Magnetic resonance imaging in prenatal diagnosis of tuberous sclerosis complex: a case report

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INTRODUCTION

Current knowledge of the general and specific clinical manifestations of Bourneville–Pringle disease (tuberous sclerosis complex [TSC]), a rare genetically determined disease of the phakomatosis group, combined with advancements in imaging techniques enables highly accurate prenatal diagnosis. In the Khanty-Mansi Autonomous Okrug–Yugra, 8 cases of TSC were identified among 40,000 births between 2022 and 2024, of which 6 were genetically confirmed [1].

TSC is a rare chronic multisystem disease with a progressive course, leading to disability and poor outcomes. Genetically, Bourneville–Pringle disease is a monogenic disorder classified as neurocutaneous syndromes (phakomatoses) and is characterized by wide-ranging clinical phenotypes. Notably, there is currently no etiologic treatment for TSC, and the development of such treatment, particularly targeted therapy, remains largely ineffective. Despite advancements in early genetic diagnostics of this condition, challenges in differential diagnosis persist. This is due to its marked clinical polymorphism and age-dependent onset of symptoms, warranting further research into the patterns of TSC [2]. A potential solution to the challenge of prenatal diagnostics is the use of magnetic resonance imaging (MRI) in cases with inconclusive findings of instrumental methods, particularly ultrasound performed during the first and second trimesters of pregnancy. Central nervous system involvement is considered a hallmark feature of TSC. In >90% of cases, it is associated with the development of subependymal nodules, which are not reliably detectable by prenatal ultrasound. MRI allows for high-quality anatomical and functional imaging of the brain in various planes, improving the sensitivity and diagnostic value for early (prenatal) detection of cerebral manifestations of TSC. Additionally, MRI detects mediastinal masses. This indicates the need for a comprehensive approach in diagnosing TSC, with MRI as the primary method for assessing the fetus’ cardiovascular and central nervous systems. The presented clinical case demonstrates the importance of prenatal MRI when ultrasound findings in the first and second trimesters are inconclusive and underscores its role as an expert-level diagnostic tool.

CASE DESCRIPTION

Anamnesis Morbi

Ultrasound examination of a 26-year-old pregnant woman at 28 weeks and 2 days of gestation showed space-occupying lesions in the fetal heart. These lesions demonstrated no blood flow on color Doppler imaging and were located in the left ventricle, within the interventricular septum, and in the right atrial cavity (Fig. 1). Because of the inconclusive ultrasound findings, a case conference consisting of medical geneticists and obstetrician–gynecologists decided to perform a prenatal fetal MRI.

 

Fig. 1. Results of fetal cardiac ultrasound in the third trimester (28 weeks and 2 days of gestation). Elongated hyperechoic masses are visualized: a, within the interventricular septum; b, in the cavity of the left ventricle.

 

Diagnostic Assessment

Prenatal fetal MRI was performed at 29 weeks and 4 days of gestation in three planes using a GE Optima MR450w® scanner (GE Healthcare, United States) with a magnetic field strength of 1.5 T. Scanning was carried out using an optimized protocol with pulse sequences (Table 1). Diffusion-weighted imaging was performed with a b-value = 800 s/mm², and the apparent diffusion coefficient was measured as 10^-6 mm²/s. Intravenous contrast enhancement was not administered because of the patient’s pregnancy status. MRI revealed a single fetus in a cephalic presentation within the uterine cavity. In the left ventricle of the fetal heart, a round-shaped lesion with a hyperintense signal on T2-weighted images (WI) measuring 11.0 × 12.0 mm was visualized. A similar lesion measuring 5.5 × 8.5 mm was noted in the right atrium (Fig. 2).

