Noonan syndrome is a multiorgan system disorder mediated by genetic defects along the RASknown as RASopathies. It is the second most common syndromic cause of congenital heart disease and, in ∼20% of the cases, is associated with severe lymphatic disorders, including chylothorax and protein-losing enteropathy. Recently, we reported on the use of mitogen-activated protein kinase inhibition in a patient with an ARAF mutation and severe lymphatic disorder leading to an abrupt improvement in symptoms and complete remodeling of the central lymphatic system. Here, we present a patient with Noonan syndrome and severe lymphatic abnormality, leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. The patient stopped responding to medical therapy and underwent several lymphatic interventional procedures, which led only to a temporary improvement in symptoms. Because of a lack of other treatment options, an expanded access approval was obtained, and the patient initiated treatment by mitogen-activated protein kinase inhibition using trametinib. This led to resolution of her symptoms, with complete normalization of her electrolyte levels, hemoglobin, and albumin within 3 months of starting the drug. Similar to the previously reported case, she also had complete and generalized remodeling of her lymphatic system. In patients with RAS pathway defects complicated by a severe lymphatic disorder, inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

Noonan syndrome (NS) is a congenital autosomal dominant multisystem disorder. It is the second most common syndromic cause of congenital heart disease after trisomy 21.1  In addition, NS is associated with characteristic facial features, short stature, and skeletal abnormalities. Pulmonary stenosis and hypertrophic cardiomyopathy are the most common cardiac manifestations of the syndrome. Lymphatic abnormalities are common in patients with NS and present in ∼20% of patients. The most common lymphatic manifestation is lymphedema, but protein-losing enteropathy (PLE), pulmonary and intestinal lymphangiectasia, ascites, and chylothorax are also common.2  NS is a genetically heterogeneous disorder, with multiple mutations in genes along the RAS-MAPK pathway. To date, germ-line mutations have been identified in >10 genes, with PTPN11, SOS1, and RAF1 being the most commonly involved.3,4 

RAS pathway defects (RASopathies) can lead to severe lymphatic abnormalities and have been discovered in patients with kaposiform lymphangiomatosis, generalized lymphatic anomaly, and other lymphatic conduction disorders.57  Recently, Li et al8  reported mitogen-activated protein kinase (MEK) inhibition in a patient with a severe lymphatic disorder and ARAF mutation, which lead to complete remodeling of the central lymphatic system and resolution of symptoms. Here, we report on the use of MEK inhibition with trametinib in a patient with NS and severe lymphatic dysfunction as well as transfusion-dependent upper gastrointestinal bleeding.

An ex–28 weeks’ gestational–age girl with NS (SOS1, c.2536G>A:p.[E846K]), Hashimoto thyroiditis, delayed puberty, growth hormone deficiency, attention-deficit/hyperactivity disorder, resolved ventricular septal defect (without intervention) initially presented at age 5 with a 2-month inpatient hospitalization for persistent chylothorax, after a lung biopsy was performed because of concern with pleural thickening. She eventually stopped draining and was discharged from the hospital. Over the next few years, she was overall well but had difficulty gaining weight, delayed puberty, and chronic fatigue, until age 14 when she presented to an outside hospital with pallor, abdominal pain, melena, and anemia, with hemoglobin of 5.7 g/dL. She was diagnosed with upper gastrointestinal bleeding and new-onset PLE, with albumin levels <3 g/dL. Her α-1 antitrypsin was markedly elevated at 1400 mg/mL. She was transfused packed red blood cells and had an extensive workup, focused on primary gastrointestinal sources of hemorrhagic duodenitis as seen on duodenoscopy. She was found to have mesenteric and retroperitoneal lymphangiectasia with friable, bleeding mucosa on capsule endoscopy. In addition, she developed a left chylothorax. She was started on octreotide, a low-fat diet, oral budesonide, and albumin infusions, which she was getting every 2 days. Despite aggressive medical therapy, she continued to bleed, requiring multiple transfusions and regular albumin supplementation. She was subsequently transferred to our institution for lymphatic evaluation and further management.

