Diagnostic features of tuberous sclerosis complex: case report and literature review

Introduction

Tuberous sclerosis complex (TSC) is a rare autosomal dominant multisystem syndrome characterised by formation of hamartomas in multiple organs of the body including the skin, brain, kidneys, lungs, and heart. It presents as a wide variety of phenotypic manifestations of varying severity. TSC is caused by mutations in the tumour suppressor genes TSC-1 (TSC1), which encodes hamartin protein (130-kDa) on the long arm of chromosome 9 (9q34) or TSC-2 (TSC2), which encodes tuberin protein (200-kDa) on the short arm of chromosome 16 (16p13) (1-3). TSC affects the central nervous system in the majority of patients causing a wide range of structural abnormalities such as cortical tubers, and subependymal nodules (SENs) and functional manifestations such as seizures, intellectual disability and behavioural changes. It classically presents in childhood with the Vogt triad of seizures, adenoma sebaceum (facial angiofibromas), and intellectual disorders. Seizure, and facial angiofibromas present in three quarters of patients and intellectual disorders presents in half of patients; the full triad is only seen in a minority of patients. Therefore, diagnostic criteria have been established to aid the diagnosis of TSC (1,2,4). The second “International Tuberous Sclerosis Complex Consensus Conference” held in Washington, DC, in 2012 revised the clinical diagnostic criteria for TSC and classified them as major and minor features (Figure 1). The most significant change was the incorporation of TSC1 and TSC2 molecular testing into diagnostic criteria. The diagnosis of definitive TSC requires at least two major features or one major and at least two minor features (Figure 1). Genetic diagnostic criteria include identification of a pathogenic mutation in TSC1 or TSC2 in normal tissue which is sufficient to diagnose TSC (4,5).

Figure 1 Major and minor features for TSC diagnosis according to the revised clinical diagnostic criteria in the second “International Tuberous Sclerosis Complex Consensus Conference” held in Washington, DC, in 2012. TSC-1, tuberous sclerosis complex-1, TSC-2, tuberous sclerosis complex-2.

Diagnosis of TSC by medical imaging includes detection of any of the following manifestations: (I) renal angiomyolipomas (AMLs), hepatic AMLs, splenic hamartomas, and renal cysts; (II) intracranial SENs, cortical tubers, and subependymal giant cell astrocytoma (SEGA); (III) lung lymphangioleiomyomatosis (LAM), (IV) cardiac rhabdomyomas; (V) bone lesions. These manifestations occur at different ages. For instance, cortical tubers and cardiac rhabdomyomas may occur in the antenatal period; SENs, and SEGAs may occur in childhood to adolescence; and renal AMLs may occur from childhood to adulthood (5,6). Medical imaging modalities such as multidetector computed tomography (MDCT), magnetic resonance imaging (MRI), and ultrasonography are highly valuable methods for confirming diagnosis of TSC, determining its extent, monitoring progression of disease, and early screening. The surveillance guidelines were recommended by the consensus conference in 2012 including: (I) brain and abdominal MRI every 1–3 years until 25 years old age in symptom-free TSC patients, and more frequently in patients with SEGA or AMLs with progressive growth; (II) echocardiography every 1–3 years for paediatric TSC patients to monitor cardiac rhabdomyomas; (III) chest MDCT every 5–10 years for women with risk of LAM; (IV) annual detailed dermatologic, ophthalmologic and pulmonary function testing examinations (6,7).

The main goal of this article was to state two cases of TSC and review the most commonly reported major and minor diagnostic clinical features and the most common features that led to an investigation of TSC diagnosis. The novelty of this review lies in the focus on features that led clinicians to suspect that patients had TSC and make a diagnosis of the disease. The literature review included case reports published from January 2016 to June 2020 in journals indexed in PubMed. Case reports were located by conducting a PubMed search with the term “tuberous sclerosis complex case reports”. Suitable articles included case reports published in English that reported full information about all systems of the body. Original articles, review articles and case reports that focused only on specific points or that were available in other languages were excluded.

Case presentation

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient or legal guardian.

