Fetal and maternal manifestations of tuberous sclerosis complex: Value of fetal MRI

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by benign hamartomas in various organ systems of the body. Prenatal screening of fetuses of mothers affected with TSC using ultrasonography (US) may detect cardiac lesions. Fetal US is not sensitive for evaluation of the brain. We describe brain MRI findings in a fetus with cardiac rhabdomyomas identified on prenatal screening US. Postnatal brain MRI at 5 days of age demonstrated fetal MRI findings without significant added information. Fetal MRI is the imaging modality of choice for evaluation of cerebral manifestations of TSC. Maternal manifestations of TSC in the abdomen or pelvis may also be demonstrated on fetal MRI.

Introduction

Tuberous sclerosis complex (TSC) is a multisystemic autosomal dominant disease that manifests with the growth of benign hamartomas in various organ systems, including the central nervous system, kidneys, and skin. TSC has an incidence rate of one in 6000 to one in 10,000 newborns.^1–3 Prenatal genetic testing for a mutation (1) has a high false-negative rate, (2) is time consuming, and (3) is not widely available because of genetic heterogeneity and a high rate of de novo mutations,^4,5 thus highlighting the importance of reliable imaging techniques in establishing a prenatal diagnosis. Fetal ultrasonography (US) is generally the first-line imaging modality. Fetal US demonstrates cardiac rhabdomyomas that have been shown to be predictive of TSC.^6–8 However, fetal US it is not sensitive enough to evaluate cerebral lesions, except for large subependymal tumors, and cannot easily differentiate subependymal nodules (SENs) from subependymal hemorrhage.⁴ On the other hand, fetal magnetic resonance imaging (MRI) plays a key role in the accurate evaluation of the complex fetal brain anatomy by better demonstrating cerebral lesions in TSC.³

We report the prenatal and postnatal brain MRI findings in a fetus with maternal history of TSC and cardiac rhabdomyomas identified on screening US. In this case report, we highlight (1) the fetal brain MRI findings of TSC not depicted on US, (2) the absence of significant added value of the postnatal brain MRI, and (3) the evaluation of maternal manifestations of TSC within the field of view of the fetal MRI.

Case presentation

A 24-year-old G4P2012 woman with TSC presented to our tertiary maternal-fetal medicine center at 35 weeks of gestation with premature rupture of membranes. She received betamethasone and was admitted for preterm labor. Maternal history was notable for preterm delivery at 34 and 35 weeks. Both children had TSC manifestations. In the current pregnancy, screening fetal US at 22 weeks revealed cardiac masses contiguous with the myocardium consistent with rhabdomyomas. A cardiac rhabdomyoma adjacent to the left ventricular free wall measuring 1.3 × 1.9 × 1.3 cm³ increased in size to 2.4 × 1.8 × 2 cm³ by US at 24 weeks. No intracranial abnormality was observed on fetal US. Prenatal US images from the outside facility were not available for our review.

The history of maternal TSC, presence of cardiac rhabdomyomas on fetal US and increase in size of a lesion necessitated a fetal MRI to evaluate for cerebral lesions. Fetal MRI was performed at 31 weeks. Fetal MRI confirmed the presence of T2-hypointense lesions arising from the left ventricular free wall (Figure 1(a)) and left atrium (Figure 1(b)), consistent with cardiac rhabdomyomas. Fetal brain MRI revealed the presence of multiple T2-hypointense subependymal nodules (Figure 2). In addition, within the field of view of the maternal pelvis, multiple T2-hypointense bilateral renal angiomyolipomas were demonstrated (Figure 3).

Figure 1.

Fetal MRI performed at 31 weeks of gestation. Coronal (a) and sagittal (b) T2-weighted HASTE images demonstrate hypointense cardiac rhabdomyomas arising from the left ventricular free wall (arrow in (a)) and left atrium (arrow in (b)). MRI: magnetic resonance imaging; HASTE: half-Fourier acquisition single-shot echo.

Figure 2.

Fetal MRI performed at 31 weeks of gestation. Axial T2-weighted HASTE image demonstrates multiple hypointense nodules (arrows) in a periventricular location consistent with subependymal nodules. MRI: magnetic resonance imaging; HASTE: half-Fourier acquisition single-shot echo.

Figure 3.

Fetal MRI performed at 31 weeks of gestation. Axial T2-weighted image acquired through the maternal pelvis shows bilateral T2-hypointense lesions (arrows) in the kidneys consistent with renal angiomyolipomas. MRI: magnetic resonance imaging.

