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.
RASA1 gene mutations have typically been associated with capillary malformation–arteriovenous malformations (CM-AVMs).1 RASA1 mutations that have been associated with cases of CM-AVM typically result in a loss of function of the p120-RasGAP domain, affecting vascular endothelial cell function.1 RASA1 mutations may also cause overgrowth in vascular tissue, leading to CM-AVMs, with particularly high risk of central nervous system involvement.2 RASA1 mutations also impact lymphatic vessel development leading to lymphatic malformations,3 with lymphedema and chylothorax reported as part of the RASA1 mutation phenotype.4,5 Mice experiments have revealed chylothorax in mice when RASA1 pathway–associated proteins were altered, supporting theories of RASA1 impact of lymphatic leakage.6–8
The lymphatic system serves 3 main functions: transport of lipid solutions and vitamins to circulation, collection of extravasated fluids and proteins, and returning lymphocytes to circulation.9 Chyle is a fluid composed of fats, electrolytes, cholesterol, glucose, and proteins with lymphocytes. Chylothorax occurs when chyle accumulates in the pleural space from disruption of the thoracic duct. Complications can be numerous, including severe respiratory distress, along with concerns for malnutrition, vitamin deficiencies, fluid imbalances, risk of thrombosis and immonodeficiences.9 Treatment priorities include management of respiratory complications, treatment or repair of underlying causes, and careful management of associated nutrition and immune complications.9 Although chylothorax occurrence is relatively rare in neonates and children, prompt diagnosis and treatment are important in preventing severe complications.9,10
Chylothorax is especially rare in neonates, with incidence in the United States estimated as 1:15 000 live births, with a usual 2:1 male/female ratio.10 Causes of chylothorax in neonates can include thoracic anomalies (including diaphragmatic hernia and congenital pulmonary malformations) and lymphatic malformation (isolated or as part of complex genetic syndromes).9,11 In pediatric patients, causes expand to include complications of trauma or thoracic surgery or as part of malignant or inflammatory conditions.9 Neonatal lymphatic flow may be up to 5 times that of adults,10 which can exacerbate the risk of development of complications from a lymphatic malformation.10 Congenital chylothorax can have significant complications, including pulmonary hypoplasia and compression of cardiac structures leading to heart failure.10 Cases of nonimmune hydrops fetalis associated with RASA1 mutation have been reported; however, these infants have also had detected CM-AVM abnormalities. Our case is the first to our knowledge of an infant with congenital chylothorax with no associated structural anomalies with a finding of a RASA1 mutation and no other CM-AVM abnormalities.
Because a number of genetic syndromes can be associated with the lymphatic disorders, a genetic workup is recommended in the evaluation of these infants.10
Institutional Research Ethics Board approval and informed consent from legal guardian were obtained before the development of this case report.
Case Presentation
A female infant was born at 34 + 4/7 weeks’ gestational age to a 24-year-old mother with A+ blood type. The mother’s medical history included an intellectual disability, with no additional known medical conditions. There were no reported teratogenic exposures during pregnancy. Ultrasounds done in pregnancy included a 22 + 2/7-week scan, which revealed possible ventricular septal defect. Follow-up fetal echo at 25 + 6/7 weeks revealed normal cardiac anatomy and small pleural effusion. The mother presented to a level 2 hospital in labor at 34 + 3/7 weeks. Ultrasound at presentation revealed signs of hydrops fetalis, including ascites, skin edema, and bilateral pleural effusions in the fetus. Maternal transfer to our center was completed for newborn care in the tertiary NICU at Kingston Health Sciences Centre.
Hospital Course
The infant was delivered at 34 + 4/7 weeks’ gestational age by cesarean delivery because of progression of maternal labor and concern for fetal distress. At delivery, the infant was extremely edematous, consistent with antenatal diagnosis of hydrops, with no respiratory effort. Birth weight was 4010 g (>97th percentile), head circumference was 32.9 cm (75th–90th percentile) and length was 49 cm (90th–97th percentile). Poor respiratory effort necessitated need for intubation at delivery.
Initial chest radiograph (CXR) revealed large, bilateral, pleural effusions (Fig 1), with the right side significantly larger than the left, resulting in left-sided mediastinal shift. This shift resolved on repeat imaging after insertion of a right-sided chest tube shortly after birth (Fig 2).
CXR after chest tube insertion on first day of life, anteroposterior view. L, left side.
CXR after chest tube insertion on first day of life, anteroposterior view. L, left side.
Drainage of the pleural fluid was initially serosanguineous. Initial analysis of the pleural fluid revealed a cell count of 1390 × 106/L with a differential of 89% lymphocytes and total protein level of 18.8 g/dL. The triglyceride level on initial analysis was 0.42 mmol/L, but, of note, the infant had not yet been fed. This analysis was consistent with published criteria for chylous fluid.11 Repeat testing after initiation of feeds revealed increasing fluid triglycerides and ongoing elevated protein.
The infant was started on total parenteral nutrition (TPN) on day 1 of life. Hemodynamic concerns of low blood pressures in the first week of life required inotropic support and albumin infusions for serum hypoalbuminemia. The chest tube maintained an output >1 L per day during the first week of life. By the second week of life, inotrope support was weaned and blood pressures remained stable.
Echocardiogram in the first week revealed a small patent ductus arteriosus with bidirectional flow and evidence of pulmonary hypertension with normal ventricular function.