 

Table 1. Magnetic resonance imaging sequence parameters used in fetal imaging

Sequence	Repetition time (TR), ms	Echo time (TE), ms	Slice thickness (T), mm
Т2 Sag	631.0	90.9	6.0
Т2 Ax	1000.0	92.9	6.0
Т2 Ax SSFSE FS	1000.0	92.4	6.0
FIESTA Ax	3.3	1.2	6.0
3D Ax LAVA Flex IO BH	6.5	3.5	6.0
T2 Sag CHEST	1227.7	118.6	4.0
T2 Cor CHEST	1227.7	118.6	4.0
T2 Ax CHEST	1235.7	122.3	4.0
T2 Sag CHEST	1235.7	120.0	3.0
T2 Cor CHEST	1235.7	120.5	3.0
T2 Ax CHEST	1235.7	121.3	3.0
3D Ax LAVA Flex IO BH	6.4	3.1	4.0
3D Ax LAVA Flex FAT	6.5	3.1	6.0
3D Ax LAVA Flex FAT	6.5	3.1	4.0
3D Ax LAVA Flex IO InPhase	6.5	4.3	6.0
3D Ax LAVA Flex IO OutPhase	6.5	4.3	4.0
Note. TR, duration between two radiofrequency pulses; TE, duration between a radiofrequency pulse and the peak of the signal (echo); Sag, sagittal plane; Ax, axial plane; SSFSE, single-shot fast spin echo; FS, fat signal suppression; FIESTA, fast imaging employing steady-state acquisition; CHEST, chest imaging region; Cor, coronal plane; LAVA, liver acquisition with volume acceleration; Flex, fat suppression technology; IO, sequence accounting for phase interaction of fat and water; BH, breath-hold test; InPhase, fat and water signals are in phase; OutPhase, fat and water signals are in opposite phase.

 

Fig. 2. Prenatal fetal chest magnetic resonance imaging in the axial plane using a T2-weighted sequence (T2 Ax CHEST). Third trimester of pregnancy (29 weeks and 4 days of gestation). Masses with signal patterns characteristic of rhabdomyoma in the left and right ventricles of the heart (white arrows).

 

Subependymal nodules of varying sizes were identified along the contours of the lateral ventricles, exhibiting hypointense signal on T2-WI and hyperintense signal on T1-WI (Fig. 3). No other abnormalities were detected in the fetus by MRI.

 

Fig. 3. Prenatal fetal brain magnetic resonance imaging in the third trimester of pregnancy (29 weeks and 4 days of gestation): a, subependymal hypointense foci on T2-weighted imaging (black arrows); b, subependymal hyperintense foci on T1-weighted imaging (white arrows).

 

In the fetal ultrasound performed at 39 weeks and 5 days of gestation, the previously visualized lesions persisted: in the left ventricle (16 × 9.1 mm), within the interventricular septum (11.7 × 5.9 mm), and in the right atrium (16.8 × 13.1 mm). Color Doppler imaging again revealed no blood flow within the lesions, supporting the earlier suspicion of cardiac rhabdomyoma.

The kidney ultrasound performed on September 7, 2023, revealed multiple small cysts (up to 3 mm) in the renal parenchyma. No dilation was observed in the right renal collecting system; however, the left renal pelvis was dilated up to 7 mm. Thus, the patient with TSC demonstrated multiple renal cysts and left-sided pyelectasis on ultrasound scan.

At week 40 of gestation (September 16, 2022), the patient underwent a cesarean section. A live, full-term newborn was delivered with a birth weight of 3550 g and Apgar scores of 8 and 9 at 1 and 5 min, respectively. According to a clinical geneticist’s consultation, the clinical phenotype included cutaneous manifestations: multiple hypopigmented macules on the newborn’s skin. High-throughput parallel sequencing of the TSC1 and TSC2 genes was performed to confirm the diagnosis, identifying two mutations in the TSC2 gene: c.1934_1935del (p.V645fs) and c.4524_4526del (p.1508_1509del). The final diagnosis was autosomal dominant TSC.

At 2 months after birth (November 16, 2022), the infant underwent brain MRI. Multiple areas of abnormal signal intensity were identified in the white matter of the cerebral hemispheres (frontal, parietal, temporal, and occipital lobes), predominantly in intra- and subcortical regions and periventricular areas. These foci had ill-defined and irregular margins and tended to coalesce:

• Hyperintense on T2-WI
• Iso- to hypointense on fluid-attenuated inversion recovery (FLAIR) images
• Hyperintense on T1-WI.

The corpus callosum was hypoplastic. Thus, postnatal MRI findings were consistent with prenatal imaging findings regarding the presence of subependymal nodules, which are pathognomonic for TSC. On T2-WI, the subependymal nodules appeared hypointense, indicating calcification in their structure (Fig. 4).

