Sirolimus for Recurrent Chylothorax and Edema in an Infant with Noonan Syndrome after Resolved Hydrops Fetalis: A...

Noonan syndrome (Online Mendelian Inheritance in Man #163950) is a RASopathy caused by germline mutations in the RAS/RAF/mitogen-activated protein kinase signaling pathway and characterized by distinctive facial features, musculoskeletal abnormalities, and congenital heart defects. A subset of patients with RIT1 mutations present with hypertrophic cardiomyopathy and generalized lymphatic anomalies. While sirolimus, a mammalian target of rapamycin inhibitor (mTOR), has been shown to suppress lymphangiogenesis, its efficacy in Noonan syndrome remains unclear.

We report the case of an infant with Noonan syndrome and RIT1 mutation who developed recurrent refractory chylothorax and edema. Despite multiple interventions, including corticosteroids, octreotide, thoracic duct ligation, and pleurodesis, the patient's condition remained critical and refractory. Skin biopsy revealed lymphatic malformations. Sirolimus (0.6 mg/day) was initiated at 220 days of age, but was discontinued due to a markedly elevated serum level (88.2 ng/mL) and a lack of therapeutic effect. The patient died of Escherichia coli sepsis at 235 days of age.

Although sirolimus was ineffective in this case, initiation of treatment at a lower dose may be advisable for patients with compromised hepatic function or concurrent infections. Further studies are warranted to clarify the appropriate indications, dosage, and timing of sirolimus therapy for Noonan syndrome.