the reported cases in the literature.

Clinical characteristics and risk factors of mirror syndrome: a retrospective case-control study.

BACKGROUND: Mirror syndrome (MS) is a rare obstetric disorder complicated with high maternal morbidity and fetal mortality. MS is often misdiagnosed or underdiagnosed due to the low incidence and lack of awareness of its diverse features. This study aimed to summarise the etiology, clinical characteristics, and risk factors of MS among mothers with fetal hydrops. METHODS: This retrospective case-control study included 37 pregnant women with fetal hydrops in the second and third trimesters from 58,428 deliveries performed at the Third Affiliated Hospital of Sun Yat-Sen University between January 2012 and December 2020. Cases were categorized as MS and non-MS according to the presence or absence of maternal mirroring symptoms. Binary logistic regression was performed for analysis. RESULTS: Fourteen women developed MS with an overall incidence of 0.024% (14/58,428) and 37.8% (14/37) in the fetal hydrops cases. Among the 11 MS cases with known associated etiologies, seven had alpha thalassemia major. Onset of fetal hydrops was later (27.8 vs. 23.0 weeks) and the rate of placental thickening was higher (85.7% vs. 34.8%) in the MS group than in the non-MS group (P < 0.05). Regarding maternal characteristics, the MS group had higher maternal morbidity (85.7% vs. 8.7%), more weight gain (9.0 vs. 5.5 kg), higher rates of hypertension (35.7 vs. 0%) and proteinuria (64.3% vs. 4.3%), and lower levels of hemoglobin (88 vs. 105 g/L) and serum albumin (25.8 vs. 35.0 g/L) than the non-MS group (P < 0.05). Logistic regression analysis showed that onset of fetal hydrops at ≥24 weeks and placental thickening were associated with the risk of MS among fetal hydrops cases (OR 15.83, 95% CI 1.56-160.10 and OR 8.63, 95% CI 1.29-57.72, respectively). CONCLUSIONS: MS is relatively common among fetal hydrops cases in the late second and third trimesters, and alpha thalassemia major is the main etiology for fetal hydrops and also MS in this population. Complicated with high maternal morbidity, the key maternal features of MS include more weight gain, hemodilution, and hypertension. Among those with fetal hydrops, the onset time of ≥24 weeks and placental thickening are risk factors for MS.

Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients.

Hereditary erythrocytes disorders include a large group of conditions with heterogeneous molecular bases and phenotypes. We analyzed here a case series of 155 consecutive patients with clinical suspicion of hereditary erythrocyte defects referred to the Medical Genetics Unit from 2018 to 2020. All of the cases followed a diagnostic workflow based on a targeted next-generation sequencing panel of 86 genes causative of hereditary red blood cell defects. We obtained an overall diagnostic yield of 84% of the tested patients. Monogenic inheritance was seen for 69% (107/155), and multi-locus inheritance for 15% (23/155). PIEZO1 and SPTA1 were the most mutated loci. Accordingly, 16/23 patients with multi-locus inheritance showed dual molecular diagnosis of dehydrated hereditary stomatocytosis/xerocytosis and hereditary spherocytosis. These dual inheritance cases were fully characterized and were clinically indistinguishable from patients with hereditary spherocytosis. Additionally, their ektacytometry curves highlighted alterations of dual inheritance patients compared to both dehydrated hereditary stomatocytosis and hereditary spherocytosis. Our findings expand the genotypic spectrum of red blood cell disorders and indicate that multi-locus inheritance should be considered for analysis and counseling of these patients. Of note, the genetic testing was crucial for diagnosis of patients with a complex mode of inheritance.

Manifestations of thrombospondin type-1 domain-containing protein 1 gene mutation in an extremely premature infant with nonimmune hydrops fetalis.

Homozygous variants of the thrombospondin type-1 domain-containing 1 (THSD1) gene have recently been associated with nonimmune hydrops fetalis (NIHF; OMIM 236750) in infants, as well as with congenital heart disease, hemangiomas, prematurity, and embryonic lethality. Here, we report the first case of a biallelic variant of THSD1 in an extremely premature infant (25 weeks) who suffered from NIHF (eventually resolved) and other manifestations of the THSD1 variant, such as congenital heart disease and hemangiomas. Her prematurity was complicated by pulmonary hypertension and chronic lung disease. This case indicates that biallelic homozygous variants of THSD1 are among the likely causes of NIHF. Information from this case report will aid in determining the prognosis of NIHF caused by such variants in premature infants.

Lymphedema distichiasis syndrome may be caused by FOXC2 promoter-enhancer dissociation and disruption of a topological associated domain.

