Introduction
Fetal cardiac rhabdomyoma is associated with tuberous sclerosis complex (TSC) which is an autosomal dominant genetic disorder. It is caused by mutations in the TSC1 or TSC2 gene, which can involve multiple organs and systems such as the heart, brain, kidney, lung, skin, and so on.
Cardiac rhabdomyoma is the most common fetal heart tumor, accounting for about 60% of cases.1 It is closely related to TSC and may be the only manifestation of TSC which occurs during the fetal period.2 TSC is an autosomal dominant hereditary neuro-cutaneous disease with an incidence of approximately 1 in 5 000 to 10 000 live birth.3 Here we report the clinical data of a neonate with TSC diagnosed with fetal cardiac rhabdomyomas and confirmed by amniocentesis prenatal diagnosis as gene testing TSC1 positively. Parental consents were obtained for publication of the clinical histories of the children and the pictures.
Case presentation
A male baby was examined 1 hour after birth who was term infant born by vaginal delivery to a 34 years old woman with gravida 2 para 2. His birth weight was 3 490 g with no history of asphyxia. His parents did not have a consanguineous marriage, and also denied any family history of inherited diseases. His sister's heart was reversed and there was a possibility of the heart being on the right side of the chest. However, his sister is a healthy baby girl born two years previously. The parents and the elder sister denied any history of epilepsy, heart disease, and skin damage.
At 23 weeks of gestation, a systemic ultrasound at our hospital found a moderately enhanced echo of 9.3 mm × 6.3 mm in the size of the left ventricular wall of the fetal heart. This was considered to be cardiac rhabdomyoma (Figs. 1A, B), but no abnormalities were found in head, kidney, lung. Prenatal tests were performed on the amniotic fluid cells obtained via amniocentesis, that chromosomal analysis (G-banded karyotype) and single nucleotide polymorphism analysis were normal, whole exome sequencing results showed there was a heterozygous mutation in the exon 15 sequence of the TSC1 gene (NM_000368), c.1888_1891delAAAG (Fig. 2). The parents had no such mutation. The elder sister's blood sample could not be collected because she was separated temporarily without gene sequencing. No abnormalities were found on magnetic resonance imaging at 35 weeks of gestation.
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Figure 1: Multiple rhabdomyomas of the fetal heart, with irregular four-chamber view. A The left ventricle can be seen as a round-shape with a slightly higher echo mass with a clear boundary. B The right ventricle can be seen as a round-shaped with a slightly higher echo mass with a clear boundary. LV: Left ventricle; RV: Right ventricle.
Figure 2: Whole exome sequencing results: there was a heterozygous mutation in the exon 15 sequence, c.1888_1891delAAAG, and the TSC1 gene (NM_000368) was changed only in amniotic fluid sample; pregnant woman and husband were wild type.
Examination of the infant after birth showed an active, loud crying baby with an irregular hypo-pigmented spot on the back (Fig. 3A), and two circular hypo-pigmented spots with diameters of approximately 5 mm on the right groin (Fig. 3B). There were no sebaceous adenoma and shark-like plaques, and no brown fibrous plaques were seen on the forehead. The heart sounded strong and the rhythm was uniform with continuous murmur (II/VI) heard in the precordial region and the bottom of the heart. The examinations of the lungs, abdomen, and nervous system were normal. At 8 hours after birth, an echocardiogram showed a slight increase in the values obtained from the right atrium and right ventricle, the arterial catheter was not closed (diameter 3.7 mm), a defect was seen in the atrial septum (diameter 4.5 mm), multiple abnormal echo structures were seen in the left and right ventricles (Figs. 4A, B) which were considered to be cardiac rhabdomyomas, and no abnormalities were found in head, kidney, abdomen under ultrasound.
Figure 3: Multiple hypo-pigmented spots visible throughout the neonatal skin. A The back. B The right groin.
Figure 4: Multiple rhabdomyomas and atrial septal defect (ASD) of the neonatal heart. A The left and right ventricle all can be seen as a round-shape with a slightly higher echo mass with a clear boundary. B Atrial septum echo interrupted, size 3.7 mm.