 

Fig. 4. Brain magnetic resonance imaging in the patient at 2 months old: a, images acquired using an inversion recovery sequence with long T1 (FLAIR). Multiple pathological foci in the periventricular and subcortical regions (white arrows); b, T2-weighted images. Subependymal nodules show low signal intensity (black arrows), indicating calcification.

 

Electroencephalography (EEG) performed on November 17, 2022, revealed multifocal epileptiform activity and unstable EEG patterns.

Diagnosis

The infant was evaluated by a pediatric neurologist. Based on clinical and diagnostic findings, the following diagnosis was established: cryptogenic focal epilepsy, TSC associated with a TSC2 gene mutation, subclinical multifocal epileptiform activity, single febrile seizure.

DISCUSSION

This article presents a clinical case highlighting the use of MRI in the prenatal diagnosis of Bourneville–Pringle disease and discusses the typical cerebral manifestations of this condition.

TSC has a population prevalence of approximately 1:10,000 and arises from de novo oligonucleotide mutations in the TSC1 and TSC2 genes. Mutations in the TSC1 gene (9q34), which encodes the protein hamartin, account for up to 30% of Bourneville–Pringle disease cases. The remaining cases are associated with mutations in the TSC2 gene (16p13), which encodes the protein tuberin [3]. Mutations in these genes lead to loss of gene function and mTOR kinase dysregulation. As a result, the PI3K/Akt/mTOR signaling pathway is activated, disrupting the cell cycle stages. This biological feature forms the basis for the development of carcinogenic processes that may potentially occur in all tissues of patients with this condition [4]. TSC is characterized by the development of multiple hamartomas (benign tumor-like lesions) in various organs, affecting the gastrointestinal tract; lungs; central nervous system; cardiovascular, endocrine, skeletal, and urinary systems (kidneys); visual organs; and skin. During the intrauterine period, typically beginning around week 20 of gestation, cardiac tumors are often detected, most frequently in the form of multiple rhabdomyomas, which may reach several centimeters in size and can be located in all cardiac chambers [5]. Massive cardiac tumors may result in antenatal fetal death or preterm birth. In live-born neonates with TSC, rhabdomyomas are observed in 30%–60% of cases and occur nearly twice as frequently in males.

In the perinatal period, subependymal brain nodules are present in 98% of patients and are often accompanied by epileptic seizures in utero and renal cysts and angiomyolipomas in 40% and 75% of cases, respectively. During the neonatal period, patients often present with partial epileptic seizures with potential secondary generalization. In infants, West syndrome, multiple retinal hamartomas, hypopigmented skin macules, and psychomotor developmental delay are commonly identified. Central nervous system involvement is manifested by subependymal nodules (tubers) in >90% of cases. Morphologically, tubers represent areas of disrupted six-layered cortical cytoarchitecture with a decreased number of GABAergic neurons (cells that release γ-aminobutyric acid as a neurotransmitter), which leads to focal cortical dysplasia. This condition is prone to calcification in over 50% of cases [6]. Ophthalmologic manifestations of TSC include retinal hamartomas. Renal involvement is most commonly associated with angiomyolipomas and renal cysts, which may be solitary or multiple. Gastrointestinal involvement may present as fibromas or papillomas of the tongue and palate, enamel defects, pancreatic lipomas and angiomyolipomas, and rectal polyps. In the lungs, cyst-like lesions resembling pneumatoceles of varying sizes and quantities are often detected; their rupture may cause dyspnea and hemoptysis [7].

The definitive diagnosis of TSC is established by identifying a pathogenic mutation in one of the candidate genes, TSC1 or TSC2, which function as tumor suppressor genes involved in cell cycle regulation [8]. Notably, prior to the era of genetic verification, the diagnosis was based on major and minor clinical criteria, which were subsequently structured into modern clinical diagnostic criteria. According to the 2018 Clinical Consensus Conference classification for TSC, a presumptive diagnosis can be established when either two major features or one major and two minor features are present [9]. The minor diagnostic features include the following:

• More than three dental enamel defects
• More than two oral fibromas
• Multiple hamartomas of internal organs
• Retinal achromia
• “Confetti” skin lesions
• Multicystic kidney disease [10].

