Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders

Rationale: Noonan Syndrome Spectrum Disorders (NSSDs) are caused by pathogenic variants in genes of the Ras/MAPK signaling pathway, and belong to the RASopathy.

Lymphatic disease occur in 36% of patients with Noonan Syndrome (NS) during their lifetime, with different symptoms, severity, and onset. However, it is unknown how many patients with RASopathy are exactly impaired with lymph flow disorders, since many of these patients have unrecognized symptoms and go undiagnosed. For example, patients diagnosed with primary lymphedema (which implies being without known etiologic cause) may have an anatomic or functional abnormality of the central conducting lymph system that is not diagnosed as the causative lymph flow problem. With the diagnosis being based on the symptoms and not on the underlying pathophysiological mechanism, therapy will focus on diminishing symptoms and not on healing the pathophysiological cause. To eventually improve therapeutic intervention, a better understanding of the pathophysiology is necessary, and may be found by studying the central conducting lymphatic system of patients with NS and lymphatic disease, and adult volunteers with Noonan Syndrome without lymphatic disease. Objective: 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) Study design: A single center, prospective collection of data Study population: Adult volunteers with Noonan Syndrome without (a history of) complaints or signs of lymphatic disease. Intervention: Three questionnaires (general health, lymphatic abnormalities and general MRI safety) will be taken prior to the dynamic MR lymphangiography. In addition to standard physical examination and electronic patient file screening, for inclusion and exclusion purposes. Subsequently, the MR lymphangiography will be performed. After 24 hours, the subject will be called for a follow-up by phone. Main study parameters/endpoints: the anatomy of the central lymph vessels, the velocity and direction of lymph flow, which can be compared with reference values. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: 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

Inclusion criteria

• Noonan Syndrome confirmed by genetic test with a class 4 or 5 pathogenic variant according to ClinVar
• 18 years and older (no restriction for sex)
• Willing and able to have MR lymphangiography scanning in the Radboudumc
• Oral and written informed consent
• None of the exclusion criteria

Exclusion criteria

• unsuitable for MRI (e.g. metallic objects in the body, severe claustrophobia)

• A history of symptoms related to lymphatic disease
• pregnancy
• renal insufficiency
• liver cirrhosis
• History of surgery related to cardiovascular disease with hemodynamic consequence
• Other genetic diseases