The infant was eventually weaned to noninvasive ventilation. Medical therapy with octreotide and medium chain fatty acid formula were then initiated, with a subsequent decrease in chest tube drainage. Octreotide is a somatostatin analogue used to treat chylothorax. Although variation exists in octreotide treatment regimens used in neonates, available evidence suggests that octreotide may be more effective in treating congenital forms of chylothorax when compared to acquired forms in this population.12 However, after reaching full feed volumes, there was a recurrence in respiratory symptoms and an increase in chest tube drainage volumes, and the infant was again placed on TPN support. CXR revealed reaccumulation of fluid in the right lung (Fig 3). Needle aspiration was performed, and chylous fluid was drained, with improvement in respiratory symptoms.
CXR revealing reaccumulation of chylothorax after feed trial on day of life 36, anteroposterior view. R, right side.
CXR revealing reaccumulation of chylothorax after feed trial on day of life 36, anteroposterior view. R, right side.
The infant was transferred to the pediatric medicine inpatient unit on day of life 125 and was initially maintained on a low long-chain fatty acid formula with small right-sided effusion and no respiratory symptoms. On day of life 140, she again developed respiratory symptoms and was found to have reaccumulation of the chylothorax. She was treated again with octreotide and TPN. A chest tube was reinserted at this time. The chylothorax resolved with octreotide treatment, and feeds with low long-chain fatty acid formula were resumed and the chest tube removed. She was also found to have a Klebsiella bacteremia at this time, which was treated with a course of intravenous antibiotics. She was ultimately discharged from the hospital at the age of 160 days.
The infant was again admitted at 7 months of age for a viral respiratory infection that did not require any respiratory support. Repeat CXRs did not reveal reaccumulation of fluid or new pleural effusions, and she was discharged from the hospital after rehydration.
At the time of this report, the infant is awaiting an appointment for further imaging workup with lymphangiography at a quaternary pediatric center to better characterize the structure of the patient’s lymphatic system and potentially localize the site of a lymphatic malformation. At her most recent follow-up in our pediatric respirology clinic at the age of 9 months, she remained stable on low long-chain fatty acid formula feeds, and a plan was put in place to transition to standard formula and pureed food feeds.
Workup
After birth, an initial diagnosis of nonimmune fetal hydrops with chylothorax was made without a known etiology. The initial hemoglobin level was within normal range (152 g/L) and direct antigen testing results were negative, supporting a nonimmune etiology. Infectious disease workup, including cytomegalovirus, enterovirus, parechovirus, syphilis, toxoplasmosis, and parvovirus B19, was negative for congenital infections. Routine provincial newborn screening performed at 24 hours of age was positive for severe combined immunodeficiency disorder, which was felt to be a false-positive due to loss of proteins, lymphocytes, and immunoglobins through chest tube drainage from the chylothorax. Repeat newborn screen and immune workup were later negative for severe combined immunodeficiency disorder.
Genomic microarray was done, which revealed a deletion of 0.099 Mb on chromosome region 5q14.3, encompassing exon 2 to 11 of the RASA1 gene. A genetic history did not reveal family members with a similar phenotype. Genetic testing on the infant’s mother was positive for the same RASA1 mutation. The mother did not have any history of congenital chylothorax or similar phenotype to the infant, but has been diagnosed with intellectual disability. She is planned for imaging investigations in the future. Family history was significantly limited on the father’s side.
Imaging investigations, including a general and targeted abdominal ultrasound, a targeted head ultrasound, a computed tomography chest scan, and an MRI of the brain and spine, did not reveal any arteriovenous malformations (AVMs). In addition, there was no evidence on imaging or clinical for intravascular clots or coagulopathy.
An incidental finding of a new right humerus fracture was made on CXR during the first week of life. There was no history of trauma at birth or during admission. No additional fractures were seen elsewhere, and bone health bloodwork profiles revealed normal results. The bone revealed normal signs of healing on follow-up imaging.
Discussion
RASA1 mutations are classically known to cause AVMs, with evidence of lymphatic malformations as well. This is the first reported case in our knowledge to describe a congenital chylothorax in a human neonate found to have a RASA1 deletion. Although congenital vascular malformations and hydrops fetalis in neonates with RASA1 mutations have been described, this case is also the first to our knowledge to describe an occurrence of hydrops fetalis without an associated CM-AVM in an infant with the finding of chylothorax. In our case, the infant had no other identified infectious, iatrogenic, or anatomic risk for the development of nonimmune hydrops fetalis or congenital chylothorax, aside from the genetic finding of RASA1 deletion. Because both nonimmune hydrops fetalis and congenital chylothorax are rare, this case highlights the importance of keeping an underlying genetic cause on the differential in the workup of these infants. Although classically described phenotypes of RASA1 mutations present with venous malformations, in this case no such malformations were present. This is an important point to take away from this case because the infant’s eventual genetic diagnosis did necessitate near–full-body imaging to rule out a possible internal CM-AVM, given the high risk with the condition. Although this infant’s workup did not reveal internal AVMs, the potential implications of missing a significant vascular malformation can be deadly, especially in the brain. This highlights the importance of knowledge regarding nonclassic presentations of RASA1 mutations to appropriately workup for potentially life-threatening complications that may not otherwise be obvious on physical examination.
Conclusions
In cases of congenital chylothorax, especially with nonimmune hydrops fetalis, genetic testing should be included as part of a complete workup. RASA1 mutations, which can cause lymphatic malformations, should be considered as part of the differential diagnosis, and comprehensive screening for associated vascular anomalies should be performed.
Dr Gallipoli reviewed the patient chart and drafted the initial manuscript; Drs Sehgal, Maclean, and Walia critically reviewed and revised the manuscript for important intellectual content; and all authors conceptualized and designed the case report, reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
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