Prenatal ultrasound diagnosis of fetal cardiac rhabdomyoma and analysis of clinical outcomes

Introduction

Fetal cardiac tumors are rare among congenital heart diseases (CHDs), with an incidence ranging from 0.0017% to 0.4000%. The majority of fetal cardiac tumors are benign, with cardiac rhabdomyoma (CR) being the most common type during the fetal period (1). According to the literature, CR typically presents as single or multiple round masses with higher echogenicity than the ventricular wall. These tumors vary in location and exhibit limited mobility during cardiac activity, with most growing inward; larger lesions may occasionally protrude outward, potentially causing compressive symptoms (2). Fetal CR is often an early manifestation of tuberous sclerosis complex (TSC). Although ultrasound alone cannot reliably distinguish isolated CR from TSC-associated CR, their prognoses differ significantly: Isolated CR (after excluding TSC) typically requires no intervention and often regresses spontaneously postnatally. TSC-associated CR carries a poor prognosis; early prenatal counseling and clinical intervention are strongly recommended (3). This study aimed to summarize the ultrasound image characteristics of fetal CR and to explore the clinical value of CR detection by combining comprehensive information from magnetic resonance imaging (MRI) examination, genetics, and postpartum clinical outcomes. Some cases were followed up to observe changes in CR from the prenatal period to 1 year postpartum, as well as the occurrence of TSC in affected children. Previous studies have primarily focused on the diagnosis of CR detected by prenatal ultrasound or the management of pediatric cardiac space-occupying lesions postnatally. To some extent, this study fills a gap in the integrated prenatal and postnatal management of CR, which may effectively improve overall fetal outcomes and the long-term quality of life for affected children. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1208/rc).

Methods

A total of 36 fetuses diagnosed with CR by prenatal ultrasound at Gansu Provincial Maternity and Child-Care Hospital between May 2021 and December 2023 were included in this study. The gestational age at diagnosis was 22–37 weeks (mean: 29±4 weeks); maternal age was 21–40 years (mean: 28.05±4.78 years); and all cases were singleton pregnancies. This study excluded pregnant women with other maternal diseases, fetuses with other complex malformations, and multiple pregnancies. All examinations are conducted by three physicians with specialist qualifications (at the level of deputy director or above) who had undergone standardized training in image interpretation consistency and passed the assessment. Images are retained for analysis, and in cases of disagreement regarding image analysis, the three physicians entered discussion to reach a consensus. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Gansu Provincial Maternity and Child-Care Hospital (approval No. 2021-30KYSL), and written informed consent was provided by all participating mothers and their families.

Ultrasound examination protocol

The fetal heart was diagnosed using the Voluson E10 color Doppler ultrasound diagnostic instrument (GE Healthcare, Chicago, IL, USA) and an abdominal volume probe with a frequency of 2.0–5.0 MHz. All fetal cardiac ultrasound examinations were performed in strict accordance with the 2023 International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) Guidelines for fetal cardiac screening, with systematic acquisition of the following standard views (4): fetal heart position, four-chamber view, outflow tract, three vessels, and three-vessel tracheal view. The pediatric heart was diagnosed using the Philips EPIQ7C color Doppler ultrasound diagnostic instrument (Philips, Amsterdam, Netherlands), and the pediatric heart probe was placed at the apex of the heart and continuously tracked and scanned from longitudinal, transverse, and oblique directions, with a focus on observing whether there are space-occupying lesions in the heart chamber and myocardium. Measurements were taken using the maximum diameter, recording the location, number, size, and presence of associated secondary lesions of the CR. The evaluation also included determining whether there were concurrent malformations in other systems, with follow-up records of pregnancy outcomes maintained.

MRI examination and methodology

A Philips Achieva 1.5-T MRI scanner was used to perform standard axial, coronal, and sagittal scans of the fetal brain. The scans focused on detecting abnormal signals and their locations. The total acquisition time for all sequences did not exceed 15 minutes.