Lymphedema distichiasis syndrome (LDS) is a rare autosomal dominant condition characterized by lower limb lymphedema, distichiasis, and variable additional features. LDS is usually caused by heterozygous sequence variants in the FOXC2 gene located at 16q24, but in one previous instance LDS has resulted from a balanced reciprocal translocation with a breakpoint at 16q24, 120 kb distal to the FOXC2 gene suggesting a position effect. Here, we describe a second family with LDS caused by a translocation involving 16q24. The family were ascertained after detection of a paternally inherited balanced reciprocal translocation t(16;22)(q24;q13.1) in a pregnancy complicated by severe fetal hydrops. There was a past history of multiple miscarriages in the father's family, and a personal and family history of lymphedema and distichiasis, consistent with the diagnosis of LDS. Using whole genome amplified DNA from single sperm of the male proband, bead array analysis demonstrated that the FOXC2 gene was intact and the chromosome 16 breakpoint mapped to the same region 120Kb distal to the FOXC2 gene. This case highlights the clinical consequences that can arise from a translocation of genomic material without dosage imbalance, and that it is increasingly feasible to predict and characterize possible effects with improved access to molecular techniques.

Clinical characteristics of mirror syndrome: a retrospective study of 16 cases.

The exact prevalence of mirror syndrome remains unclear, and the precise clinical features need to be disclosed. We retrospectively reviewed 85 cases of foetal hydrops from a total of 98,484 deliveries. Of these 16 showed mirror syndrome, while 69 did not. The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Maternal symptoms of mirror syndrome included anaemia (n = 15), hypertension (n = 7), proteinuria (n = 8), pulmonary oedema (n = 3), cardiac failure (n = 2) and HELLP syndrome (n = 2). Placental thickness, placental weight and amniotic fluid index were significantly different between the groups. In the mirror syndrome group, uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher (p < .05), whereas haemoglobin, serum albumin levels, haematocrit value and platelet count were significantly lower (p < .05). Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.Impact statementWhat is already known on this subject? As mirror syndrome is uncommon and under-diagnosed, its exact incidence is not yet clear, and most publications are case reports or reviews of case reports.What the results of this study add? The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Pregnant women who develop mirror syndrome may show severe complications of pregnancy. Attention should be paid to the further progress of the condition. Placental thickness, placental weight and amniotic fluid index were significantly different between those with mirror syndrome and those without. In the mirror syndrome group, the uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher (p < .05), whereas haemoglobin level, haematocrit value, platelet count and serum albumin level were significantly lower (p < .05).What the implications are of these findings for clinical practice and/or further research? Mirror syndrome is not rare among patients with foetal hydrops. Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.

Case report of neonatal ductus venosus atresia.

INTRODUCTION: In the fetus, the ductus venosus (DV) connects the umbilical vein and the portal veins to the inferior vena cava in order to bypass the high-resistance hepatic vascular network. Via the Eustachian valve, the DV directs umbilical venous blood with the highest oxygen content preferentially towards the myocardium and the brain. An absence (agenesis) or a secondary obliteration of an initially normally developed DV (atresia) is associated with various shunt types and may lead to severe hydrops. CASE REPORT: A routine check-up of a healthy 34-year-old woman at 27 5/7 wks GA revealed a severe hydrops fetalis with pleural effusions and ascites. After birth at 28 0/7 wks GA, the bilateral pleural effusions needed drainage via thoracic drains. Arterial hypotension was initially treated with volume replacement and dopamine, later on adrenaline and hydrocortisone were added. The initial echocardiography showed normal anatomic structures and normal bi-ventricular function. Despite maximal intensive care treatment, a global respiratory and cardiovascular insufficiency developed. The girl died on fourth day of life. At autopsy, a secondary atresia of the DV was identified, and moreover a pathogenic de novo heterozygous mutation in the KRAS gene was found in the chorion biopsy probe. DISCUSSION: For all cases of non-haemolytic hydrops fetalis, a prenatal or postnatal sonography with Doppler examination of the venous system and of the heart should be performed. Furthermore, testing for RASopathies should be recommended especially in presence of increased nuchal translucency thickness and polyhydramnios.

Recurrent prenatal PIEZO1-related lymphatic dysplasia: Expanding molecular and ultrasound findings.

