Question of the Week 591
Authors: Manal Mirreh, MD AND Lea Matthews, MD - Children’s Hospital of Philadelphia
A 6-week-old, former 36-week infant undergoes surgical repair of pulmonary valve stenosis. On postoperative day 3, chest tube output increases substantially and becomes milky in nature after advancement of feeds, and testing of the pleural fluid confirms chylothorax. Genetic testing is sent at that time, with RASopathy suspected. Which of the following RASopathies is MOST LIKELY to cause clinically significant lymphatic disease, including chylothorax?
EXPLANATION
RASopathies are a group of genetic syndromes caused by germline mutations in genes encoding components of the RAS/MAPK signaling pathway, which is well-characterized in cancer biology for its role in regulating cell proliferation, differentiation, and survival. When dysregulated during development, RAS/MAPK pathway activation produces a family of clinically overlapping syndromes that share characteristic features including facial dysmorphism, congenital heart disease, short stature, and variable lymphatic disease.1 Recognized RASopathies include Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines (formerly LEOPARD syndrome), Legius syndrome, and neurofibromatosis type 1, among others.1,2
Noonan syndrome (Answer C) is among the best-established causes of RASopathy-associated lymphatic disease. It is associated with central conducting lymphatic anomalies including thoracic duct dysplasia, chylothorax, pulmonary lymphangiectasia, and protein-losing enteropathy. Costello syndrome, caused by gain-of-function HRAS mutations, can present similarly, with fetal chylothorax and generalized lymphedema, though lymphatic involvement is less prominent than in Noonan.2
By contrast, Legius syndrome (Answer A), caused by loss-of-function mutations in SPRED1, is frequently mistaken for neurofibromatosis type 1 given its overlapping phenotype of cafe-au-lait macules, axillary freckling, macrocephaly, and mild neurocognitive findings. However, lymphatic disease is not a recognized clinical feature of Legius syndrome.1 Neurofibromatosis type 1 (Answer B) has a well-described vascular phenotype, including arterial dysplasia and aneurysm formation, but clinically significant lymphatic disease is not considered a characteristic feature of the syndrome, in contrast to the well-characterized, syndrome-defining lymphatic anomalies seen in Noonan syndrome.
Isolated case reports have described chylothorax, lymphedema, and pericardial effusion in patients with NF1, presumed to reflect the same vasculopathy that predisposes to arterial aneurysms and stenoses in this condition.4 These reports remain rare exceptions rather than an expected part of the phenotype, so lymphatic disease is not something to anticipate or screen-for in NF1 the way it is in Noonan syndrome.
First-line treatment of lymphatic disease depends on the presentation and includes conservative measures such as dietary modification, compression therapy, and pharmacotherapy, as well as surgical interventions including lympho-venous anastomosis or selective embolization of abnormal or leaky lymphatic channels. Molecular therapies targeting the RAS/MAPK pathway, particularly MEK inhibitors such as trametinib, have shown great promise in patients with severe or treatment-refractory lymphatic disease, including chylothorax, protein-losing enteropathy, and chylous ascites.3
REFERENCES
1. Rauen KA. What is a RASopathy? In: Rauen KA, ed. The RASopathies. Springer; 2024. Accessed August 3, 2026. https://doi.org/10.1007/978-3-031-62945-7_1
2. Landis BJ, Lisi MT. Syndromes, genetics, and heritable disease. In: Ungerleider RM, Meliones JN, eds. Critical Heart Disease in Infants and Children. 3rd ed. Elsevier; 2019:897–898.
3. Sheyanth IN, Kelly B, Mohanakumar S, et al. Lymphatic abnormalities in Noonan syndrome extend beyond clinically apparent disease. Am J Med Genet A. 2026:1-13. Accessed August 3, 2026. https://doi.org/10.1002/ajmg.a.70146
4. Finsterer J, Stollberger C, Stubenberger E, Tschakoschian S. Lymphangiopathy in neurofibromatosis 1 manifesting with chylothorax, pericardial effusion, and leg edema. Int J Gen Med. 2013;6:743-746. https://doi.org/10.2147/IJGM.S45825