Discussion
Cardiac rhabdomyoma is the most common benign tumor which can occur in the fetal period. It often occurs in the ventricular wall or the heart cavity. It is typically multifocal and involves the ventricles, but the atrium and pericardium are rarely affected. With echocardiography it is usually characterized by round-shaped structures, which have homogeneous strong echo groups with clear boundaries, so it is very easy to find prenatal ultrasound. The clinical manifestations vary greatly and are related to the size and location of the tumors. Smaller tumors can be asymptomatic during the fetal period, but larger tumors will increase fetal edema and arrhythmia, and can cause obstruction of the inflow or outflow tracts, heart failure, and even fetal death.4 The prognosis of cardiac rhabdomyoma is relatively good when it occurs alone, but it is easy to merge with TSC, especially where multiple tumors are present and these are more likely to be combined with TSC in comparison to a single tumor.5 In this patient, multiple ultrasound examinations during pregnancy revealed abnormal intra-ventricular echoes, which were consistent with rhabdomyomas. There was no fetal edema, arrhythmia and hemodynamic changes, but the abnormal intra-ventricular echoes gradually increased, so the possibility of TSC increased.
According to the “Updated Diagnostic Criteria for Nodular Sclerosis” issued in 2013, it is clear that TSC diagnosis is positive for TSC1 or TSC2 gene mutations, or fetal cardiac rhabdomyomas with intracranial nodules.6 In this patient, as the genetic test results were unclear, only cardiac rhabdomyomas with no intracranial nodules, and TSC could not be diagnosed conclusively. About 80% of TSCs are caused by neonatal mutations, of which the incidence of neonatal mutations of TSC2 is about four times that of TSC1, and the mutation rates of TSC1 and TSC2 in familial TSC cases are basically equal.7 The genetic mutations of TSC can be different, resulting in different ages of onset and severity of the disease. TSC1 gene mutations are mostly point mutations, and TSC2 gene mutations are mostly missing large fragments of the sequence. Hence, the clinical symptoms of TSC2 mutations are usually worse than those of TSC1. This manifests as a younger age at which the onset of seizures occur, with a more obvious cranial imaging seen and the probability of higher cognitive dysfunctions occurring with TSC2 mutations.8,9
The genetic test report of this patient showed that the TSC1 gene was mutated, so there was no abnormal echo seen in the cranium during the fetal period. 81% to 95% of TSC patients have one of the following skin lesions10,11: hypo-pigmented spots, facial angio-fibroma, brown fiber plaques on the forehead, shark-like spots, finger nails, and so on. The commonest and earliest symptom is the occurrence of hypo-pigmented spots. In this patient, multiple hypo-pigmented spots (diameter >5 mm) were found immediately after birth, which is consistent with previous studies.12
When fetal cardiac rhabdomyomas are found during pregnancy, it should be fully communicated with the pregnant women and their families. There is a necessity of TSC genetic testing, and a comprehensive assessment of whether to merge TSC with tumors in multiple organs either to continue pregnancy or termination of pregnancy. In this patient, multiple ultrasound examinations during pregnancy revealed abnormal intra-ventricular echoes, which were shown to increase progressively. TSC should have been highly suspected. However, due to the influence of the sudden coronavirus disease 2019 (COVID-19) epidemic, the TSC genetic test report was not obtained until 38 weeks of pregnancy.
In conclusion, TSC is an autosomal dominant genetic disorder and caused by a mutation in either the TSC1 gene or the TSC2 gene. De novo mutations account for approximately 80% of TSC cases, as in the case above. The characteristic cardiac feature of TSC is a rhabdomyoma and the diagnosis of TSC is based upon genetic testing and clinical criteria. Most patients with TSC have epilepsy, and one-half or more have cognitive deficits and learning disabilities. So rigorous follow-up will continue for the case we reported.
In the near future, as the molecular pathogenic mechanism of TSC becomes clear, the mechanistic target of rapamycin inhibitors such as rapamycin (also known as sirolimus) and its derivatives (everolimus) may be used to improve the clinical symptoms of TSC patients.
Acknowledgments
The authors would like to thank Dr. Dev Sooranna, Imperial College London, for editing the manuscript.
Funding
This work was supported by the National Key Research and Development Program of China (No. 2018YFC1002900) and the National Natural Science Foundation of China (No. 81671527), China.
Conflicts of Interest
None.
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