PMC9550924_01
(A) Patient A with typical facies of Noonan syndrome, including moderate ptosis, down-slanting palpebral fissures, marked neck webbing, bilateral epicanthic folds, and low-set posteriorly rotated ears. (B) Bilateral lower limb lymphoedema with mild scrotal and penile oedema.
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F1
Examination revealed typical facies of Noonan syndrome (Figure 1A). Bilateral lower limb lymphoedema and mild scrotal lymphoedema was present, but no evidence of cutaneous chylous lymphangiectasia (Figure 1B).
Patient A: (A) Heavy T2 weighted coronal MRI image demonstrating moderate left sided pleural effusion (wide white arrow) and soft tissue oedema (narrow white arrow). (B) Post contrast MRI coronal MIP image demonstrating bilateral flow of contrast from the inguinal lymph nodes into the retroperitoneal lymphatics and up into the distal thoracic duct. (C) Termination of the thoracic duct at the level of the carina (white arrow) at the site of surgical ligation. No single point of drainage into the terminal thoracic duct from the abdomen is identified. No leakage of contrast is seen into the pleural effusions.
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F2
DCMRL was performed with intranodal injection of gadolinium into the inguinal lymph nodes on both sides (Figures 2A-C). Initial T2 weighted imaging was undertaken prior to contrast and demonstrated a moderate left sided pleural effusion (Figure 2A) and marked soft tissue oedema. This demonstrated bilateral drainage of contrast from the iliac systems into the cisterna chylii (Figure 2B). The thoracic duct appeared interrupted which was in keeping with the history of surgical ligation of the thoracic duct (Figure 2C: White arrow).
(A) Patient B Typical Noonan facies with hypertelorism, down slanting palpebral fissures. (B) Scrotal oedema age 16 years with lymphangiectactic blisters. (C) progressively worsening scrotal oedema age 24 years.
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F3
Patient B was known to have a diagnosis of Noonan syndrome due to a de novo pathogenic variant in RIT1 [c.246T>G: p. (Phe82Leu)], with the typical facial features, a mild pulmonary stenosis at birth (not requiring surgery) but with normal intelligence and normal stature (Figure 3A). At the age of 22 he was noted to have progressive peripheral lymphoedema and his genital lymphoedema had dramatically progressed despite the use of compression garments (Figures 3B,C).
Patient B: (A) Reflux of contrast into the penoscrotal mass from the right inguinal lymphatics. (B) Non contrast CT showing bilateral pleural effusions, ascites and the penoscrotal mass. Long white arrows show residual lipiodol leakage into the pleural effusions bilaterally. Arrowhead shows lipiodol in the small bowel mesentery. Short white arrow shows lipiodol reflux into the scrotum. (C) Echocardiogram, 2 months after pericardiocentesis -parasternal long axis view showing a large >2 cm pericardial effusion (white asterix) adjacent to the left ventricular posterior wall. (D) Echocardiogram, 4 months after commencing treatment with trametinib parasternal short axis view confirming reduction in pericardial effusion size around the left ventricle (marked with a white asterix).
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F4
The initial study and the delayed x-ray confirmed reflux of lymphatic fluid into the penoscrotal mass (Figure 4A). A delayed non contrast CT scan performed 4 h later demonstrated leakage of contrast (lymphatic fluid) bilaterally into the pleural effusions and leakage or reflux of contrast into the small bowel mesentery (Figure 4B) but this was not felt to be amenable to surgery or embolisation. All echocardiographic signs of hemodynamic compromise were noted including ~50% trans-tricuspid respiratory Doppler variation, systolic collapse of the right atrium, diastolic collapse of the basal right ventricular free wall and a dilated and fixed inferior vena cava (Figure 4C). The pericardial effusion took longer to resolve but 18 months into treatment, the fluid was considerably reduced with only small to moderate fluid (Figure 4D).
Bar chart demonstrating the 36 item Short Form (SF36) health related quality of life score for patient B; completed at baseline before Trametinib (baseline), week 9 after commencing Trametinib (T1) and at 1 year follow up (T2).
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F5
Trametinib, week 9 after Trametinib intervention and at 1 year follow up. The patient's SF36 score improved across all domains (except limitations due to emotional health) between all time points. The most drastic improvements were in physical functioning and general health change (Figure 5).