Nonimmune Hydrops Research Articles

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis.

Nonimmune hydrops fetalis (NIHF) has varied etiology. We assessed the etiological spectrum and evaluated the utility of fetal whole exome sequencing (fWES) for the diagnosis of NIHF. In this prospective cohort study, we evaluated antenatally diagnosed fetuses with NIHF between July 2018 and December 2019 according to the routine diagnostic algorithm. Fetuses that remained undiagnosed after routine NIHF workup were subjected to fetal chromosomal microarray and/or WES. Pregnancies were followed up for clinical outcomes. Of the 45 fetuses, consanguinity and recurrent hydrops fetalis were observed in 13.3% (6/45) and 28.8% (13/45), respectively. Overall, an etiological diagnosis was possible in 75.5% (34/45) of fetuses, while the cause remained unknown in 24.4% (11/45). A genetic etiology was identified in 46.6% (21/45): aneuploidy and monogenic disorders in 28.8% (13/45) and 17.8% (8/45), respectively. fWES on 19 fetuses detected disease-causing variants in 42.1% (8/19). Nine novel variants were detected in RAPSN, ASCC1, NEB, PKD1L1, GUSB, and PIEZO1. Only 8.8% (4/45) of the cohort survived without morbidity. This study describes the etiological spectrum and the disease-causing variants in an Indian cohort of hydropic fetuses.

Midgut volvulus and meconium peritonitis induced non-immune hydrops

Meconium peritonitis (MP) is a rare cause of nonimmune hydrops and only few of those cases have been reported in literature. Here is to report on a case of FH secondary to perforated midgut volvulus and MP with special interest in the discussion of pathophysiology and clinical strategies. We report on a preterm male neonate diagnosed with FH at 29th week of gestational age (WGA) and EXIT at 30 WGA. In addition, he presented with abdominal mass, respiratory distress syndrome and hypoglycemia. Emergent endotracheal intubation and mechanical ventilation rescued the baby. All maternal and infant viral panel, Toxoplasmosis, Sars-Covid 2 and indirect/direct coombs tests were negative. . At laparotomy, we found a midgut volvulus interesting nearly all the jejunum but sparing the ileum which appeared hypoplastic. One of intestinal loop was completely perforated with diffuse MP. Distal to the first jejunal loop, the jejunum appeared necrotic and then resected with bowel exteriorization (terminal jejunostomy and ileostomy). The postoperative course was complicated by worsening of respiratory distress, acute tubular necrosis and renal failure unresponsive to medical therapy and fatal outcome. In conclusion, we believe that hydrops secondary to midgut volvulus and meconium peritonitis has its own pathophysiological and clinical characteristics that make this disease at high risk of unfavourable outcome when compared with prenatal cases of midgut and/or meconium peritonitis without hydrops.

Parvovirus b19 infection in pregnancy – A review

Parvovirus B19 (B19V) is a widespread infection that may affect 1–5% of pregnant women, mainly with normal pregnancy outcome. Vertical transmission occurs in 33–51% of cases of maternal infection. B19V infection is an important cause of fetal morbidity (fetal anaemia and non-immune hydrops) and mortality, predominantly in the second trimester.Diagnosis of B19V infection requires a multi-method approach using mainly serology and PCR techniques. Severe fetal anaemia is managed with intrauterine transfusion with perinatal survival rates following intrauterine transfusion ranging from 67% to 85%. If fetal anaemia is mild, and considering that hydrops can spontaneously resolve, invasive therapy is not recommended and B19V complicated pregnancy may be non-invasively monitored by serial ultrasound examination and MCV-PSV measurements. As an alternative, intrauterine IVIG therapy has been described with successful treatment of fetal hydrops.No specific antiviral therapy or vaccine is presently available for B19V infection but efforts in the search for compounds inhibiting B19V replication are now being pursued. New virus-like-particle based parvovirus B19 vaccine candidates, produced by co-expressing VP2 and either wild-type VP1 or phospholipase-negative VP1 in a regulated ratio from a single plasmid inSaccharomyces cerevisiae have been developed and show sufficient promise to test in humans.

