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.

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.

Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome.

Pathogenic variants in RASA1 are typically associated with a clinical condition called "capillary malformation-arteriovenous malformation" (CM-AVM) syndrome, an autosomal dominant genetic disease characterized by a broad phenotypic variability, even within families. In CM-AVM syndrome, multifocal capillary and arteriovenous malformations are mainly localized in the central nervous system, spine and skin. Although CM-AVM syndrome has been widely described in the literature, only 21 cases with prenatal onset of clinical features have been reported thus far. Here, we report four pediatric cases of molecularly confirmed CM-AVM syndrome which manifested during the prenatal period. Polyhydramnios, non-immune hydrops fetalis and chylothorax are only a few possible aspects of this condition, but a correct interpretation of these prenatal signs is essential due to the possible fatal consequences of unrecognized encephalic and thoracoabdominal deep vascular malformations in newborns and in family members carrying the same RASA1 variant.

Next Generation Sequencing in a Case of Early Onset Hydrops: Closing the Loop on the Diagnostic Odyssey!

Non-immune fetal hydrops (NIFH) is an etiologically heterogeneous condition. Cardiac anomalies are one of the common causes of NIFH. Cardiac anomalies can be isolated, multifactorial malformations or have a genetic basis. PLD1 variants have been associated with developmental defects involving the right heart. We present a NIFH with a PLD1 associated right heart malformation.We describe a spontaneously aborted 14 weeks old NIFH fetus with a rudimentary right ventricle, pulmonary valve atresia and pulmonary artery stenosis found at fetopsy. After a normal microarray, whole exome sequencing revealed a homozygous missense variant c.2023 C > T (p. Arg675Trp) in the PLD1 gene. Conclusion: Detailed fetopsy and genetic evaluation in this NIFH allowed an etiological explanation, further corroborated the association of PLD1 gene variants and developmental right heart defects, and that this defect can be associated with NIHF.

Atrial fibrillation with rapid ventricular response as a maternal presentation of mirror syndrome: a case report.

Mirror syndrome is the phenomenon of fetal hydrops causing maternal edema and weight gain. Here, we report a case of arrhythmia as the primary maternal symptom. A 36-year-old woman, G2P1001, at 34.5 weeks of gestation presented with new-onset fetal hydrops combined with maternal weight gain and edema. She developed atrial fibrillation with rapid ventricular response; cardiac workup was unremarkable. Rate control was achieved with diltiazem. She underwent delivery and reverted to normal sinus rhythm on post-operative day 1. Volume overload causes atrial wall stress and neurohormonal changes that may trigger atrial fibrillation. Optimization with rate control facilitated good maternal and fetal outcomes in this case.

Clinical Course and Outcome of Non-Immune Fetal Hydrops in Singleton Pregnancies.

Nonimmune fetal hydrops is a condition defined by abnormal fluid accumulation in two or more body compartments. The aim is to evaluate factors associated with adverse outcome in diagnosed fetal hydrops and to investigate the aspects for the decision making in the case of termination of pregnancy. Therefore, a retrospective data analysis of pregnancies complicated by non-immune hydrops fetalis between 2004 and 2018 was performed in a single tertiary referral center. Of 361 pregnancies with diagnosed fetal hydrops, in 183 cases (50.7%), the parents decided to terminate the pregnancy. A strong relationship between etiology and termination of pregnancy was demonstrated, whereas the highest rates of termination of pregnancy were found if a chromosomal aberration was diagnosed. Of the remaining 178 cases, 51 cases (28.7%) had a miscarriage, 33 cases (18.5%) had an intrauterine fetal death, and 94 cases (52.8%) were live born, whereas 26 (27.7%) of these offspring died within the first week of life. The risk of an adverse outcome increased with lower gestational age at diagnosis (p < 0.001). A nuchal translucency thickness greater than 2.5 mm was associated with an adverse outcome (p < 0.01). Furthermore, pregnancies with adverse outcome had significantly more affected compartments (median: 3; IQR 2), compared with live born cases (median: 2; IQR 1; p < 0.01). In conclusion, adverse outcome in pregnancies with fetal hydrops was associated with a lower gestational age at diagnosis, nuchal translucency greater than 2.5 mm and a higher count of affected compartments. These results confirm that a precise clinical workup to identify the underlying etiology of non-immune fetal hydrops is essential for a better prognostic assessment and accurate counselling of parents.

