Lymphatic Phenotype in Noonan Syndrome Spectrum Disorders

NCT ID: NCT06267807

Last Updated: 2025-04-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-27
• Study Completion Date: 2025-04-01

Brief Summary

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

Detailed Description

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

Conditions

Lymphatic System Disorders Congenital; Lymphatic Diseases; Noonan Syndrome; Lymphatic Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

MR lymphangiography contrast injection

GBCM will be administered. Any routinely used macrocyclic GBCM can be used for MR lymphangiography, we generally use Dotarem® (Gadoteric acid- gadoterate meglumine). The dose used is the same standard dose of 0.1 mmol/kg of body weight used for routine intravenous injection. The guidelines and precautions used for intravenous injection of GBCM, should be followed for MR lymphangiography.

Subsequently, post-contrast imaging is performed (again, this will take around 20 minutes)

Group Type: OTHER

Dynamic contrast-enhanced lymphangiography

Intervention Type: DIAGNOSTIC_TEST

The subject is placed supine on a detachable MR imaging table, outside the scanning room. Both inguinal regions are prepared under sterile conditions. Using Ultrasound guidance, the thoracic duct outlet at the left venous angle is identified. Under US guidance, a small 25 gauge needle is placed at the corticomedullar junction of an inguinal lymph node on each side. The needle position is confirmed and checked that there is no extravasation at saline injection under US visualization. The subject is then transferred to the MR imaging machine. First, pre-contrast imaging is performed, this takes around 20 minutes.

Interventions

Dynamic contrast-enhanced lymphangiography

The subject is placed supine on a detachable MR imaging table, outside the scanning room. Both inguinal regions are prepared under sterile conditions. Using Ultrasound guidance, the thoracic duct outlet at the left venous angle is identified. Under US guidance, a small 25 gauge needle is placed at the corticomedullar junction of an inguinal lymph node on each side. The needle position is confirmed and checked that there is no extravasation at saline injection under US visualization. The subject is then transferred to the MR imaging machine. First, pre-contrast imaging is performed, this takes around 20 minutes.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

MR lymphangiography

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Radboudumc

Nijmegen, Gelderland, Netherlands

Countries

Netherlands

Other Identifiers

NL84520.091.23

Identifier Type: OTHER

Identifier Source: secondary_id

114369

Identifier Type: -

Identifier Source: org_study_id