Exome sequencing vs targeted gene panels for the evaluation of nonimmune hydrops fetalis

Next-generation sequencing is increasingly used in prenatal diagnosis. Targeted gene panels and exome sequencing are both available, but the comparative diagnostic yields of these approaches are not known. We compared the diagnostic yield of exome sequencing with the simulated application of commercial targeted gene panels in a large cohort of fetuses with nonimmune hydrops fetalis. This was a secondary analysis of a cohort study of exome sequencing for nonimmune hydrops fetalis, in which recruitment, exome sequencing, and phenotype-driven variant analysis were completed in 127 pregnancies with features of nonimmune hydrops fetalis. An Internet search was performed to identify commercial laboratories that offer targeted gene panels for the prenatal evaluation of nonimmune hydrops fetalis or for specific disorders associated with nonimmune hydrops fetalis using the terms "non-immune hydrops fetalis," "fetal non-immune hydrops," "hydrops," "cystic hygroma," "lysosomal storage disease," "metabolic disorder," "inborn error of metabolism," "RASopathy," and "Noonan." Our primary outcome was the proportion of all genetic variants identified through exome sequencing that would have been identified if a targeted gene panel had instead been used. The secondary outcomes were the proportion of genetic variants that would have been identified by type of targeted gene panel (general nonimmune hydrops fetalis, RASopathy, or metabolic) and the percent of variants of uncertain significance that would have been identified on the panels, assuming 100% analytical sensitivity and specificity of panels for variants in the included genes. Exome sequencing identified a pathogenic or likely pathogenic variant in 37 of 127 cases (29%) in a total of 29 genes. A variant of uncertain significance, strongly suspected to be associated with the phenotype, was identified in another 12 cases (9%). We identified 7 laboratories that offer 10 relevant targeted gene panels; 6 are described as RASopathy panels, 3 as nonimmune hydrops fetalis panels, and 1 as a metabolic panel. The median number of genes included on each of these panels is 22, ranging from 11 to 148. Had a nonimmune hydrops fetalis targeted gene panel been used instead of exome sequencing, 13 to 15 of the 29 genes (45%-52%) identified in our nonimmune hydrops fetalis cohort would have been sequenced, and 19 to 24 of the pathogenic variants (51%-62%) would have been detected. The yield was predicted to be the lowest with the metabolic panel (11%) and the highest with the largest nonimmune hydrops fetalis panel (62%). The largest nonimmune hydrops fetalis targeted gene panel would have had a diagnostic yield of 18% compared with 29% with exome sequencing. The exome sequencing platform used provided 30× or more coverage for all of the exons on the commercial targeted gene panels, supporting our assumption of 100% analytical sensitivity for exome sequencing. The broader coverage of exome sequencing for genetically heterogeneous disorders, such as nonimmune hydrops fetalis, made it a superior alternative to targeted gene panel testing.

Lysosomal storage disorders as an etiology of nonimmune hydrops fetalis: A systematic review

We performed a systematic review of the literature to evaluate the incidence and types of lysosomal storage disorders (LSD) in case series of nonimmune hydrops fetalis (NIHF). PubMed and Ovid were reviewed for case series evaluating the workup of NIHF diagnosed in utero or in the neonatal period in human subjects from 1979 to August 2020. Retrospective case series with at least five cases of fetal and/or neonatal NIHF with its workup mentioned were identified. Idiopathic NIHF was defined as NIHF without an apparent cause after initial standard-of-care workup. In total, twenty-two case series with 2,678 total cases of NIHF were identified. The overall incidence of LSD was 6.6% (177/2,663) in NIHF cases that were tested for any LSD, and 8.2% (177/2,151) in idiopathic NIHF cases. The most common LSD identified in cases of NIHF were mucopolysaccharidosis type VII, galactosialidosis, infantile sialic acid storage disease, Gaucher disease, GM1 gangliosidosis and sialidosis. More than 40% of the most common LSD causes of NIHF have a potential postnatal treatment. LSD testing for NIHF allows for early diagnosis, better counseling and appropriate management, planning for possible early treatment, and counseling for recurrence risk.