The major diagnostic features include

• More than three facial angiofibromas
• More than three hypomelanotic macules measuring ≥5 mm in diameter
• At least two periungual fibromas of nontraumatic origin
• One shagreen patch
• Cardiac rhabdomyomas
• Multiple retinal hamartomas
• More than three cortical dysplasias (tubers or white matter migration tracts)
• More than two subependymal nodules
• Subependymal giant cell astrocytoma
• Pulmonary involvement
• Multiple renal angiomyolipomas [11].

A fetus with cardiac rhabdomyoma detected in the prenatal period requires comprehensive, longitudinal monitoring to promptly identify neoplasms at other sites using MRI and genetic testing, including testing of relatives, to rule out TSC. Ultrasound methods have limited sensitivity for detecting subependymal nodules in the fetal brain because of the physical limitations of the technology. However, MRI is considered a clarifying method with significant potential for targeted diagnosis of cerebral pathologies in the fetus starting at week 18 of gestation. The experience of federal-level perinatal centers indicates that the optimal timing of MRI depends on the expected developmental stage of the suspected abnormal structure initially visualized by ultrasound [12]. Pathological patterns of subependymal nodules on MRI are often stereotypical and characterized by hyperintense signal on T1-WI and T2 FLAIR, whereas the signal intensity on T2-WI varies depending on gestational age [13]. Subependymal nodules are located along the walls of the lateral ventricles and are often not visualized by ultrasound [14]. The main challenges in diagnosing TSC include the following:

• A broad spectrum of clinical presentation;
• Age-dependent manifestation of the main clinical symptoms;
• Presence of signs that require instrumental diagnostic methods for detection;
• Limited access to prenatal MRI and sequencing of the TSC1 and TSC2 genes.

CONCLUSION

Prenatal diagnosis of TSC can be optimized using MRI, which provides more accurate information. The presented case demonstrates the feasibility of using MRI to detect cerebral lesions and cardiac rhabdomyomas in a fetus with TSC during the third trimester of pregnancy. Because ultrasound has limitations in identifying cerebral manifestations of this condition, fetal MRI is recommended when TSC is suspected.

ADDITIONAL INFORMATION

Funding source. This article was not supported by any external sources of funding.

Disclosure of interest. The authors declare that they have no relationships, activities or interests (personal, professional or financial) with third parties (commercial, non-commercial, private) whose interests may be affected by the content of the article, as well as no other relationships, activities or interests over the past three years that must be reported

Authors’ contribution. T.V. Ivlyukova: appointment and description of of the examination results, subsequent examination of the patient, editing the article; D.D. Bugrova: concept of the work, writing and editing the article, collection and analysis of literary data; A.A. Melnikov: collection and analysis of literary data, editing the article; L.D. Belotserkovtseva editing the final version of the manuscript; N.V. Klimova: development of the concept of the work, editing the manuscript. Thereby, all authors provided approval of the version to be published and agree to be 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.

Consent for publication. Written consent was obtained from the patient’s law representatives for publication of relevant medical information and all of accompanying images within the manuscript in Digital Diagnostics journal.

About the authors

Tatiana V. Ivlyukova

Surgut District Clinical Centre of Maternity and Childhood health care

Email: ivlukova1978@mail.ru
ORCID iD: 0000-0001-5927-6392
SPIN-code: 6454-1164
Russian Federation, Surgut

Daria D. Bugrova

Surgut State University

Author for correspondence.
Email: bugrova_dd@edu.surgu.ru
ORCID iD: 0009-0007-1304-1839
SPIN-code: 7060-8369
Russian Federation, Surgut

Alexander A. Melnikov

Petrovsky National Research Center of Surgery

Email: alexradiology@rambler.ru
ORCID iD: 0009-0008-7409-0957
SPIN-code: 2129-3238

MD, Cand. Sci. (Medicine)

Russian Federation, Moscow

Larisa D. Belotserkovtseva

Surgut District Clinical Centre of Maternity and Childhood health care; Surgut State University

Email: info@surgut-kpc.ru
ORCID iD: 0000-0001-6995-4863
SPIN-code: 2555-8470

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Surgut; Surgut

Natalia V. Klimova

Surgut State University; Surgut Regional Clinical Hospital

Email: knv@mail.ru
ORCID iD: 0000-0003-4589-6528
SPIN-code: 6411-0879

MD, Dr. Sci. (Medicine), Professor

Russian Federation, Surgut; Surgut

References

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