Neonatal rhabdomyoma with cardiac dysfunction: favourable response to sirolimus

Discussion

Congenital cardiac rhabdomyoma is the most common cardiac tumour in childhood, comprising up to 45% of all tumours.1 They are predominantly diagnosed on fetal ultrasounds (30.3%) in the second or third trimesters antenatally, or in infants who develop symptoms of impaired cardiac function in the postnatal period.2

Rhabdomyomas are well known to spontaneously regress after birth and often remain asymptomatic. The mechanism of involution is not well understood but is postulated to be due to rhabdomyoma cells losing their ability to divide once fetal somatic growth is complete.2 In a series of 154 patients by Jóźwiak et al, partial regression was achieved in 50% of cases and complete resolution in 18%.6 A smaller percentage, however, can progress and develop complications, including arrhythmias, outflow track obstruction, conduction disorders and congestive heart failure.1 Treatment is indicated if there are concerns for haemodynamic compromise and risk of mortality.7 8

Complications are found to be associated with larger tumours, carrying a greater risk of poor perinatal outcomes.5 In this patient, the predominant tumour measured 48.7 × 27.1 mm, a significant size compared with cases in existing literature.5 There was notable coronary perfusion mismatch as evidenced by ischaemic changes on ECG and raised cardiac enzymes. The 2DE also revealed persistent dyskinetic movements of the interventricular septum and posterior wall. These features, coupled with declining clinical condition, were concerning for compromised cardiac function, leading to our decision to initiate treatment with M-TOR inhibitors.

Cardiac rhabdomyomas are a major feature of TSC based on existing clinical diagnostic criteria.4 They can occur as solitary or multiple cardiac tumours, with the latter having an association rate of up to 90% with TSC.9 TSC is an autosomal dominant genetic disorder, related to de novo mutations in the TSC1 and TSC2 tumour suppressor genes, resulting in downstream abnormal cellular proliferation in multiple systems.10 Despite an uncertain diagnosis of TSC in our reported case, it remains possible as the presence of large multifocal cardiac rhabdomyomas fulfils a major feature. Notably, negative genetic tests do not completely rule out TSC because a pathogenic variant may not be identified in 10%–15% of patients with clinically defined TSC.11

In recent years, the M-TOR pathway inhibition has increasingly been used in TSC-related tumour growths, replacing the need for surgical resection in symptomatic cardiac rhabdomyomas. Rhabdomyomas consist of proliferating aberrant myocytes that show evidence for complete loss of TSC1/TSC2 genes with high expression of phospho-S6.12 This molecular signature of M-TOR activation is similar to that seen in many other TSC lesions, consistent with the function of the TSC1/TSC2 proteins in regulating the activation of M-TOR.6 As a key signalling pathway that controls cellular growth and metabolism, M-TOR inhibition appears to be a promising molecular target for treatment.13

A case series by Safarri et al confirms that M-TOR inhibitors are highly effective and well tolerated in the neonatal age group.13 Everolimus has gained approval for the treatment of TSC-related subependymal giant cell astrocytomas and renal angiomyolipomas, with recent large clinical trials demonstrating significant rates of seizure reduction in patients with intractable epilepsy.14 15 Extending the use of M-TOR inhibitors for treatment of cardiac rhabdomyomas, sirolimus was selected for this patient based on its relative ease of access locally. Most studies describe significant reduction in the size of cardiac rhabdomyomas with M-TOR inhibitors, but none in recent publications provides a visual illustration of the regression process. Our case report aims to demonstrate such response via a series of 2DE images.

The infant was monitored with serial echocardiograms, which were performed at bi-weekly intervals at the start, then reduced to monthly as his clinical condition stabilised. There was visible shrinking of the tumour size and improvement in cardiac function seen on 2DE, as illustrated in figure 5. Almost complete resolution of the cardiac tumour was achieved at 4 months of life. The speed of involution in our case is more likely a reflection of response to the M-TOR inhibitor treatment, rather than natural regression of rhabdomyomas. Without treatment, most rhabdomyomas are expected to regress at a slower rate and are seen at their highest frequency in children less than 2 years old.4 Several published case reports have concluded similar efficacious sirolimus treatment for clinically significant rhabdomyomas, with time to best cardiac response ranging 0.8–4.7 months.16 Reassuringly, no substantial reoccurrence of the tumours was discovered in the short term with discontinuation of therapy.17

As demonstrated, echocardiography is a useful tool in guiding management of cardiac rhabdomyomas, allowing consistent assessment of cardiac anatomy and function. It also provides valuable information on the optimal timing to initiate and terminate therapy. Serial studies can be used to monitor response to therapy. There was no interval MRI done as it was not necessary from the response we saw on serial echocardiograms and child’s improving clinical status.

In conclusion, our report adds to existing literature describing successful use of M-TOR inhibition in large cardiac rhabdomyomas. We recommend monitoring of treatment response by serial echocardiography, and long-term follow-up for development of future TSC-related features in these patients. Possible directions for further research include examining M-TOR inhibitor effects on the cardiovascular system, regression physiology of rhabdomyomas, prediction of cardiac phenotype and outcomes based on genotypes are possible directions of investigation.4 Considering the variability of clinical manifestation in TSC, guidelines for screening and surveillance for cardiac disease will facilitate disease identification and provide opportunities for early intervention.