The many etiologies of nonimmune hydrops fetalis diagnosed by exome sequencing.

To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. We encountered 144 families with NIHF. Genetic investigation was performed by chromosomal microarray analysis (CMA) in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic. As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF.

Urinary Type Hydrometrocolpos and Polydactyly in Two Newborns: Case Report

Background: Abdominal masses secondary to urinary retention are rare among female neonates and approaching this pathologic condition, inevitably, poses a diagnostic challenge. Hydrometrocolpos is one example of this disease category which is responsible for only 15% of such cases whose association with polydactyly appears to be even less common. The present study aimed to report the accounts of two neonates with cystic abdominal masses diagnosed as urinary type hydrometrocolpos secondary to urogenital sinus anomaly. Autosomal recessive disorders are characterized by vaginal atresia with hydrometrocolpos, polydactyly, congenital heart defects, and non-immune mediated hydrops fetalis. The triad of hydrometrocolpos, polydactyly, and cardiac anomaly in the two patients presented herein is strongly suggestive of a case of McKusick-Kaufman syndrome. Case report: This study reported two neonates with abdominal mass, polydactyly, and genitourinary tract malformation, with no family history. Relief of urinary obstruction by exploratory laparotomy, aspiration of fluid, and vaginal reconstruction gradually reversed the hydronephrosis and renal failure. Conclusion: It can be concluded thatin hydrometrocolpos causing urinary obstruction, decompression of hydrometrocolpos can save the kidneys.

Nonimmune hydrops fetalis with intrauterine fetal demise presenting at 41-weeks gestational age: the ultrasonographic findings and case report

Hydrops fetalis is the abnormal accumulation of fluid in two or more different fetal compartments and most times associated with polyhydramnios and placental edema, and has an estimated incidence of about 1 in 3000 pregnancies. A 27-year-old multigravida; G8P7, was referred for the first ultrasonography in the Index pregnancy on account of not feeling/observing fetal movement for about two-weeks. The obstetric ultrasonography demonstrated a single fetus with absent fetal heartbeat, in hyper-flexed position, accumulation of fluid in the abdominal cavity; right sub-diaphragmatic region and in the right pleural cavity in keeping with fetal ascites and fetal effusion. There is overriding of fetal skull with Thickened/edematous placenta with a thickness of about 7cm, and fetal skin thickness of about 10mm. There is associated intrafetal gas. The estimated femoral length gave a gestational age approximating 41-weeks. A diagnosis of hydrops fetalis most likely non-immune form with fetal demise presenting at 41-weeks gestational age in a multiparous woman with features anemia presumably from sepsis and urinary tract infection (bilateral pyelonephritis and cystitis) in a setting of poor antenatal care was entertained. The fetus was expelled following induction of labor at the peripheral centre, the patient had transfusion done with commencement of antibiotics for correction of anemia and sepsis with plans of further clinical and laboratory evaluation. We present the ultrasonographic features of hydrops fetalis with intrauterine fetal demise due to its unique presentation

Antenatal diagnosis and management of cystic hygroma with hydrops fetalis

Cystic hygroma is a congenital thin-walled cyst that contains lymphatic fluids. Ultrasonography has helped in detecting more and more cases of cystic hygroma with fetal hydrops. Fetal hydrops and cystic hygroma can be diagnosed in the first and second trimesters of gestation and are associated with a higher incidence of aneuploidy and have higher mortality rate. The mortality rate of cystic hygroma diagnosed before 30 weeks is 93%, and 84% of those are associated with progressive non-immune hydrops. We present three case series of cystic hygroma progressing to hydrops fetalis.

