<i>In‐utero</i> treatment of large symptomatic rhabdomyoma with sirolimus

A healthy 27-year-old woman was referred to our hospital at 21 weeks' gestation. Fetal echocardiography revealed multiple cardiac rhabdomyomas, with the largest lesion in the left ventricle measuring 10 × 5 mm. Neurosonography and fetal magnetic resonance imaging demonstrated cerebral tubers. The kidneys appeared normal. Fetal tuberous sclerosis was suspected but confirmatory amniocentesis was declined. After multidisciplinary counseling, the couple chose to continue the pregnancy. Progressive growth of the cardiac rhabdomyomas was noted on serial echocardiography, the largest measuring 47 × 39 mm at 31 weeks of gestation (Figure 1). Concomitant deterioration of cardiac function was noted (tricuspid regurgitation and biventricular systolic and diastolic dysfunction) and the fetus developed pericardial effusion (Figure 2). Given the poor neonatal prognosis of such large lesions, the option of experimental prenatal treatment with an inhibitor of the mammalian target of rapamycin (mTOR) pathway was offered. The patient received multidisciplinary counseling and provided written informed consent to experimental administration of this medication. Transplacental treatment with sirolimus was initiated at 31 + 4 weeks of gestation. An oral loading dose of 15 mg was administered to the mother, followed by 5–8 mg daily, aiming for maternal serum trough levels between 10 and 15 ng/mL. With this treatment, the mass shrank (Figure 1), ventricular function improved (left ventricular ejection improved from 18% to 33% and right ventricular ejection fraction from 28% to 46%) and we saw resolution of tricuspid regurgitation within 4 weeks. Sirolimus was discontinued at 36 weeks' gestation. Rebound growth of the rhabdomyoma was seen. The patient delivered at 39 weeks' gestation. The male neonate weighed 4300 g and was hemodynamically stable. The postnatal echocardiogram confirmed multiple cardiac masses, mildly reduced biventricular systolic function and trivial pericardial effusion. Treatment with phenobarbital was started for epileptiform activity noted on electroencephalography. A de-novo pathogenic mutation in the TSC2 gene was confirmed. Fetal rhabdomyomas do not usually require intervention as they regress in childhood. In lesions larger than 2 cm, however, complications such as arrhythmia, hydrops, vascular obstruction, spontaneous fetal demise and neonatal death can occur1. Neonatal treatment with mTOR inhibitors, which target the upregulated mTOR pathway in tuberous sclerosis complex, has been reported previously for symptomatic rhabdomyomas2. To our knowledge, this is the second case of successful prenatal mTOR inhibitor treatment for fetal rhabdomyoma3. Similar to our case, the other fetus had a good prenatal response to the medication and an uneventful neonatal course, but had rebound growth after cessation of the medication. mTOR inhibitors have also been used in pregnant women with a solid organ transplant4. No adverse fetal outcomes have been reported but potential maternal side effects include hypertriglyceridemia, impaired renal function, proteinuria and hypertension4. Impaired wound healing has been reported in transplant patients on multiagent immunosuppression5. We therefore discontinued the medication a few weeks prior to delivery. This case suggests sirolimus is a therapeutic option for the treatment of large cardiac rhabdomyomas in utero. Nonetheless, given the limited safety data, this option should be reserved for cases with a poor prognosis. We would like to thank Dr Han-Shin Lee, Dr Karen Chong and Dr Susan Blaser for their help in managing this patient.

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