Lymphatic Dysplasia Research Articles

Central conducting lymphatic anomaly with pulmonary lymphatic dysplasia causes restrictive lung disease and chronic pleural effusion.

Central conducting lymphatic anomaly with pulmonary lymphatic dysplasia causes restrictive lung disease and chronic pleural effusion.

The Possible Role of Lymphaticovenous and Lymph Node to Vein Anastomosis for Improvement of Milroy Disease Related Congenital Chylothorax and Lower Extremity Lymphedema.

Primary lymphedema is characterized by lymphatic dysplasia in which one variant is Milroy's disease. The association with congenital chylothorax is even rarer with poor outcome. This is the first report to utilize peripheral lymphovenous anastomosis (LVA) and lymph node to vein anastomosis (LNVA) for the management of such condition. Retrospective chart review of patients with Milroy's disease with complication of chylothorax between 2019 till 2023 was performed. Clinical assessment and radiological investigations were reviewed. Six patients with mean age of 12±3.9 years and disease duration of 10.5±2.8 years were reviewed. Three had ISL stage 3 while others had stage 2 late disease. All had bilateral lower extremity lymphedema and chylothorax with history of chest tube drainage. After LVA and LNVA, significant reduction in extremity volume was noted (p=0.028) along with near complete resolution of chylothorax was noted during the long-term follow-up (32 ±17.9 months). Milroy's disease complicated with chylothorax remains to be challenging. This is the first report utilizing peripheral bypass (LVA and LNVA) which resulted in improvement of both lower extremity lymphedema and chylothorax. The utility of this approach represents a promising modality in the management of this devastating condition.

Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.

The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.

PIEZO Ion Channels in Cardiovascular Functions and Diseases.

The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells and tissues. Thus, this system is primed with mechanosensory structures that respond and adapt to changes in mechanical stimuli. Since their discovery in 2010, PIEZO ion channels have dominated the field of mechanobiology. These have been proposed as the long-sought-after mechanosensitive excitatory channels involved in touch and proprioception in mammals. However, more and more pieces of evidence point to the importance of PIEZO channels in cardiovascular activities and disease development. PIEZO channel-related cardiac functions include transducing hemodynamic forces in endothelial and vascular cells, red blood cell homeostasis, platelet aggregation, and arterial blood pressure regulation, among others. PIEZO channels contribute to pathological conditions including cardiac hypertrophy and pulmonary hypertension and congenital syndromes such as generalized lymphatic dysplasia and xerocytosis. In this review, we highlight recent advances in understanding the role of PIEZO channels in cardiovascular functions and diseases. Achievements in this quickly expanding field should open a new road for efficient control of PIEZO-related diseases in cardiovascular functions.

The phosphodiesterase 2A controls lymphatic junctional maturation via cGMP-dependent notch signaling

The molecular mechanisms by which lymphatic vessels induce cell contact inhibition are not understood. Here, we identify the cGMP-dependent phosphodiesterase 2A (PDE2A) as a selective regulator of lymphatic but not of blood endothelial contact inhibition. Conditional deletion of Pde2a in mouse embryos reveals severe lymphatic dysplasia, whereas blood vessel architecture remains unaltered. In the absence of PDE2A, human lymphatic endothelial cells fail to induce mature junctions and cell cycle arrest, whereas cGMP levels, but not cAMP levels, are increased. Loss of PDE2A-mediated cGMP hydrolysis leads to the activation of p38 signaling and downregulation of NOTCH signaling. However, DLL4-induced NOTCH activation restores junctional maturation and contact inhibition in PDE2A-deficient human lymphatic endothelial cells. In postnatal mouse mesenteries, PDE2A is specifically enriched in collecting lymphatic valves, and loss of Pde2a results in the formation of abnormal valves. Our data demonstrate that PDE2A selectively finetunes a crosstalk of cGMP, p38, and NOTCH signaling during lymphatic vessel maturation.

Death of children with Down syndrome by gestational age and cause.

