Lymphatic Abnormalities in Noonan Syndrome Extend Beyond Clinically Apparent Disease

Abstract

Lymphatic disease represents a well-described manifestation of Noonan syndrome (NS), yet the full phenotypic spectrum remains incompletely characterized, especially in asymptomatic individuals. We conducted a cross-sectional study including 10 individuals with NS (four with peripheral lymphedema and six without) and 10 age- and sex-matched cardiovascularly healthy controls. Central lymphatic anatomy was visualized using non-contrast T2-weighted MR-lymphangiography, and peripheral lymphatic morphology and function were assessed with near-infrared fluorescence (NIRF) imaging and strain gauge plethysmography (SGP). Variations in thoracic duct morphology were observed in 89% (8/9) of NS individuals compared to 20% (2/10) of controls. Thoracic lymphatic classifications (Biko/Dori scale) differed significantly in NS individuals, both with and without lymphedema, compared with healthy controls (p < 0.05). Central lymphatic abnormalities were observed in five of nine NS individuals, including three without clinical signs of lymphatic disease. Abnormal peripheral conduction in collective vessels, characterized by retrograde or absent flow, was detected in all four NS individuals with lymphedema (p < 0.05), while normal conduction was observed in asymptomatic NS individuals and controls. Findings from this study indicate that central lymphatic abnormalities may be present in NS regardless of symptom status, with abnormal peripheral conduction developing later in association with clinically manifest lymphedema. Central lymphatic abnormalities extend beyond clinically apparent disease and broaden the recognized phenotype, highlighting the value of lymphatic imaging for diagnosis and monitoring.