On arrival, she had a blood positive stool result and an albumin level of 2.9 g/dL. Her electrolytes were abnormal, with a low calcium of 7.5 mg/dL and sodium of 135 mmol/L. Heavily weighted T2 magnetic resonance lymphatic mapping revealed diffuse mesenteric edema and left-sided pulmonary interstitial edema and atelectasis (Fig 1A). She underwent intranodal and intrahepatic dynamic contrast magnetic resonance lymphangiography (DCMRL), which revealed a diffusely abnormal central lymphatic system with retrograde mesenteric flow. On intrahepatic DCMRL, she had leak of contrast into the duodenal lumen (Fig 2A insert). She also had extensive perfusion of the left chest and lung (Fig 2A). Endoscopy revealed diffuse duodenal lymphangiectasia and vascular ectasia (Fig 3A). She underwent a lymphatic embolization procedure with glue embolization of hepatoduodenal connections that resulted in temporary stabilization of her albumin and hemoglobin levels. However, within 2 months, her PLE and gastrointestinal bleeding recurred. Over the next 8 months, she underwent 2 additional lymphatic imaging and intervention procedures as well as intraduodenal cauterization of large areas of vascular ectasia. She had transient stabilization of hemoglobin and albumin after each procedure and then recurrence of symptoms within 3 months.

FIGURE 1

Coronal maximal intensity projection of T2-weighted MRI (A) before and (B) after treatment, showing resolution of mesenteric (arrows) and pulmonary interstitial (arrowhead) edema.

FIGURE 1

Coronal maximal intensity projection of T2-weighted MRI (A) before and (B) after treatment, showing resolution of mesenteric (arrows) and pulmonary interstitial (arrowhead) edema.

Close modal
FIGURE 2

Coronal maximal intensity projection of DCMRL (A) before and (B) after treatment showing near complete resolution of left-sided lung perfusion (arrow) and disappearance of large left-sided ducts.

FIGURE 2

Coronal maximal intensity projection of DCMRL (A) before and (B) after treatment showing near complete resolution of left-sided lung perfusion (arrow) and disappearance of large left-sided ducts.

Close modal
FIGURE 3

Endoscopy revealing (A) lymphangiectasia and vascular ectasia in the first portion of the duodenum before treatment and (B) complete normalization of the duodenal mucosa after treatment.

FIGURE 3

Endoscopy revealing (A) lymphangiectasia and vascular ectasia in the first portion of the duodenum before treatment and (B) complete normalization of the duodenal mucosa after treatment.

Close modal

On the basis of the nature of the gain of function effect of the SOS1 mutation, patient’s poor quality of life, and concern for the imminent deterioration of symptoms as well as the failure of all known therapies, we obtained expanded access to trametinib (Novartis, Basel, Switzerland) to target the RAS-MAPK pathway. She was started on a low dose of 0.5 mg daily (0.01 mg/kg per dose) for tolerability for 1 week and then the dose was escalated to 1 mg daily. Within 8 weeks of starting the medication, the patient’s symptoms resolved. Her chest radiograph significantly improved (Fig 4). Her albumin and hemoglobin levels normalized and she no longer needed supplementation or transfusions (Fig 5). Her electrolytes also normalized, with calcium improving from 8 to 9.7 mg/dL and sodium improving from 134 to 142 mmol/L. The patient’s overall quality of life substantially improved after MEK inhibition. She had improved exercise tolerance, was no longer tired, had resolution of chronic abdominal pain, and was gaining weight on a regular diet. Repeat T2-weighted lymphatic mapping and intrahepatic DCMRL and intranodal DCMRL 3 months after starting treatment revealed resolution of pulmonary interstitial and mesenteric edema (Fig 1B). She had re-expansion of her left lung and disappearance of the abnormal left-sided pulmonary interstitial and posterior intercostal lymphatic networks (Fig 2B). She had a significant reduction in retrograde mesenteric flow and resolution of the lymphatic leaks into her duodenum. Concurrent endoscopic examination of her duodenum revealed complete normalization of the duodenal mucosa, without evidence of lymphatic or vascular ectasia (Fig 3B). At the time of data collection, the patient was on medical therapy for 6 months.