We often encounter preterm infants with Down syndrome (DS) who die in the neonatal intensive care unit (NICU). In this study, we examined survival until NICU discharge and assessed the developmental prognosis of preterm infants with DS. We retrospectively reviewed 416 infants with DS hospitalized during the past 27 years at our NICU. Death occurred in 8/20 (40%) infants at <32 weeks' gestation, 11/23 (48%) at 32-33 weeks, 9/99 (9%) at 34-36 weeks, and 9/274 (3%) at >36 weeks. In total, 84% of infants who died and 25% of those who survived had a non-reassuring fetal status (p < 0.001). Sex, small-for-gestational-age status, and postnatal transport were not associated with death. The main causes of death were bronchopulmonary dysplasia in 4/8 (50%) infants at <32 weeks' gestation, transient abnormal myelopoiesis in 11/20 (55%) and lymphatic dysplasia in 6/20 (30%) at 32-36 weeks, and varied causes at >36 weeks. Among survivors born at <34 weeks' gestation, 6/19 (32%) aged >2 years had moderate or severe cerebral palsy. These data on the high mortality and morbidity of preterm infants with DS may be useful for patient treatment and parent counseling in NICUs treating critically ill infants. Most infants with Down syndrome born at <34 weeks' gestation are born by cesarean section because of the non-reassuring fetal status. The mortality rate before discharge for infants with Down syndrome born at <34 weeks' gestation was 40%, and 30% of survivors developed moderate or severe cerebral palsy. The risk of death due to bronchopulmonary dysplasia and pulmonary hypertension was high in very preterm infants with Down syndrome despite the absence of chorioamnionitis. Infants with Down syndrome were born 1-2 weeks earlier than unaffected controls.

A high-throughput electrophysiology assay to study the response of PIEZO1 to mechanical stimulation.

PIEZO1 channels are mechanically activated cation channels that play a pivotal role in sensing mechanical forces in various cell types. Their dysfunction has been associated with numerous pathophysiological states, including generalized lymphatic dysplasia, varicose vein disease, and hereditary xerocytosis. Given their physiological relevance, investigating PIEZO1 is crucial for the pharmaceutical industry, which requires scalable techniques to allow for drug discovery. In this regard, several studies have used high-throughput automated patch clamp (APC) combined with Yoda1, a specific gating modifier of PIEZO1 channels, to explore the function and properties of PIEZO1 in heterologous expression systems, as well as in primary cells. However, a combination of solely mechanical stimulation (M-Stim) and high-throughput APC has not yet been available for the study of PIEZO1 channels. Here, we show that optimization of pipetting parameters of the SyncroPatch 384 coupled with multihole NPC-384 chips enables M-Stim of PIEZO1 channels in high-throughput electrophysiology. We used this approach to explore differences between the response of mouse and human PIEZO1 channels to mechanical and/or chemical stimuli. Our results suggest that applying solutions on top of the cells at elevated pipetting flows is crucial for activating PIEZO1 channels by M-Stim on the SyncroPatch 384. The possibility of comparing and combining mechanical and chemical stimulation in a high-throughput patch clamp assay facilitates investigations on PIEZO1 channels and thereby provides an important experimental tool for drug development.

Chylous ascites as a rare complication of abdominal trauma in a 7‐year‐old girl: A case report

Key Clinical MessageAbdominal trauma can be one of the causes of chylous ascites in pediatric cases, along with tuberculosis and malignancy. However, a definitive diagnosis is more reasonable to be done by excluding other causes.AbstractChylous ascites (CA) is a rare type of ascites. Though it has high mortality and morbidity rates, which usually happen due to the rupture of lymph vessels into the peritoneal cavity. Congenital abnormalities, including lymphatic hypoplasia or dysplasia, are the most causes in pediatrics. CA following trauma in children is very rare, and to the best of our knowledge, there are very few reports in this regard. Here, we report a 7‐year‐old girl who was referred to our center with CA after a car accident.

A very rare disease of lymphatic malformation 6: five new patients and review of the literatur

Objective: Lymphatic Malformation 6 (MIM no:616843) is characterized by generalized edema, bilateral pleural effusions, ascites and non-immune hydrops fetalis. PIEZO1 gene has been associated with the LMPHM6 disorder. Here, we aimed to evaluate five patients from two different families, with various clinical presentations of generalized lymphatic dysplasia.&#x0D; Materials and Methods: Between January 2015 and January 2021, 5 cases with were evaluated with a pre-diagnosis of congenital lymphatic malformation. Whole exome sequencing was performed on the probands, and family segregation analysis was performed by Sanger sequencing.&#x0D; Results: We identified a novel compound heterozygous PIEZO1 gene: NM_001142864.4: c.4030_4032delGAG (E1344del)/ c.5455_5456delAA (K1819Efs*46) variants in the first family and a novel homozygous PIEZO1 gene: c.5876A&gt;G (D1959G) variant in the second family.&#x0D; Conclusion: This study, which presents the clinical features and variations of five patients with long-term follow-up, contributed to the phenotypic and mutation spectrum of Lymphatic Malformation 6. The novel compound heterozygous E1344del/K1819Efs*46 variation leads to a premature stop codon that caused a shorter protein product. It was thought that two compound nonsense variations might be associated with the poor prognosis of family 1. Also, the second novel c.5876A&gt;G (D1959G) biallelic homozygous mutation was thought to be associated with impaired PIEZO1 by causing loss of function. This study was the first LMPHM6 report from the Turkish population.&#x0D; Keywords: Neurofibromatosis type 1, Next generation DNA sequencing, NF1 gene, novel variants

