Significance: Generalized lymphatic anomaly and Gorham–Stout disease are extremely rare diseases with severe symptoms and poor prognosis. The etiology and clinical presentation of the patients remain poorly defined, but recent research has attempted to determine the pathogenesis of these diseases.

Recent Advances: In recent years, the characteristics of complex lymphatic anomalies have been revealed. Kaposiform lymphangiomatosis is recognized as a new entity that has an aggressive course and poor prognosis. Genetic analysis revealed somatic mutations in genes associated with the phosphoinositide 3-kinase (PI3K) pathway in lymphatic malformation lesions. Somatic NRAS mutation in lymphatic endothelium from a generalized lymphatic anomaly patient was also detected as a potential cause of disease. Furthermore, studies demonstrated the efficacy of the mammalian target of rapamycin (mTOR) inhibitor sirolimus for these lymphatic diseases.

Critical Issues: These diseases have overlapping symptoms, imaging features, and complications, leading to difficulty in their differential diagnosis. In addition, there are no standard therapies. Therefore, we need to determine the differences among these diseases to not only diagnose but also treat them appropriately.

Future Directions: Further investigations should reveal differences in the clinical features and findings of radiological, pathological, and genetic examinations to manage each disease appropriately. Somatic mutation in genes encoding RAS/PI3K/mTOR signaling pathway components could be associated with the pathogenesis of these diseases and may be novel targets for drug therapies.