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

Abstract

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.

EPHB4-RASA1-Mediated Negative Regulation of Ras-MAPK Signaling in the Vasculature: Implications for the Treatment of EPHB4- and RASA1-Related Vascular Anomalies in Humans

“…For EPHB4 , these include lymphatic-related hydrops fetalis (LRHF, accumulation of fluid in the fetus because of lymphatic dysfunction), central conducting lymphatic anomaly (a lymphatic vessel flow disorder) and lymphedema (tissue edema consequent to lymphatic dysfunction) [ 35 , 36 , 37 , 38 ]. Similarly, germline inactivating RASA1 mutations have been reported in LRHF and lymphedema [ 39 , 40 ].…”

Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema

“…Central conducting lymphatic anomaly (CCLA), in which the development and function of large, truncal collecting lymphatic vessels is affected, is a severe lymphatic malformation for which few effective treatments are available (3)(4)(5). Recent work revealed a recurrent, gain-of-function pathogenic variant in ARAF, affecting activity of the RAS/mitogen activated protein kinase (MAPK) signaling pathway, underlying CCLA (6), and pathogenic variants in RAS/MAPK pathway genes including PTPN11, KRAS, BRAF, SOS1, HRAS, ARAF, RAF1, CBL, RIT1, and RASA1 are established to cause developmental lymphatic vascular malformations manifesting in chylothorax (the accumulation of lipid-rich chyle in the thoracic cavity caused by lymphatic vessel dysfunction), pleural or pericardial effusions, lymphangiectasia, and lymphedema (6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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

“…While more than 300 individuals affected by the condition have been reported worldwide [ 14 ], prenatal manifestations of CM-AVM syndrome have been rarely discussed. The condition is probably underdiagnosed, since our knowledge of its antenatal and neonatal presentation is still poor, with only 21 cases with prenatal onset of the disorder described to date [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

“…The following supporting information can be downloaded at: , Table S1: List of primer sequences; Table S2: Additional clinical features and molecular data of reported patients affected by CM-AVM Syndrome with prenatal onset of symptoms. Abbreviations: pn, postnatal finding; CMs pn, capillary malformations (postnatal diagnosis); AVMs, arteriovenous malformations; AVF, arteriovenous fistulas; PWS pn, Parkes Weber Syndrome (postnatal diagnosis); VGAM, vein of Galen aneurysmal malformations; n/a, not applicable; n/r, not reported; PDA, patent ductus arteriosus; PFO, patent foramen ovale; AMI, Acute myocardial infarction; FCM, fetal cardiomyopathy; 1 , unilateral pyelectasis; 2 , pelviectasis/hydronephrosis; CM, cardiomegaly [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”