In-silico assessment of high-risk non-synonymous SNPs in ADAMTS3 gene associated with Hennekam syndrome and their impact on protein stability and function

Hennekam Lymphangiectasia–Lymphedema Syndrome 3 (HKLLS3) is a rare genetical disorder caused by mutations in a few genes including ADAMTS3. It is characterized by lymphatic dysplasia, intestinal lymphangiectasia, severe lymphedema and distinctive facial appearance. Up till now, no extensive studies have been conducted to elucidate the mechanism of the disease caused by various mutations. As a preliminary investigation of HKLLS3, we sorted out the most deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) that might affect the structure and function of ADAMTS3 protein by using a variety of in silico tools. A total of 919 nsSNPs in the ADAMTS3 gene were identified. 50 nsSNPs were predicted to be deleterious by multiple computational tools. 5 nsSNPs (G298R, C567Y, A370T, C567R and G374S) were found to be the most dangerous and can be associated with the disease as predicted by different bioinformatics tools. Modelling of the protein shows it can be divided into segments 1, 2 and 3, which are connected by short loops. Segment 3 mainly consists of loops without substantial secondary structures. With prediction tools and molecular dynamics simulation, some SNPs were found to significantly destabilize the protein structure and disrupt the secondary structures, especially in segment 2. The deleterious effects of mutations in segment 1 are possibly not from destabilization but from other factors such as the change in phosphorylation as suggested by post-translational modification (PTM) studies. This is the first-ever study of ADAMTS3 gene polymorphism, and the predicted nsSNPs in ADAMST3, some of which have not been reported yet in patients, will serve for diagnostic purposes and further therapeutic implications in Hennekam syndrome, contributing to better diagnosis and treatment.

Recurrent Nonimmune Fetal Hydrops Due to a Novel Pathogenic Variant in PIEZO1 Gene: A Case Report from South India

AbstractNonimmune fetal hydrops (NIFH) has underlying diverse etiology with generalized lymphatic dysplasia being one such cause. Lymphatic malformation-6 is a type of lymphatic dysplasia that is due to homozygous or compound heterozygous variants in the PIEZO1 gene. The clinical features associated with this condition during fetal life are nonimmune fetal hydrops that manifests with widespread lymphatic edema, with other systemic manifestations like pericardial/pleural effusions, chylothorax along with lymphangiectasia seen primarily in lungs and intestines. We present a case of recurrent NIFH in a family due to a novel pathogenic mutation in PIEZO1 gene. This variant was identified in homozygous state in all the three affected fetuses and in heterozygous state in both the parents. The couple were counseled regarding recurrence of this condition and given reproductive options for future pregnancies.

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition.

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Novel small-molecule modulation of PIEZO1 investigated by conventional and automated patch-clamp.

PIEZO1 trimers form mechanically-activated calcium-permeable non-selective cation channels which are expressed in many types of cells. Mutations in the PIEZO1 gene are associated with generalised lymphatic dysplasia, varicose vein disease, dehydrated hereditary stomatocytosis, malarial resistance and other conditions. Pharmacological modulation of PIEZO1 has been achieved using various compounds, most notably the small-molecule agonist Yoda1 and its inhibitor Dooku1. However, improvements in the potency and pharmacokinetic properties of such compounds are required to increase the usefulness, and small-molecule inhibitors of PIEZO1 are largely lacking. We sought to identify novel small-molecule agonists and inhibitors of mouse and human PIEZO1 channels. Analogues of Yoda1 were generated by medicinal chemistry approaches and a library of 11,200 compounds was screened in a calcium assay using cells overexpressing human PIEZO1. Analogues of hits from the screen were designed and synthesised and then tested for effectiveness in cells overexpressing mouse or human PIEZO1 using an orthogonal calcium assay, conventional (manual) patch-clamp and automated patch-clamp in 384-well format (SyncroPatch 384). We identified Yoda1 analogues with better aqueous solubility and microsomal stability than Yoda1 and improved potency. We identified and validated two novel structurally distinct small-molecule inhibitors of PIEZO1. Automated patch-clamp techniques were refined for activation of PIEZO1 channels by fluid flow in 384-well format. Novel small-molecule modulators of the channels were tested in these automated assays and confirmed as PIEZO1 modulators. We gained preliminary knowledge of the structure-activity relationships and promising compounds for further development. Supported by British Heart Foundation.

