Cardiac tumors occur in only 0.027% of children, and cardiac rhabdomyoma (CR) comprises 45% of these occurrences [1]. Approximately 70–90% of CR patients also present with cerebral tuberous sclerosis, exhibiting a phenotype of tuberous sclerosis complex (TSC) [2]. Pathologically, CR is a type of hamartoma composed of striated muscles that usually follows a benign course of spontaneous regression after 2 years [1, 3]. However, when a CR severely obstructs the cardiac inflow or outflow tract of a neonate, urgent cardiac surgery to remove the tumors must be considered [1‐5]. Since 2012, five case reports have been published in the relevant English literature that present successful cases of using everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), to trigger tumor regression in neonatal patients with CR [6‐10]. These case reports offer hope of nonsurgical survival among high-risk patients. However, the proper dosage and duration of using everolimus in neonates, and knowledge about avoiding its side effects are largely unknown [2]. Over the past 2 years, we have observed three neonates prenatally diagnosed with CR, including one with total left ventricular obstruction. Attempting to reduce the drug’s potential side effects as much as possible, we used a lower-than-recommended-dosage regimen of everolimus on all three patients.

A 38-week-old female neonate, born to a 35-year-old woman by cesarean section, was found to have a large, high echogenic cardiac tumor occupying the apical half chamber of the left ventricle (LV), and a small tumor in the right ventricle (RV) free wall, suggesting a case of CR. The baby was born weighing 2800 gm, with pink skin color, cool limbs, tachycardia (150 bpm), tachypnea (40 per min’), and subcostal retractions. Electrocardiography showed a normal sinus rhythm, and echocardiographic measurements of the LV tumor by 4-chamber view revealed a surface area of 2.19 cm² (Fig. 1a). Although the LV ejection fraction in the parasternal long axis view remained normal (69.2%), its compliance appeared decreased, as reflected by a reversed E/A ratio in the mitral valve flows (0.46/0.66 M/s), a high Tei index (0.9), and a low Z score (0.75). Additionally, the brain and renal ultrasound studies were both normal.

After providing an explanation to the parents, we began an off-label use of oral low-dose everolimus therapy (0.0625 mg/day, 1/4 of a 0.25 mg tablet, equivalent to 0.334 mg/M²/day), aiming to achieve a trough serum everolimus level of 3–7 ng/mL. Her cardiac function was also supported with digoxin and furosemide. We monitored the complete blood counts, renal and liver functions, and serum everolimus levels once a week. After the first week, the everolimus level was 3.50 ng/mL. We escalated the dosage to 1/3 tablet a day (0.427 mg/M²/day) for the second week, and 1/2 tablet a day (0.558 mg/M²/day) for the third week. Echocardiography revealed a remarkable reduction of tumor size. With the same dose, she was discharged on the 17th day of therapy. By the 50th day of therapy, the LV tumor had reduced to 0.29 cm² surface area, approximately one-eighth of the original size (Fig. 1b). However, the everolimus serum level unexpectedly rose to 20 ng/mL (Fig. 4) and we tapered the dosage back to 1/4 tablet a day (0.241 mg/M²/day). The serum level remained high (14.18 ng/mL) on the 80th day of therapy, so we further decreased the dosage to 1/8 tablet a day (0.12 mg/M²/day). Two weeks later, she suffered fever, cough and respiratory distress. Everolimus was withheld by the parents, and she was readmitted to our ward. Her weight (3.9 kg), height (55 cm) and head girth (39 cm) were all below the third percentile for an average 3-month-old female infant. The chest roentgenogram showed an interstitial type of pneumonia, and adenovirus was isolated from her throat. Because the everolimus serum level had become immeasurable (<1.5 ng/mL), we suspended the therapy. She was discharged after 1 week. Later, follow-up echocardiograms noticed a slow but steady increase in the tumor size, whose surface areas were 0.69 cm² at 4 months, 0.86 cm² at 5 months, 1.05 cm² at 9 months, and 1.13 cm² at 1-year-and-4 months of age (Fig. 1c). However, with growing of the LV chamber and its improving compliance, the cardiac output remained adequate. By the age of 1-year-11-months, her bodily statistics had improved to the 50–70th percentile for her age: she weighed 10 kg, was 93.8 cm tall, and had a head circumference of 47.5 cm. Finally, the genetic studies for TSC-1 and TSC-2 anomalies were both negative.

A 37-week-old, 2880 gm male neonate, born to a G6P3A3, 40-year-old mother, was transferred to the pediatric intensive care unit of this tertiary referral hospital from an obstetric hospital on his second day of life because of a large cardiac tumor that had completely obstructed the inflow and outflow tracts of the LV. The cardiac tumor had been observed by fetal ultrasonography since the 32nd week of pregnancy, and was assumed to be a nonsurviving case. Upon admission, the patient was in distress, with tachypnea (60 per min), tachycardia (160 beats per min), grunting sounds, and hypoxemia (SaO2 85%). He immediately received tracheal intubation and a dopamine infusion. Echocardiography revealed a large, high echogenic tumor with three lobes in the basal area of the LV. Its wide base was attached firmly at the outlet septum, extended to the LV free wall, and involved the lateral papillary muscle of the mitral valve. The LV inflow, the mitral valve orifice, and the LV outflow (i.e., the subaortic area) were completely occluded by the tumor (Fig. 2a, b). Hence, all of the pulmonary venous return flows had to be shunted across the atrial septal defect, mixed with the systemic venous returns in the right heart, and pumped together into the main pulmonary artery (MPA). The MPA flow then divided a large portion of its flow across the ductus arteriosus, providing complete aortic blood flow. Thus, the patient was dependent on single ventricle circulation to survive.