High diagnosis rate for nonimmune hydrops fetalis with prenatal clinical exome from the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) Study

PurposeNonimmune hydrops fetalis (NIHF) presents as life-threatening fluid collections in multiple fetal compartments and can be caused by both genetic and non-genetic etiologies. We explored incremental diagnostic yield of testing with prenatal exome sequencing (ES) for NIHF following a negative standard NIHF workup. MethodsParticipants enrolled into the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study met a strict definition of NIHF and had negative standard-of-care workup. Clinical trio ES from fetal samples and parental blood was performed at a CLIA-certified reference laboratory with clinical reports returned by geneticists and genetic counselors. Negative exomes were reanalyzed with information from subsequent ultrasounds and records. ResultsTwenty-two fetal exomes reported 11 (50%) diagnostic results and five possible diagnoses (22.7%). Diagnosed cases comprised seven de novodominant disorders, three recessive disorders, and one inherited dominant disorder including four Noonan syndromes (PTPN11, RAF1, RIT1, and RRAS2), three musculoskeletal disorders (RYR1, AMER1, and BICD2), two metabolic disorders (sialidosis and multiple sulfatase deficiency), one Kabuki syndrome, and one congenital anemia (KLF1). ConclusionThe etiology of NIHF predicts postnatal prognosis and recurrence risk in future pregnancies. ES provides high incremental diagnostic yield for NIHF after standard-of-care testing and should be considered in the workup.

Nonimmune Hydrops Fetalis — More Than Meets the Eye?

(N Engl J Med. 2020;383:1785–1786) Nonimmune Hydrops Fetalis (NIHF) is typically defined as fetal fluid accumulation in two sites and affects up to 1 in 1,700 fetuses. There are multiple causes, including chromosomal abnormalities and structural malformations. Perinatal mortality is high in pregnancies where NIHF is present in the first trimester. In two different studies, diagnostic variants were identified in 9% and 24% of fetuses with NIHF using exome sequencing.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

(N Engl J Med. 2020;383:1746–1756) Nonimmune hydrops fetalis (NIHF) is a severe disorder associated with a high risk of stillbirth, preterm birth, neonatal death, and neonatal complications. NIHF is a shared presentation of a number of genetic disorders. Using standard genetic testing with karyotyping or chromosomal microarray, the cause of NIHF can be determined in only 25% of cases. Single-gene disorders may substantially contribute to NIHF, but this is not yet clear. This study aimed to explore the use of exome sequencing for diagnosing single-gene disorders in unexplained NIHF cases and establish the diagnostic yield of exome sequencing.

Mucopolysaccharidosis VII in Brazil: natural history and clinical findings

BackgroundMucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, caused by deficiency of the lysosomal enzyme β-glucuronidase, is an ultra-rare disorder with scarce epidemiological data and few publications about natural history and clinical spectrum.MethodsWe conducted a case series report which included retrospective data from all MPS VII patients diagnosed through the “MPS Brazil Network” who were known to be alive in 2020 in Brazil (N = 13). Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population.ResultsThe majority of the patients were from the Northeast region of Brazil. Among the signs and symptoms that raised the clinical suspicion of MPS, coarse face was the most frequent; 58% of the patients had a history of non-immune hydrops fetalis. All the subjects presented short neck and trunk. The majority presented typical phenotypical signs of MPS disorders. They all presented neurodevelopmental delay and cognitive impairment. About half of this cohort had knees deformities. Dysostosis multiplex was identified in almost all patients and cardiomyopathy was less frequent than observed in other types of MPSs. The mean age at diagnosis was 5 years, ranging from 1 to 14 years. Almost all patients (12/13) were homozygous for the c.526C>T (p.Leu176Phe) mutation. A novel variant of the GUSB gene was found, the c.875T>C (p.Leu292Pro), in a compound heterozygous with the c.526C>T (p.Leu176Phe) variant.ConclusionsThis case series is the biggest data collection of MPS VII patients alive in Latin America. The overall clinical picture of the MPS VII patients is very similar to other MPS disorders, including a spectrum of severity and delayed diagnosis.

