Improving the understanding of the anatomy and lymph flow in the central lymphatic system in patients with Noonan Syndrome Spectrum Disorder

Noonan Syndrome Spectrum Disorders (NSSDs) are attributed to pathogenic
variants in genes associated with the Ras/MAPK signaling pathway and are
categorized as RASopathies. Lymphatic diseases manifest in approximately 36% of
individuals with NS over their lifetime, displaying varying symptoms, severity,
and onset. However, the precise prevalence of lymph flow disorders among
RASopathy patients remains unknown, primarily due to the presence of
unrecognized symptoms and the subsequent lack of diagnosis.

Presently, there is no established protocol for diagnosing lymph flow
disorders. In many instances, the diagnosis is primarily based on symptomatic
presentation rather than an assessment of the underlying abnormal lymph anatomy
or flow. Tests such as lymph scintigraphy exist to evaluate lymph flow, but
they suffer from limited spatial and temporal resolution. Some medical
institutions employ MR T2 imaging, which visualizes fluid (lymph) but not its
flow. A more recent advancement in diagnosis is the implementation of dynamic
MR lymphangiography (DMRL) with intranodal contrast injection, initially
developed in Philadelphia and subsequently introduced at Radboudumc. This DMRL
scan enables visualization of lymph flow within the central lymph vessels,
facilitating the diagnosis of anatomical and flow irregularities.

By relying solely on symptom-based diagnoses without addressing the underlying
cause, therapeutic interventions tend to focus on alleviating symptoms rather
than addressing the pathological factors. For instance, patients diagnosed with
primary lymphedema (which implies an unknown etiological cause) may possess
anatomical or functional abnormalities within the central conducting lymphatic
system that are not identified as the causative factors of lymph flow issues.
Enhancing the diagnostic process requires a comprehensive understanding of the
pathophysiology, which can be achieved by studying the central conducting
lymphatic system in NS patients with and without lymphatic diseases. This
research endeavor aims to ultimately refine therapeutic interventions tailored
to the specific pathological causes underlying these conditions.

To get a better insight into the central conducting lymphatic system in adult
volunteers with Noonan Syndrome (NS) without clinical symptoms or signs of
lymphatic disease compared to NS and CardioFacioCutaan syndrome patients with
severe lymphatic disease and healthy volunteers. (ongoing study: (Lymphomics;
improving the understanding the anatomy of the lymphatic system and the
direction and velocity of lymph flow; approved by the Medical Ethics Committee
at Radboud University Medical Center Nijmegen file number 2021-7514).

- The anatomy of the central lymph vessels will be studied in NSSD patients
without (a history of) lymphatic symptoms. This will be done using dynamic MR
lymphangiography (DMRL) with intranodal contrast injection. End point is an
overview of the anatomy of the central lymph vessels in lymph-healthy NS
patients. This will be compared with the anatomy of the central lymph vessels
in healthy volunteers without NS and without lymphatic symptoms, and patients
with NSSD and a history of lymphatic symptoms.

- The velocity and direction of the contrast in the central lymphatics will be
studied in NSSD patients without (a history of) lymphatic symptoms. This will
be done using the same DMRL. End point will be an overview of normal values of
contrast velocity and direction This will be compared with the velocity and
direction of flow in healthy non-NS volunteers as reference.

This is a single center, prospective collection of data of MR lymphangiography
in our center.
The anatomy of the central lymph vessels will be studied. The MR
lymphangiography scans
will also be reviewed for measurements such as the width of the thoracic duct
and the
location of inflow into the subclavian vein. In addition, the velocity of the
contrast will be
measured on the post-contrast MR images.

Participation in this study places subjects at minimal risk. Subjects will
undergo placement of a small needle in an inguinal lymph node on both sides,
with very little risk of bleeding and/or infection, as with other minimal
invasive procedures. The dynamic MR lymphangiography will take approximately
two hours.