FIGURE 4

Chest radiograph (A) before treatment and (B) 1 month after starting treatment, revealing significant improvement in both lung fields, with near complete resolution of chylothorax on the left.

FIGURE 4

Chest radiograph (A) before treatment and (B) 1 month after starting treatment, revealing significant improvement in both lung fields, with near complete resolution of chylothorax on the left.

Close modal
FIGURE 5

This figure demonstrates rapid normalization of the patient’s (A) hemoglobin level and (B) albumin level after initiation of therapy. The first data point on each graph was the value measured on the day that therapy was initiated.

FIGURE 5

This figure demonstrates rapid normalization of the patient’s (A) hemoglobin level and (B) albumin level after initiation of therapy. The first data point on each graph was the value measured on the day that therapy was initiated.

Close modal

RASopathies constitute a group of genetic syndromes including NS, Costello syndrome, Legius syndrome, and others.9  RASopathies, such as NS, can be associated with severe life-threatening lymphatic abnormalities, including chylothorax and PLE. Biko et al10  showed that patients with NS have certain characteristic central lymphatic defects, including diffuse retrograde lymphatic flow, absent or abnormal thoracic duct, and retrograde intercostal flow. The patient described in this study had no discernable normal thoracic duct with retrograde mesenteric flow and retrograde flow toward the left lung. In addition, she had the characteristic duodenal leak seen with intrahepatic DCMRL. Embolization of these hepatoduodenal lymphatic connections resulted in temporary normalization of her albumin levels and resolution of bleeding and both duodenal lymphangiectasia and vascular ectasia completely resolved with medication, suggesting a correlation between lymphangiectasia and the vascular ectasia seen by duodenoscopy.

In the patient described here, there was complete remodeling of the entire central lymphatic system similar to that previously described in a patient with an ARAF mutation treated with trametinib.7  The effect of MEK inhibition on the lymphatic system appears to be comprehensive and generalized. How this process occurs is not fully understood but is remarkable in speed and extensiveness. This patient, in particular, developed no toxicities attributable to the MEK inhibitor. However, well-documented toxicities, including retinal vein occlusion and significant skin rashes, such as acneiform dermatitis, have been seen with MEK inhibition. Further studies should be conducted to determine the durability and reversibility of this effect. This information will be especially critical if patients are going to be weaned from the medication.

MEK inhibition has the potential to have significant effects on other organ systems affected by RAS-MAPK gene defects. Recently, it was reported that MEK inhibition can potentially improve hypertrophic cardiomyopathy in patients with NS and a RIT1 mutation.11  MEK inhibition could potentially treat other complications in patients with NS and should be studied.

MEK inhibition in patients with RASopathies and severe lymphatic disorders can lead to rapid resolution of symptoms and a comprehensive remodeling of the central lymphatic system. This treatment modality has the potential to improve other complications of genetic defects in the RAS-MAPK pathway. In patients with RASopathies and severe lymphatic dysfunction, this treatment modality should potentially be considered as the first line of therapy.

Dr Dori conceptualized and designed the study, performed the MRI studies and lymphatic interventional procedure, coordinated and supervised data collection, drafted the manuscript, critically reviewed the manuscript for important intellectual content, and is accountable for all aspects of this work; Dr Smith, Ms Pinto, Dr Snyder, and Dr March acquired and analyzed data, critically reviewed and revised the manuscript, and is accountable for all aspects of this work; Dr Hakonarson acquired, analyzed, and interpreted data, critically reviewed and revised the manuscript, and is accountable for all aspects of this work; Dr Belasco conceptualized and designed the study, obtained approval for medical therapy, supervised the patients’ medical management, edited the manuscript, supervised data collection, critically reviewed the manuscript for important intellectual content, and is accountable for all aspects of this work; and all authors approved the final manuscript as submitted

FUNDING: No external funding.

     
  • DCMRL

    dynamic contrast magnetic resonance lymphangiography

  •  
  • MEK

    mitogen-activated protein kinase

  •  
  • NS

    Noonan syndrome

  •  
  • PLE

    protein-losing enteropathy

  •  
  • RAS-MAPK

    rat sarcoma–mitogen-activated protein kinase

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.