Considering its difficulty and high risk of mortality, our cardiac surgeon elected to not perform tumor resection. After a consultation with the parents, they agreed to off-label everolimus therapy. We began the therapy at 0.0625 mg/day (1/4 tablet, 0.316 mg/M²/day), in addition to a combination of intravenous vasoactive drugs (namely, dopamine, bosmin, and prostaglandin E1). Although cerebral ultrasound did not find a significant tubercle in the brain, a generalized seizure occurred the next day, so the anticonvulsant therapy of dilantin and phenobarbital was begun. The everolimus serum level was 5.53 ng/mL on the 7th day of therapy, but decreased to 1.68 ng/mL on the 14th day, which was assumed to be caused by a drug–drug interaction with anticonvulsants (Fig. 4). Nevertheless, echocardiography observed an initiation of tumor regression, and both mitral flow and subaortic flow along the shrunken tumor appeared. We then increased the everolimus dosage to 0.125 mg/day (0.613 mg/M²/day), but the serum level remained at 1.92 ng/mL on the 21st day, and even dropped to less than 1.5 ng/mL on the 28th day, when the phenobarbital serum level rose to 80 mg/L. Thereafter, we reduced the phenobarbital dosage and increased everolimus to 0.25 mg/day (1.2 mg/M²/day). On the 35th day, the serum level rose to 5.59 ng/mL (Fig. 4). Another echocardiogram displayed a remarkable regression of the tumor, and blood flow through both the mitral and aortic valves became satisfactory. We ended all the courses of anticonvulsants and reduced everolimus to 0.125 mg/day (0.6 mg/M²/day). Finally, the endotracheal tube was removed on the 37th day of therapy. The patient was discharged on the 74th day of therapy when his weight was 4.4 kg (3rd percentile) and his height was 56 cm (5–15th percentile).

After discharge, the tumor continued to reduce in size. At 6 months of age, under an everolimus dose of 0.35 mg/M²/day (serum level: 1.81 ng/mL), the remaining tumor appeared as only a small nodule attached at the lateral papillary muscle of the LV (Fig. 2c, d). We thus suspended everolimus therapy. However, 16 days later, the shrunken tumor rebounded to a surface area of 1.35 cm² producing a mild degree of mitral regurgitation. Everolimus therapy was reinstituted at 0.125 mg/day (1/4 tablet bid, 0.35 mg/M²/day). Although all serum levels afterwards were less than 1.5 ng/mL, the tumor remained as a small nodule throughout follow-up. At 1 year of age, his weight (8.8 kg), height (75 cm) and head girth (45.5 cm) had all improved to the 15–50th percentile for his age, his development was normal, and the gene studies of TSC-1 and TSC-2 were both negative.

A fetal ultrasound screening on a 35-year-old pregnant woman revealed a large (3.10 cm²), high echogenic tumor in the LV outlet septum of a 34-week-old male fetus. He was born by cesarean section at 37.5 weeks, with a weight (2.72 kg), height (48 cm), and head girth (33.5 cm) that were all within the 15–50th percentile. Echocardiography showed that the tumor not only exerted compression on the LV outflow tract, but also extended outward to the septum between the ascending aorta and the MPA, pushing them apart (Fig. 3a, b). The surface areas of the tumor were 2.60 cm² in the long axis view and 4.10 cm² in the short axis view. Electrocardiograms also detected frequent episodes of isolated ventricle premature contractions (VPC). We began everolimus therapy at 0.125 mg/day (0.658 mg/M²/day), along with a low dose of digoxin (5 μg/kg/day) on his second day of life. On the fifth day of therapy, the serum level was 16.12 ng/mL (higher than our target range); therefore, we reduced the daily dose to 0.0625 mg (0.33 mg/M²/day) (Fig. 4). The following three weekly serum levels of everolimus were 4.41, 3.39, and 2.86 ng/mL, respectively. When he was discharged on his 32nd day of life, we increased the dose to 0.125 mg/day (0.51 mg/M²/day). Three months later, echocardiography revealed a remarkable shrinkage of the tumor (0.80 cm² in long axis view, Fig. 3c), but his weight and height had decreased to less than 15th percentile for age; thus, we suspended the everolimus therapy. However, follow-up echocardiograms revealed a steady regrowth of the tumor. Specifically, its surface area increased to 0.99 cm² after 2 weeks and to 2.97 cm² after 2 months; the compression effect on the LV outflow tract also recurred. When he was 5 months old, we reinstituted everolimus therapy at 0.125 mg/day (0.379 mg/M²/day). Although all of the follow-up serum levels were less than 1.5 ng/mL, the tumor regressed smoothly. At 9-months-old, he contracted chicken pox, and the therapy was stopped again. He recovered smoothly without using antichicken pox medication. At 10 months of age, his weight (8.3 kg) and head girth (44.5 cm) had improved to the 15–25th percentile for his age, but his height (70.5 cm) remained below the 15th percentile. The specific loci for TSC-1 and TSC-2 gene abnormality were also negative.