Improved PIEZO1 agonism through 4-benzoic acid modification of Yoda1.

The protein PIEZO1 forms mechanically activated, calcium-permeable, non-selective cation channels in numerous cell types from several species. Options for pharmacological modulation are limited and so we modified a small-molecule agonist at PIEZO1 channels (Yoda1) to increase the ability to modulate these channels. Medicinal chemistry generated Yoda1 analogues that were tested in intracellular calcium and patch-clamp assays on cultured cells exogenously expressing human or mouse PIEZO1 or mouse PIEZO2. Physicochemical assays and wire myography assays on veins from mice with genetic disruption of PIEZO1. A Yoda1 analogue (KC159) containing 4-benzoic acid instead of the pyrazine of Yoda1 and its potassium salt (KC289) have equivalent or improved reliability, efficacy and potency, compared with Yoda1 in functional assays. Tested against overexpressed mouse PIEZO1 in calcium assays, the order of potency (as EC50 values, nM) was KC289, 150 > KC159 280 > Yoda1, 600). These compounds were selective for PIEZO1 over other membrane proteins, and the physicochemical properties were more suited to physiological conditions than those of Yoda1. The vasorelaxant effects were consistent with PIEZO1 agonism. In contrast, substitution with 2-benzoic acid failed to generate a modulator. 4-Benzoic acid modification of Yoda1 improves PIEZO1 agonist activity at PIEZO1 channels. We suggest naming this new modulator Yoda2. It should be a useful tool compound in physiological assays and facilitate efforts to identify a binding site. Such compounds may have therapeutic potential, for example, in diseases linked genetically to PIEZO1 such as lymphatic dysplasia.

LACK OF EMBRYONIC HOMOZYGOUS OR ADULT HETEROZYGOUS LYMPHATIC PHENOTYPES FOR A Sos1 MUTATION AND LACK OF LYMPHATIC EMBRYONIC PHENOTYPES FOR A HOMOZYGOUS Cx47 MUTATION IN MICE

We have studied the lymphatic phenotypes of 2 mutations, known to cause abnormalities of lymphatics in humans, in mice. The Cx47 R260C mutation (variably penetrant in humans heterozygous for it and causing limb lymphedema) had an adult mouse phenotype of hyperplasia and increased lymph nodes only in homozygous condition but we did not find any anatomical phenotype in day 16.5 homozygous embryos. Mice harboring the Sos1 mutation E846K (causing Noonan's in man which occasionally shows lymphatic dysplasia) had no adult heterozygous phenotype in lymphatic vessel appearance and drainage (homozygotes are early embryonic lethals) while day 16.5 heterozygous embryos also had no detectable anatomical phenotype.

Galactosialidosis presenting as non-immune hydrops in a newborn: A case report

Galactosialidosis is a rare autosomal recessive lysosomal storage disorder (LSD). It results from defects in glycoprotein degradation due to mutation in a single gene, encoded by the protective protein cathepsin A, (CTSA), located on chromosome 20q13.12. Most cases of non-immune hydrops fetalis (NIHF) nowadays being recognized are due to cardiac, lymphatic dysplasia, and hematological disorders. Inborn errors of metabolism account for NIHF in 1.3% of patients. Among metabolic disorders, around 14 LSDs have been reported as being associated with NIHF and congenital ascites. In the present case, we report an early infantile form of galactosialidosis with a novel homozygous miss-sense mutation c.319 A&gt;C (p. Ser107 Arg) in exon 3 of CTSA gene in a newborn who presented as non-immune hydrops. The baby also had coarse facies, wide anterior fontanelle, hypertelorism, bilateral congenital talipes equinovarus, hepatosplenomegaly, nephrocalcinosis, and disproportionately small limbs with metaphyseal irregularity. Gradually, he developed worsening cardiac functions and cardiomyopathy and succumbed to death on day 47 of life. Being an autosomal recessive disorder, it can recur in the next pregnancy and treatment is mainly supportive. Targeted prenatal diagnostics in subsequent pregnancies can help in early diagnosis.

Noonan Syndrome with Hepatomegaly and Persistently Elevated Liver Enzymes: A Case Report

Noonan’s syndrome is a polymorphic disorder with some facial features, congenital heart defects, cryptorchidism, etc., and also associated with some autoimmune diseases, lymphatic dysplasias. Here we are reporting a nine years old boy with Noonan's syndrome who has hepatomegaly with persistently raised hepatic enzymes, which remained unexplained.&#x0D; TAJ 2022; 35: No-1: 137-140

Genetics etiologies and genotype phenotype correlations in a cohort of individuals with central conducting lymphatic anomaly.