TSC genetic testing and diagnostic approach

Amniotic fluid obtained through amniocentesis or umbilical cord blood was subjected to karyotype analysis, single-nucleotide polymorphism-based comparative genomic hybridization, or whole exome sequencing (WES). According to the updated International Diagnostic Criteria and Management Recommendations for TSC (4), in addition to the identification of pathogenic TSC gene mutations, the clinical diagnostic criteria encompass 11 major features and 7 minor features. The 11 major features include: Hypopigmented macules (≥3 lesions, each ≥5 mm in diameter), cephalic fibrous plaques or facial angiofibromas (≥3 lesions), ungual fibromas (≥2 lesions), multiple retinal hamartomas, shagreen patches, lymphangioleiomyomatosis, angiomyolipomas (≥2 lesions), subependymal giant cell astrocytoma (SEGA), multiple cortical tubers and/or radial migration lines, subependymal nodules (≥2 lesions), and CR. The seven minor features include: “confetti” skin lesions, intraoral fibromas (≥2 lesions), dental enamel pits (≥3 lesions), retinal achromic patches, multiple renal tumors, non-renal hamartomas, and sclerotic bone lesions. A definitive diagnosis of TSC requires either two major features or one major feature plus two minor features. A probable diagnosis requires one major feature plus one minor feature. The first seven major features and all minor features are typically non-assessable during fetal development. Therefore, the primary diagnostic indicators for fetal TSC are CR, abnormal signal nodules under the ependymal membrane, and abnormal signals in the cerebral cortex. If two criteria are met, TSC can be diagnosed.

Results

Fetal echocardiography examination results

All 36 cases of CRs demonstrated the following sonographic features on echocardiography: circular or elliptical nodules with slightly high echogenicity, with relatively uniform internal echoes, clear contours, no posterior acoustic shadowing, no obvious blood flow signals inside, and the growth location could be distributed on the left and right ventricular surfaces of each atrium, ventricle, and interventricular septum, with the ventricle as the main focus. Among the 36 cases, there were 25 cases of multiple lesions (69.4%) and 11 cases of solitary lesions (30.6%), including 1 case in the left atrium, 6 cases in the right atrium, 24 cases in the left ventricle, 21 cases in the right ventricle, and 8 cases in the interventricular septum. The maximum diameter observed was 32 mm, and the minimum diameter was 4 mm (details are provided in Table 1).

Fetal MRI brain examination results

A total of 11 routine fetal MRI examinations were performed, of which five cases showed subependymal nodules with abnormal signal intensity, suggestive of TSC. There was one case exhibiting multiple hemorrhagic foci in the bilateral brain parenchyma and subependymal regions; one case presented with asymmetrical bilateral lateral ventricles and dilatation of the vein of Galen; and four cases revealed no abnormalities on MRI.

TSC1 and TSC2 gene family testing results

Genetic testing was performed in six cases: three cases had TSC2 gene mutations, including one case where the pregnant woman herself carried a heterozygous TSC2 mutation, suggesting familial inheritance; two cases had TSC1 gene mutations; one case showed no significant abnormalities in chromosomal banding analysis, but WES detected a pathogenic variant in a gene associated with the clinical phenotype.

Clinical outcomes

In one case, isolated multiple CRs were detected on ultrasound without other abnormalities; the pregnancy was terminated. There was one case that presented with multiple CRs and compression-induced obstruction of the left ventricular outflow tract (LVOT), leading to increased forward flow velocity; the pregnancy was terminated (Figure 1A,1B). In another case, multiple CRs were detected on ultrasound and multiple subependymal and parenchymal hyperechoic nodules on MRI, suggestive of TSC; subsequent genetic testing confirmed a TSC2 mutation, and the pregnancy was terminated. Further, two cases with multiple CRs on ultrasound underwent genetic testing, both revealing TSC1 mutations, leading to termination. In one case, multiple CRs were detected on ultrasound, and genetic testing identified a fetal TSC2 mutation; the pregnant woman herself was a heterozygous TSC2 mutation carrier, and the pregnancy was terminated. There was one case diagnosed with multiple CRs at 31 weeks, followed by polyhydramnios at 33 weeks. Some five cases were diagnosed as CR during the fetal period. After birth, cardiac ultrasound showed that one case had no significant change in size, one case showed a slight decrease in size, and three cases showed the disappearance of CR 1 year after birth (Figure 1C,1D). In one case, multiple CRs were detected by ultrasound (Figure 1E), and there were no obvious abnormalities in chromosomal banding analysis, but WES detected a pathogenic variant in a gene associated with the clinical phenotype.

Figure 1 Partial clinical results of prenatal and postpartum follow-up of CRs. (A) CR compresses the LVOT, causing a decrease in its inner diameter. (B) CR compresses the LVOT, causing an increase in forward blood flow velocity. (C) Multiple CRs during fetal development. (D) At 1 year after the birth of the fetus shown in (C), cardiac ultrasound showed that CR disappeared. (E) Ultrasound image showed multiple CRs in the fetus, and the pregnant woman chose to terminate the pregnancy. Red arrows: fetal CR. CR, cardiac rhabdomyoma; LVOT, left ventricular outflow tract.