Generalized lymphatic dysplasia (GLD), characterized by lymphedema, lymphangiectasias, chylothorax, effusions, represents a recognized cause of fetal hydrops. We describe for the first time recurrent pregnancies showing different ultrasound presentations of lymphatic dysplasia. The first fetus displayed diffuse subcutaneous cysts and septations while the second one presented fetal hydrops. Exome sequencing results at 18 gestational weeks in the second pregnancy showed compound heterozygosity for two novel PIEZO1 variants, afterwards detected also in the first fetus and in the heterozygous parents. Both ultrasound and genetic findings expand the current knowledge of PIEZO1-related GLD. We suggest exome sequencing in hydropic fetuses with normal cytogenetics and in pregnancies with recurrent hydrops/lymphatic dysplasia.

[Generalized arterial calcification in childhood: A case report]. / Calcificación arterial generalizada idiopática de la infancia: a propósito de un caso.

INTRODUCTION: Arterial calcification of infancy is a rare autosomal recessive genetic disorder with extremely poor prognosis characterized by extensive calcification of internal elastic lamina and thickened of intimal tissue of large and medium sized arteries. CASE REPORT: We present the case of a newborn necropsy with hydrops and widespread cyanosis. The internal examination revealed heart enlargement due to occlusive calcification of the arteries. DISCUSSION: The aim of the present report is to provide a correlation of clinical and pathological features. An update of genetic diagnosis is provided.

A homozygous variant in growth and differentiation factor 2 (GDF2) may cause lymphatic dysplasia with hydrothorax and nonimmune hydrops fetalis.

The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant in GDF2 (c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for the GDF2 variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant in GDF2 with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis.

Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations.

The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2-/- mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.

Gain-of-function mutations in PIEZO1 directly impair hepatic iron metabolism via the inhibition of the BMP/SMADs pathway.

Dehydrated hereditary stomatocytosis (DHS), or xerocytosis, is an autosomal dominant hemolytic anemia. Most patients with DHS carry mutations in the PIEZO1 gene encoding a mechanosensitive cation channel. We here demonstrate that patients with DHS have low levels of hepcidin and only a slight increase of ERFE, the erythroid negative regulator of hepcidin. We demonstrated that at the physiological level, PIEZO1 activation induced Ca2+ influx and suppression of HAMP expression in primary hepatocytes. In two hepatic cellular models expressing PIEZO1 WT and two PIEZO1 gain-of-function mutants (R2456H and R2488Q), we highlight altered expression of a few genes/proteins involved in iron metabolism. Mutant cells showed increased intracellular Ca2+ compared to WT, which was correlated to increased phosphorylation of ERK1/2, inhibition of the BMP-SMADs pathway, and suppression of HAMP transcription. Moreover, the HuH7 cells, treated with PD0325901, a potent inhibitor of ERK1/2 phosphorylation, reduced the phosphorylation of ERK1/2 with the consequent increased phosphorylation of SMAD1/5/8, confirming the link between the two pathways. Another "proof of concept" for the mechanism that links PIEZO1 to HAMP regulation was obtained by mimicking PIEZO1 activation by cell Ca2+ overload, by the Ca2+ ionophore A23187. There was strong down-regulation of HAMP gene expression after this Ca2+ overload. Finally, the inhibition of PIEZO1 by GsMTx4 leads to phenotype rescue. This is the first demonstration of a direct link between PIEZO1 and iron metabolism, which defines the channel as a new hepatic iron metabolism regulator and as a possible therapeutic target of iron overload in DHS and other iron-loading anemias.

Biological importance of podoplanin expression in chorionic villous stromal cells and its relationship to placental pathologies.

Podoplanin, a reliable marker of lymphatic endothelium, is a mucin-type transmembrane protein. Although the human placenta is devoid of a lymphatic system, chorionic villous stromal (CVS) cells express podoplanin. In this study, the pattern of podoplanin expression in normal and pathological placental tissues and the biological role of podoplanin were investigated. In total, 198 placental tissues belonging to 184 patients, seen at the Department of Pathology of Bulent Ecevit University Education and Research Hospital, Zonguldak, Turkey, were evaluated histopathologically and determined to meet the study criteria. The tissues were assigned to control, cisternal placental disorders, inflammation and hypoxic-ischemic pathology groups. Podoplanin expression in CVS cells was graded from 0 to 3 depending on the staining intensity, as determined by an immunohistochemical evaluation of chorionic villi in the most intensively stained tissue region. Podoplanin levels in control CVS cells increased in parallel with placental maturation, whereas in molar pregnancies podoplanin expression was lower than in control tissues. In the acute placental inflammation group, podoplanin immunoreactivity was similar to that in the control group, whereas in the preeclampsia group, podoplanin expression was higher than in all other groups. Our study showed an increase in podoplanin expression in CVS cells during pregnancy. In preeclamptic patients, the increase in podoplanin expression may be a response to hypoxic-ischemic conditions, whereas in molar pregnancies the decrease in podoplanin levels may cause villous swelling by disrupting intercellular fluid homeostasis.