Central conducting lymphatic anomaly (CCLA) is a heterogenous disorder caused by disruption of central lymphatic flow that may result in dilation or leakage of central lymphatic channels. There is also a paucity of known genetic diagnoses associated with CCLA. We hypothesized that specific genetic syndromes would have distinct lymphatic patterns and this would allow us to more precisely define CCLA. As a first step toward "precision lymphology", we defined the genetic conditions associated with CCLA by performing a retrospective cohort study. Individuals receiving care through the Jill and Mark Fishman Center for Lymphatic Disorders at the Children's Hospital of Philadelphia between 2016 and 2019 were included if they had a lymphangiogram and clinical genetic testing performed and consented to a clinical registry. In our cohort of 115 participants, 26% received a molecular diagnosis from standard genetic evaluation. The most common genetic etiologies were germline and mosaic RASopathies, chromosomal abnormalities including Trisomy 21 and 22q11.2 deletion syndrome, and PIEZO1-related lymphatic dysplasia. Next, we analyzed the dynamic contrast magnetic resonance lymphangiograms and found that individuals with germline and mosaic RASopathies, mosaic KRASopathies, PIEZO1-related lymphatic dysplasia, and Trisomy 21 had distinct central lymphatic flow phenotypes. Our research expands the genetic conditions associated with CCLA and genotype-lymphatic phenotype correlations. Future descriptions of CCLA should include both genotype (if known) and phenotype to provide more information about disease (gene-CCLA). This should be considered for updated classifications of CCLA by the International Society of Vascular Anomalies.

A single center experience in 90 cases with nonimmune hydrops fetalis: diagnostic categories ‒ mostly aneuploidy and still often idiopathic

The prognosis of nonimmune hydrops fetalis (NIHF) is still poor with a high mortality and morbidity rate despite progress in perinatal care. This study was designed to investigate etiology and outcome of NIHF. A retrospective review of 90 NIHF cases from 2007 to 2019 was conducted at University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Demographics, genetic results, prenatal and postnatal outcomes including one year survival as well as autopsy data were extracted. Etiology of hydrops was classified using 13 previously established categories. In 4 patients observed between 2016 and 2019, we used a next-generation-sequencing (NGS) panel for genetic evaluation. Ninety NIHF cases were identified, with a median gestational age (GA) at diagnosis of 14weeks. There were 25 live-born infants with a median GA of 34weeks at birth, 15 patients survived to one year. There was aneuploidy in more than one third of the cases. All 90 cases were subclassified into etiologic categories with chromosomal 35, idiopathic 15, syndromic 11, cardiovascular 9, inborn errors of metabolism 6, lymphatic dysplasia 3, thoracic 3, infections 3, gastrointestinal 3 and hematologic 2. The NGS panel was used in 4 cases and 4 diagnoses were made. In 90 cases with NIHF we identified an aneuploidy in more than one third of the cases. Improved techniques, such as possibly specific genetic analysis, could reduce the high rate of unexplained cases of NIHF.

Survival of Hydrops Fetalis with and without Fetal Intervention.

Objectives: To investigate the survival rate of hydrops fetalis after fetal interventions and neonatal intensive care. Methods: We reviewed the medical records of patients diagnosed with hydrops fetalis from January 2009 to December 2019 at Changhua Christian Children’s Hospital. All cases had abnormal fluid accumulation in at least two body compartments during pre- and postnatal examination. The primary outcome measure was the mortality rate. We also collected information regarding disease etiology, duration of hospital stay, Apgar score, gestational age at birth, initial hydrops fetalis diagnosis, fetal intervention, first albumin and pH levels, and maternal history. Results: Of the 42 cases enrolled, 30 survived and 12 died; the mortality rate was 28.6%. Furthermore, 22 cases received fetal intervention, while 20 cases did not; there was no significant difference in their survival rates (75% and 68%, respectively). Survival rate was associated with gestational age at birth, initial diagnosis time, birthweight, Apgar score, initial albumin and pH levels, and gestational hypertension. Only one case was immune-mediated. Among the nonimmune-mediated cases, the three most common etiologies were lymphatic dysplasia (12/42), idiopathic disorders (10/42), and cardiovascular disorders (5/42). Conclusions: Overall, hydrops fetalis was diagnosed early, and fetal intervention was performed in a timely manner. Preterm births were more frequent, and birthweight was lower in the cases that underwent fetal intervention than in those that did not, but there was no significant between-group difference in mortality. The initial diagnosis time, gestational age at birth, birthweight, Apgar score, and first albumin and pH levels were independently associated with mortality.