Discussion

CR is the most common cardiac tumor during the fetal and neonatal periods. It is not a true neoplastic lesion but rather a hamartoma formed by the abnormal proliferation of normal cardiomyocytes. These lesions exhibit the following distinctive characteristics: (I) predilection for females (male-to-female ratio approximately 1:1.3); (II) frequent multifocal growth (69.4% of cases in this study); and (III) unique growth patterns: may enlarge under the maternal hormonal influence during fetal development but often regress spontaneously after birth (5). Clinical studies demonstrate that clinical manifestations of CR are closely related to lesion size: smaller lesions are typically asymptomatic and rarely cause hemodynamic changes, whereas larger lesions may interfere with the cardiac conduction system or compress outflow tracts. When causing significant arrhythmias, hemodynamic instability, or even syncope, surgical resection usually yields favorable outcomes (with a 5-year postoperative survival rate of 95%). The overall prognosis primarily depends on four key factors: number of tumors, maximum diameter, specific anatomical location, and presence of associated systemic abnormalities (6).

In recent years, the application of spatio-temporal image correlation technology has further clarified the impact of space-occupying lesions on the heart, improving diagnostic and therapeutic outcomes. Its volumetric analysis function enables three-dimensional spatial localization of tumors in the heart and allows for quantitative assessment of tumor volume changes over gestational weeks (4). This technology has a high dependency on equipment and operator skill, and the success rate of data collection is low when gestational age is less than 20 weeks. In future studies, this technology should be actively integrated to conduct related research and enhance diagnostic accuracy.

The detection of CR during fetal development may serve as the earliest clinical indicator of TSC, with multiple CRs representing a robust predictive marker for TSC (7). TSC is an autosomal dominant neurocutaneous disorder caused by pathogenic variants in either the TSC1 or TSC2 genes. Epidemiological studies report a TSC incidence of approximately 1/20,000 to 1/8,500 live births, with about 35% of cases showing familial inheritance patterns and 65% resulting from de novo mutations occurring during conception or early embryonic development. This multisystem disorder typically manifests with the involvement of multiple organ systems, including the brain, heart, kidneys, and skin. Postnatally, most affected individuals develop the classic clinical triad: facial angiofibroma, epilepsy, and intellectual disability. Notably, patients with TSC2 mutations generally exhibit more severe disease manifestations compared to those with TSC1 mutations, including more extensive cutaneous and renal involvement, as well as higher frequencies of epileptic seizures (8). Current therapeutic approaches remain limited to symptomatic management, as no curative treatment exists for TSC. The condition carries a guarded prognosis with significant quality of life implications (9). Consequently, the accurate prenatal diagnosis of CR assumes critical importance for timely pregnancy termination decisions in severe cases.

Normal myocardial cells are arranged in regular bundles, whereas in patients with TSC-associated CR, the myocardial cells exhibit disorganized alignment with irregular intercellular connections and orientation. Additionally, hypertrophy of some cardiomyocytes may occur (10). Peritumoral fibrosis often develops around the rhabdomyomas, forming fibrotic zones that restrict normal myocardial motion, impair electrical conduction, and compromise blood supply, thereby exacerbating myocardial injury (11). Mechanical compression by the lesions on myocardial microstructure may also lead to reduced local contractile reserve. These pathological changes collectively decrease cardiac compliance, ultimately resulting in refractory arrhythmias and heart failure. Based on previous studies, ventricular ejection fraction (EF), myocardial strain rate, filling time fraction, and ejection time fraction serve as reliable indicators for assessing cardiac function. These parameters can effectively evaluate the impact of CRs on fetal cardiac function, with strain parameters being particularly sensitive for early detection of functional decline even when EF remains normal. Future research should focus on investigating the relationship between these functional parameters and postnatal regression patterns or complications.