Fetal giant right cervical cyst causing severe tracheal compression: A case report.

RATIONALE: Fetal giant cervical cyst (FGCC) is a rare congenital anomaly. Sometimes FGCC may extend into the mediastinum, and result in severe tracheal compression, which is a life-threatening event at birth. PATIENT CONCERNS: We present a rare case of FGCC, which extended from the right neck into the superior mediastinum, and resulted in severe tracheal compression. DIAGNOSES: An FGCC was observed by ultrasonography and magnetic resonance imaging (MRI) at 27+4 weeks' gestation (WG). Fetal MRI at 35+1 WG showed that the FGCC was 3.3 × 8.2 × 7.5 cm and extended from the right neck into the superior mediastinum. Severe tracheal compression was observed and the inside diameter of the narrowest section of tracheostenosis appeared thread-like and measured only 0.1 cm. INTERVENTIONS: Cervical cyst reduction was performed prenatally under ultrasound guidance to alleviate the tracheal compression and maximize the chance of fetal survival 2 days before birth. At 36+3 WG, cesarean section was performed, and a female neonate was immediately delivered and intubated (3.5-mm tube) by an experienced anesthesiologist. Neonatal intralesional sclerotherapy and cystic component aspiration as guided by digital subtraction angiography were performed under general anesthesia. Anesthesia was maintained only with sevoflurane 3% in 2 L/min oxygen. Extubation was performed soon after surgery. OUTCOME: The neonate recovered uneventfully and was discharged 2 days postoperatively. After 140 days of follow-up, the neonate had recovered completely. LESSONS: If an FGCC is suspected by abdominal ultrasound, a fetal MRI is recommended to assess the severity of tracheal compression before birth, if feasible. An anesthesiologist should assess the risk of intubation failure at birth according to those results. If fetal severe tracheal compression is detected and it may result in inability of intubation at birth, prenatal cervical cyst reduction under ultrasound guidance may be effective for alleviating tracheal compression at birth, if feasible. This could maximize the chance of fetal survival. Improvement of fetal short- and long-term outcomes is important.

Early fetal hydropic changes are associated with moderate dilatation of the brain ventricular system: A clue to a possible link between cervical lymphatic engorgement and ventricular dilatation?

The aim of this study is to assess whether early cervical lymphatic obstruction is associated with a sonographically detectable dilatation of the ventricular system in the 1st trimester of pregnancy. In particular, the objective is to assess whether fetuses with non-immune hydrops fetalis (NIHF), cystic hygroma, or enlarged nuchal translucency (NT) have a greater atrial width/biparietal diameter (AW/BPD) ratio than normal at time of the combined first trimester screening scan. This retrospective study included 96 first trimester fetuses (33 normal and 63 with various degree of cervical lymphatic engorgement). Inclusion criteria were CRL in the 45-84 mm range and availability of one or more three-dimensional volume datasets of the fetal head, acquired from the BPD plane. Each three-dimensional volume dataset was opened and multiplanar correlation employed to align the three orthogonal planes. The ratio between the atrial width and the BPD (AW/BPD ratio) was used to evaluate the possible presence of increased amount of cerebrospinal fluid. Abnormal cases were placed into 4 categories: 1) enlarged non-septated NT 2.5-3.9 mm, no hydrops; 2) grossly enlarged non-septated NT / edema >3.9 mm; 3) cystic hygroma and/ or NIHF; 4) major anomalies with NT <2.5 mm. Presence of dilatation of the laterocervical jugular lymphatic sacs, karyotype and presence of congenital anomalies were also recorded. The One-way ANOVA test was used to compare means. Intra- and inter-observer variability were also assessed. The AW/BPD ratio was found to be significantly higher in fetuses with grossly enlarged NT/nuchal edema and NIHF/septated cystic hygroma than in normal (p <0.05 and p <0.01, respectively). Also, the AW/BPD ratio was significantly higher in NIHF/septated cystic hygroma than in enlarged NT 2.5-3.9 mm (p <0.05). In case of enlarged NT (2.5-3.9 mm), the AW/BPD ratio is significantly higher in presence of JLS (p <0.01). At the end of the first trimester, presence of cervical lymphatic engorgement, in terms of grossly enlarged NT, nuchal edema, septated cystic hygroma, and NIHF, is statistically associated with a moderate dilatation of the ventricular system. Of note, among fetuses with moderately enlarged NT, those with evidence of dilatation of the JLS show a statistically significant increase in the AW/BPD ratio.