A baby girl was delivered at 35 weeks of gestation. Apgar scores were 9 and 9 at one and five minutes, respectively. Physical examination at birth demonstrated no evidence of neurocutaneous stigmata, encephalopathy, or tone abnormalities. Postnatal brain MRI was performed on day 5 of life in natural sleep. Postnatal brain MRI showed multiple T2-hypointense subependymal nodules (Figure 4(a)) and T1-hyperintense cortical and subcortical tubers (Figure 4(b)) in the frontal and parietal lobes. Postnatal transthoracic echocardiogram revealed multiple nonobstructive homogenous echogenic masses in both ventricles and left ventricular outflow tract, consistent with rhabdomyomas. Ancillary findings included patent foramen ovale, a small patent ductus arteriosus, as well as trivial tricuspid and mitral valve regurgitation. Abdominal ultrasound revealed no renal abnormalities. The infant remained hemodynamically stable with no significant respiratory events throughout the admission. However, the baby’s hospital course was complicated by the early development of seizures. She was discharged home on anticonvulsant therapy and is currently doing well.

Figure 4.

Postnatal brain MRI performed at day 5 of life. (a) Axial T2-weighted image demonstrates hypointense nodules (arrows) in a periventricular location consistent with subependymal nodules. (b) Axial T1-weighted image shows hyperintense nodules in the left frontal subcortical white matter consistent with tubers. MRI: magnetic resonance imaging.

Discussion

Fetal MRI is a technique with (1) excellent soft tissue contrast, (2) a large field of view, and (3) multiplanar imaging capability irrespective of the fetal lie. It is a well-established diagnostic tool in the clinical evaluation of fetuses with suspected cerebral and other congenital anomalies.^9–11 US has been the primary tool for obtaining morphological and functional information of the fetus. The attenuation of sound beams in US by bone limits the evaluation of neuroanatomical structures such as the brain contained within the calvarium.⁹

Fetal MRI is performed in the second and third trimester of pregnancy without maternal sedation. Fast sequences are used to scan the moving fetus. Single-shot fast spin-echo (SSFSE) T2-weighted imaging is the standard sequence for evaluation of the fetal brain in three planes. T1-weighted sequences are primarily used to demonstrate fat, calcification, and hemorrhage. Fetal MRI depicts cerebral lesions as T1-hyperintense and T2-hypointense relative to nonmyelinated white matter.³

In our patient, fetal MRI confirmed the presence of cardiac rhabdomyomas shown on US. Sonographically occult cerebral lesions, namely SENs were demonstrated clearly on the T2-weighted images. Fetal MRI has been shown to be sufficient for the detection of cerebral lesions in TSC.^12–14 SENs and cortical tubers are typically T2-hypointense and T1-hyperintense as in our patient.

Mühler et al. have recommended that the Tuberous Sclerosis Complex Consensus Conference (TSCCC) criteria be applied to fetal MRI.¹³ The 2012 updated TSCCC¹⁵ includes both genetic and clinical diagnostic criteria. However, genetic testing was deferred in our patient. Clinical diagnosis was made with the fulfillment of two major criteria, including cardiac rhabdomyomas and SENs.

In addition to the fetal brain MR findings, multiple renal angiomyolipomas (AMLs) as a manifestation of maternal TSC were demonstrated in the T2-weighted images acquired through the pelvis. Renal AML is a benign hamartoma composed of mature adipose tissue, smooth muscle, and blood vessels. During pregnancy, renal AML tend to grow faster because of an increase in circulating blood volume and renal blood flow, which in turn increases the risk of rupture and retroperitoneal hemorrhage.¹⁶ Renal AMLs should be identified during fetal MRI. However, fetal MRI is not the diagnostic test of choice for evaluating AMLs. Fetal demise secondary to mechanically obstructive cardiac rhabdomyomas has been documented.¹⁷ Cardiac rhabdomyomas in our patient were nonobstructive, hemodynamically not significant, and attached to the free wall.

Postnatal MRI of the brain does not add any complementary information to the fetal imaging. Cortical tubers were clearly identified only on the postnatal MRI. The number and location of cortical tubers correlates with the risk of epilepsy and neurodevelopmental outcome in children with TSC. Postnatal MRI may be performed in natural sleep or under sedation or general anesthesia. General anesthesia or sedation may be required in the setting of respiratory failure. The risks associated with sedation and general anesthesia overweigh the benefits of postnatal imaging.

In summary, fetal MRI played three important roles: (1) demonstration of sonographically occult fetal brain findings, (2) no significant additional information from postnatal brain MRI, and (3) recognition of renal AMLs as a maternal manifestation of TSC. Identification of TSC as an isolated or complex abnormality enables us to not only establish the diagnosis but also most importantly determine the prognosis of the fetal and associated maternal disease.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.