Tumor cardiaco fetal. Reporte de un caso / Fetal cardiac tumor. Report of a case

Resumen: ANTECEDENTES: Los tumores cardiacos fetales son excepcionales y se asocian con complicaciones que ponen en riesgo la vida del feto. Se diagnostican a partir del segundo trimestre y pueden provocar hidrops fetal no inmunitario, arritmias, compresión de los conductos de salida y muerte súbita. Es importante el seguimiento durante la gestación para detectar posibles complicaciones y establecer un plan de nacimiento. CASO CLÍNICO: Paciente de 35 años, multigesta, enviada a la unidad materno-fetal para valoración por embarazo de 24.2 semanas y feto con tumor cardiaco único, localizado en el ápex, de gran tamaño. No se identificó afectación de la función cardiaca, por lo que solo ameritó vigilancia prenatal. Al nacimiento, el recién nacido recibió tratamiento con everolimus, con reacción satisfactoria. CONCLUSION: El tratamiento y seguimiento de fetos con tumor cardiaco es de suma importancia para detectar complicaciones prenatales y establecer el plan de nacimiento en la unidad de tercer nivel de atención médica.

Abstract: BACKGROUND: Fetal cardiac tumors are rare, with a very low incidence, however; when they do occur, they are associated with life-threatening complications of the fetus. They are diagnosed from the second trimester and can cause non-immune fetal hydrops, arrhythmias, compression of outflow tracts, and sudden fetal death. Follow-up during pregnancy is important to detect possible complications and establish a birth plan. CLINICAL CASE: A 35-year-old multigest patient, sent to the fetal maternal unit by his treating physician for evaluation for 24.2-week pregnancy and fetus with a single cardiac tumor, located on the apex, of large size; and without compromise in cardiac function, so only prenatal surveillance was warranted. At birth, the newborn received everolimus treatment, with a good response. CONCLUSION: The case of a patient with a single pregnancy and fetus with a prenatal diagnosis of a large cardiac tumor is presented with a family history of hemangiomas. In this case, a follow-up approach to detect prenatal complications and establish a birth plan in a third level of medical care is critical for a good practice.

Hídrops fetal no inmunológico / Non-Immune Fetal Hydrops

El hídrops fetal se define como el acúmulo anormal de líquido en los tejidos blandos y cavidades serosas del feto (pleural, pericárdico y peritoneal). Se divide en dos grupos: hídrops fetal inmune e hídrops fetal no inmune. Se presenta el caso de gestante (9 semanas), calificada como riesgo genético incrementado por sus antecedentes obstétricos. Se procede según establece el Programa de Genética para la Detección Prenatal de Defectos Congénitos. Se resalta la importancia de la información de los resultados de las ecografías prenatales en el diagnóstico precoz de malformaciones congénitas y/o defectos estructurales del feto. Tras el seguimiento del caso y la realización de pruebas confirmativas se llegó al diagnóstico presuntivo de hídrops fetal no inmunológico, lo cual fue confirmado con posterioridad por anatomía patológica. Teniendo en cuenta que el pronóstico de esta entidad es generalmente desfavorable y con una tasa de mortalidad intrauterina muy alta, la pareja decidió la terminación del embarazo(AU)

serous cavities (pleural, pericardial, and peritoneal). It is divided into two groups: fetal immune hydrops and non-immune fetal hydrops. We report the case of a 9 weeks pregnant woman, classified to be at increased genetic risk by her obstetric history. We proceed as established by the Genetics Program for the Prenatal Detection of Birth Defects. The importance of the prenatal ultrasound information is relevant in the early diagnosis of congenital malformations and / or structural defects of the fetus. After the follow-up of the case and the performance of confirmatory tests, a presumptive nonimmunological fetal hydrops is diagnosed, which is subsequently confirmed by pathological anatomy. Taking into account that the prognosis of this entity is generally unfavorable and with very high intrauterine mortality rate, this couple decided to terminate the pregnancy(AU)