This study analyzed 36 cases of fetal CRs, with a particular focus on their sonographic characteristics, imaging findings, genetic associations, and pregnancy outcomes. Notably, multiple CRs demonstrated a stronger correlation with TSC compared to solitary lesions. Several studies have reported that fetal CRs may spontaneously regress within 2 years after birth. Partial resection of symptomatic tumors with residual masses has also been shown to undergo subsequent regression (12). In our study cohort of four prenatally diagnosed CR cases, one case demonstrated complete resolution at 1-year postnatal follow-up; one case showed a slight reduction in tumor size on postnatal day 1; one case maintained stable dimensions at 1-year evaluation; one case developed LVOT obstruction due to compression by a CR, ultimately leading to pregnancy termination after parental counseling. These findings are consistent with existing literature regarding the natural history of fetal CRs.

TSC exhibits diverse clinical phenotypes, often leading to missed diagnoses. According to literature reports, about 80–90% of TSC patients seek medical attention for the first time due to epileptic seizures (13). In addition, about 63–78% of TSC infants will experience focal seizures and epileptic spasms (14). Notably, most affected infants manifest their first seizure before 1 year of age, underscoring the need for early electroencephalogram (EEG) evaluation, as abnormal EEG patterns often precede clinical seizure onset (14,15). Timely intervention is necessary to mitigate neurological sequelae. Additionally, reports indicate that comparing brain tissue from fetuses with CHD undergoing termination of pregnancy with brain tissue from normal fetuses reveals overall vascular dysregulation in CHD fetuses, accompanied by central blood redistribution (low brain-placenta ratio), which may lead to impaired cerebral perfusion and subsequent neurodevelopmental disorders (16). Future research should focus on the association between CR and embryonic neurodevelopmental abnormalities to further elucidate the causes of craniofacial-related growth abnormalities in CR. In this study, one case of fetal diagnosis was CR, and an additional MRI showed multiple hypoechoic nodules under the ependymal membrane. Therefore, the clinical prenatal diagnosis was TSC. In the first 2 months after birth, frequent tonic-clonic seizures were observed as the first manifestation, and treatment with oxcarbazepine was given. Occasionally, intermittent seizures occur after treatment. This suggests that a fetal head MRI examination should be performed when cardiac CR is detected before delivery to improve the diagnostic accuracy of TSC. In this study, one case was diagnosed with CR by prenatal ultrasound, and no abnormal signal nodules were found in the fetal head MRI examination. The genetic testing result confirmed the TSC1 mutation. Therefore, when a prenatal ultrasound combined with MRI cannot make a clear diagnosis, genetic testing should be performed.

In addition, 10–15% of TSC patients who meet clinical diagnostic criteria cannot identify pathogenic variants of TSC1 or TSC2 through routine genetic testing (17,18). Therefore, when ultrasound detects no abnormalities in fetal CR combined with genetic testing, an MRI examination should also be performed to improve the detection rate of TSC. It can be seen that when CR occurs, in addition to TSC gene-related testing, WES can be performed to exclude other pathogenic gene variations. In addition, in this study, one fetus had multiple CRs, and genetic testing showed a TSC2 gene mutation in the fetus. The pregnant woman herself also had a heterozygous mutation in the TSC2 gene, indicating a familial predisposition, consistent with previous studies (19).

Precise genotyping forms the fundamental basis for genetic risk assessment in TSC. Current epidemiological data demonstrate that TSC2 mutations account for 70–80% of sporadic cases, whereas TSC1 mutations represent only 10–20% (4). In families with TSC2 mutations, there remains an approximate 1–2% recurrence risk even when parental testing yields negative results (20). When a parent is affected, offspring have a 50% inheritance probability (independent of the specific gene involved), though descendants inheriting TSC2 mutations typically manifest more severe phenotypic expressions. Patients with TSC1 mutations typically exhibit milder or delayed-onset symptoms, with some individuals presenting solely with cutaneous manifestations (e.g., facial angiofibromas) or mild epilepsy. In contrast, TSC2 mutations are associated with more severe clinical manifestations, including: higher incidence of cortical dysplasia (e.g., cortical tubers), significantly increased risk of cognitive impairment (including intellectual disability), greater prevalence of epilepsy (particularly infantile spasms), often with earlier onset, larger renal angiomyolipomas, and more frequent neurological lesions (e.g., SEGAs) (21). Early diagnosis and intervention are crucial for optimal outcomes, as evidenced by the fact that most infants with TSC experience their first epileptic seizure before 12 months of age. In addition to monitoring CR changes, long-term surveillance of subependymal nodules (which may potentially progress to SEGA) (22) is essential. Therefore, all TSC patients should undergo brain MRI scans every 1–3 years until they are 25 years old, when SEGAs are most prevalent. Recent studies indicate that known SEGAs may continue to grow during adulthood, and in rare cases, may newly develop in adult patients. Consequently, lifelong monitoring for potential SEGA growth is warranted. We recommend routine screening for TSC-associated brain lesions to improve early detection rates. Early intervention can significantly reduce the risk of seizure development and improve neurological outcomes. Notably, cardiac symptoms (such as arrhythmias) may serve as the initial manifestation of TSC, warranting prompt electrocardiogram (ECG) evaluation. For children with CR, asymptomatic patients should receive follow-up echocardiographic examinations every 1–3 years until documented regression of the CRs occurs.