Molecular detection of human parvovirus B19 in umbilical cord blood: Case study of Tehran, Iran

BackgroundHuman parvovirus B19 (HPVB19) can infect and cause abortion, non-immune hydrops fetalis, and intrauterine fetal death in pregnant women. The present study aimed to determine the molecular prevalence of HPVB19 among pregnant women in Tehran, Iran. MethodsThe present single-center cross-sectional study was conducted by screening testing for HPVB19 infection in pregnant women from February 2016 to July 2020 at Imam Hossein Hospital, Tehran, Iran. Cord blood tissue samples were collected from each pregnant woman and all samples were preserved at −70 °C. Genomic DNA was extracted from all cord blood tissue samples and the presence and frequency of HPVB19 were determined through conventional PCR assay. ResultsA total of 182 cord tissue samples were screened for HPVB19 DNA. The median age of the pregnant women was 28 years ranging from 20 to 49 years. HPBV19 was detected in 8.8% (n = 16/182) of the samples studied. The frequency of HPVB19 in pregnant women with different pregnancy conditions was as follows: IUFD (n = 2/55; 3.6%), term (n = 10/84; 11.9%), and premature (n = 4/86; 4.7%). The lowest (n = 0/25; 0%) and highest (n = 3/5; 60%) prevalence rates of HPVB infection were detected within the 21–30 weeks of gestation and post-term (>40 weeks), respectively. Moreover, the prevalence of HPVB19 infection among pregnant women with Hgb levels >10 was high (9.3%; n = 15/161). ConclusionGiven that no vaccine exists against HPVB19, it is recommended that pregnant women should be routinely screened during pregnancy to ensure immunity against HPVB19.

Narrative review of congenital lung lesions.

This article reviews the contemporary diagnosis and management of antenatally diagnosed congenital lung lesions. These anomalies, which include congenital pulmonary airway malformation (CPAM) (formerly congenital cystic adenomatoid malformation), bronchopulmonary sequestration (BPS), bronchogenic cyst, and congenital lobar emphysema (CLE), are relatively rare but are increasingly encountered by clinicians because of the improved resolution and enhanced sensitivity of fetal ultrasound. Serial assessment of these lesions throughout pregnancy remains the norm rather than the exception. Perinatal management strategies may differ based on initial size and growth patterns of these masses until delivery. Fetal magnetic resonance imaging and other diagnostic testing can sometimes be helpful in providing additional prognostic information. Over the last decade, maternal steroids have become standard of care in the management of larger lesions at risk for nonimmune hydrops. As a result, fetal surgical procedures, including open resection, thoracoamniotic shunting, and ex utero intrapartum treatment (EXIT), are less uncommonly performed. Decisions regarding whether delivery of these fetuses should occur in a tertiary care center with pediatric surgery coverage versus delivery at a local community hospital are now highly relevant in most prenatal counseling discussions with families. Large lung malformations may require urgent surgical removal in the early postnatal period because of respiratory distress. Other complications, such as recurrent pneumonia, pneumothorax, and cancer, are indications for postnatal lung resection on an elective basis. Many children are good candidates for minimally invasive (thoracoscopic) surgical approaches as an alternative to resection by thoracotomy. In the vast majority of cases, the overall prognosis remains excellent.

Value of Exome Sequencing in Diagnosis and Management of Recurrent Non-immune Hydrops Fetalis: A Retrospective Analysis.