Inversetti et al. (23) found that in patients with CHD, placental perfusion was normal in early pregnancy, but levels of pregnancy-associated plasma protein A and placental growth factor were abnormally low, and urinary tract angiography hemodynamic parameters gradually increased. These findings may directly or indirectly indicate placental dysfunction. Fetal CHD may cause hemodynamic changes, which further affect placental structure and function. Additionally, placental abnormalities may lead to uteroplacental insufficiency, affecting fetal development, particularly cardiac development, creating a vicious cycle. The author believes that CR at different locations can cause different hemodynamic changes in fetal cardiac blood flow. Pregnant women with severe fetal cardiac malformations have a significantly higher risk of preeclampsia, gestational hypertension, and small-for-gestational-age infants. Future research should focus on exploring the common pathways between cardiovascular development and placental function, and investigating the relationship between the two.

In this study, the average gestational age of fetal CR was found to be 29 weeks, which is in the late stage of pregnancy. Due to the dynamic process of fetal development, CR was not detected by echocardiography during mid-pregnancy fetal screening. Therefore, it is important to be alert to the occurrence of CR in the late stage of pregnancy (24), highlighting the importance of scheduled prenatal checkups.

There are certain limitations to this study: (I) the sample size is relatively small, and some cases have incomplete follow-up results for late pregnancy and postnatal information of CR. In this study, 12 cases (33.3%) lacked postpartum follow-up data for the following reasons: loss to follow-up across provinces (n=5), family refusal of follow-up examinations (n=4), and newborn transfer to another hospital for treatment (n=3). (II) A pregnant woman was diagnosed with multiple CRs at 31 weeks, and at 33 weeks, she was diagnosed with polyhydramnios, which is a known risk factor for premature birth or even fetal death in the uterus (25). In future studies, attention should be paid to the relationship between the two. (III) Most of the cerebral nodules and cardiac hyperechoic nodules do not have clear pathological results and are only clinical diagnostic results. (IV) In this case, only one pregnant woman had a TSC gene mutation. The family history of TSC in other cases was not recorded, and there is limited research on familial inheritance.

Conclusions

In summary, this study holds significant clinical value for the prognostic assessment of fetal CRs and early diagnosis of TSC. Prenatal echocardiography remains the primary diagnostic tool for fetal CRs. However, its efficacy may be compromised by maternal factors (e.g., thick abdominal wall, oligohydramnios) and fetal factors (e.g., suboptimal positioning, small cerebral structures). In recent years, fetal MRI has been increasingly utilized as an adjunct diagnostic modality when ultrasound detects abnormal fetal structures (26). However, compared to ultrasonography, MRI examinations are more time-consuming and costly, thus serving as a secondary complementary diagnostic approach. When CR is detected on ultrasound but MRI is negative, TSC-related genetic testing is still necessary. If CR is detected on ultrasound but no TSC-related gene abnormalities are found, an additional MRI should still be performed, as it can improve the detection rate of clinical diagnosis. Since TSC is a hereditary condition, genetic testing should also include the parents. Combined imaging and genomics diagnosis can significantly improve clinical outcomes after fetal CR diagnosis and provide genetic information for those who wish to have children in the future, thereby achieving the goal of eugenics.

Acknowledgments

The authors would like to express their gratitude to all the clinicians at the ultrasound, radiology, genetics, obstetrics, and gynecology departments of Gansu Provincial Maternity and Child-Care Hospital who provided professional advice and guidance. Additionally, the authors thank the patients and their families for their participation in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1208/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1208/dss

Funding: This study was supported by the Science and Technology Planning Project of Gansu Province (No. 23JRRA1747).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1208/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Ethics Committee of Gansu Provincial Maternity and Child-Care Hospital (approval No. 2021-30KYSL), and written informed consent was obtained from all participating mothers and their families.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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