The purpose of the study was to use exome sequencing (ES) to study the contribution of single-gene disorders to recurrent non-immune hydrops fetalis (NIHF) and retrospectively evaluate the value of genetic diagnosis on prenatal management and pregnancy outcome. From January 2012 to October 2018, a cohort of 28 fetuses with recurrent NIHF was analyzed by trio ES. Fetuses with immune hydrops, non-genetic factors (including infection, etc.), karyotype, or CNV abnormalities were excluded. Variants were interpreted based on ACMG/AMP guidelines. Fetal therapy was performed on seven fetuses. Of the 28 fetuses, 10 (36%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in eight genes (GBA, GUSB, GBE1, RAPSN, FOXC2, PIEZO1, LZTR1, and FOXP3). Five (18%) fetuses had variant(s) of uncertain significance (VUS). Of the 10 fetuses with definitive molecular diagnosis, five (50%) were diagnosed with inborn errors of metabolism. Among the seven fetuses who received fetal therapy, two had definitive molecular diagnosis and resulted in neonatal death. Among the remaining five fetuses with negative results, four had newborn survival and one had intrauterine fetal death. Trio ES could facilitate genetic diagnosis of recurrent NIHF and improve the prenatal management and pregnancy outcome.

EP112 - Significant unmet need in infants with mucopolysaccharidosis VII and non-immune hydrops fetalis: a summary of cases

eP112 - Significant unmet need in infants with mucopolysaccharidosis VII and non-immune hydrops fetalis: a summary of cases

Non-immunologic hydrops fetalis and coronavirus disease (COVID-19) – A case report

Non-immune hydrops fetalis is a severe fetal condition defined as the excessive accumulation of fetal fluid within the fetal extravascular compartments and body cavities. The prevalence of non-immune hydrops fetalis is unknown. Currently, about 90% of cases of hydrops fetalis are non-immune hydrops fetalis. Non-immune hydrops fetalis causes are multi-factorial. The pathophysiological mechanism of non-immunologic hydrops fetalis is related to abnormal fluid transportation between plasma and tissues. This is due to the increase in hydrostatic capillary pressure and capillary permeability and a reduction of the plasma osmotic pressure or lymphatic flow. A variety of viral infection agents have been associated with non-immune hydrops fetalis like parvovirus B19, herpes simplex virus, cytomegalovirus, Toxoplasma gondii, Treponema pallidum, but even other viruses that attack the maternal and fetus during pregnancy cannot be excluded as possible causes of non-immune hydrops fetalis. We present one case of non-immune hydrops fetalis who was diagnosed intra-uterine, three weeks after recovery from Coronavirus disease (COVID-19). After much investigation, we could not find any known factor that may be the cause of non-immunologic hydrops fetalis. Therefore, we predisposed a possible causal connection between nonimmunologic hydrops fetalis and Coronavirus disease (COVID-19).

Congenital Chylothorax and Hydrops Fetalis: A Novel Neonatal Presentation of RASA1 Mutation

Mutations in the RASA1 gene are known to cause arteriovenous malformations (AVMs), with evidence of associated lymphatic malformations. We report for the first time, to the best of our knowledge, an infant with RASA1 mutation presenting with hydrops fetalis and chylothorax, but without an associated AVM. Previously, researchers studying rodents have found chylothorax associated with RASA1 mutations, and, in previous case reports, researchers have reported on infants with RASA1 mutations born with hydrops fetalis and AVMs. In this report, we describe the case of a "late preterm" female infant born with nonimmune hydrops fetalis and congenital chylothorax who was detected to have a RASA1 deletion on genetic workup. Although classically described phenotypes of RASA1 mutations present with venous malformations, no such malformations were found in this infant on extensive imaging. This combination is a novel and nonclassic presentation of RASA1 mutation. In cases of congenital chylothorax, especially with nonimmune hydrops fetalis, RASA1 mutations should be considered as part of the differential diagnosis and genetic testing should be included as part of a complete workup to allow for screening for associated vascular anomalies.

Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis

(Abstracted from N Engl J Med 2020;383:1746–1756) Nonimmune hydrops fetalis (NIHF) is a condition complicating approximately 1 in 1700 to 3000 pregnancies where the fetus develops an overload of fluid, causing a wide range of outcomes such as stillbirth, preterm birth, neonatal complications, or neonatal death. Standard genetic testing with microarray or karyotype identifies a genetic cause of hydrops approximately only 25% of the time.