Case 1

A 19-year-old male presented to Rush university medical center with recurrent intractable seizures. The patient had had 3–7 attacks per day of multiple types of seizures from 6 month of age. Each attack lasts for seconds to 3 minutes. His seizures had been very difficult to control and he had tried many medications. In addition, the patient had developmental delay and was diagnosed as tuberous sclerosis and intractable seizure disorder (Lennox-Gastaut syndrome). Since the age of 1-year-old, he has had a vagus nerve stimulator (VNS), which had its battery changed when he was 9 years old. At the age of 2 years, and he underwent right craniotomy and corpus callosotomy with biopsy of ventricular lesion. After surgery, the frequency of generalised convulsions improved, but he continues to have 1–4 tonic seizures during his sleep every night, one generalised tonic clonic seizure (GTCSz) a month and daily atypical absence seizures. Seizures have decreased in frequency over time.

On examination, the patient had facial angiofibromas (Figure 1; feature 2) on his nose and nasolabial folds, a shagreen patch (Figure 1; feature 4) in occipital region and folliculitis on the thigh.

Brain CT showed multiple calcified SENs (Figure 1, feature 7; Figure 2A). The brain T2 weighted-image (T2WIs) MRI showed low signal intensity SENs (Figure 2B). Post-contrast T1-weighted images (T1WIs) MRI of the brain showed gadolinium-enhanced subependymal lesions (Figure 3A) and post-contrast T1WIs MRI of the brain showed enhanced lesion on the left side in the location of foramen of Monro representing a SEGA (Figure 1, feature 8; Figure 3B). Abdominal CT showed multiple AMLs (Figure 1, feature 11) in both kidneys (Figure 4A) with a large mass in the right kidney (Figure 4B) which represents biopsy proven AML with previous embolization after haemorrhage. Based on these clinical features and radiology findings, this case was diagnosed as TSC.

Figure 2 A 19-year-old male known tuberous sclerosis complex (Case 1) showing multiple brain lesions. (A) Axial computed tomography image of the brain showing multiple calcified subependymal nodules (SENs; arrows). (B) Axial T2 weighted-image of magnetic resonance imaging of the brain showing low signal intensity SENs (indicated by arrows) in the same patient. Multiple subcortical white matter tubers were also present (not shown here). Encephalomalacia in the right frontal lobe is post-surgery.

Figure 3 A 19-year-old male known tuberous sclerosis complex (Case 1) with multiple brain lesions. (A) Axial post-contrast T1-weighted images (WIs) magnetic resonance imaging (MRI) of the brain showing gadolinium-enhanced subependymal lesion more than 1 cm suggesting a subependymal giant cell astrocytoma (SEGA) (arrow). (B) Axial post-contrast T1WIs MRI of the brain showing left enhanced lesion more than 1 cm in size near the location of foramen of Monro representing biopsy proven SEGA (arrow) in the same patient.

Figure 4 A 19-year-old male known tuberous sclerosis complex (Case 1) with multiple renal lesions. (A) Axial non-enhanced computed tomography (NECT) of the abdomen showing multiple renal masses containing fat consistent with angiomyolipomas (AMLs) in both kidneys. (B) Axial NECT of the abdomen showing post embolization changes on renal AML previously complicated with haemorrhage in the right kidney.

Case 2

A 2.5-year-old female who had experienced seizures from 3 months of age presented to Rush university medical center with increasing seizure frequency and severity. TSC was diagnosed prenatally when a tumour was seen in her heart during antenatal ultrasonography. She was born at 40 weeks’ gestation by normal vaginal delivery. After birth, screening medical imaging was done and T1WIs MRI of the brain showed multiple low signal intensity SENs (Figure 1, feature 7; Figure 5A), and fluid attenuation inversion recovery (FLAIR) weighted-images MRI of the brain showed multiple high signal intensity SENs (Figure 1, feature 7; Figure 5B). Abdominal T2WIs MRI showed multiple high signal intensity bilateral renal lesions (simple cysts; Figure 1; feature 5+; Figure 6A), and lower chest MRI showed low signal intensity mass in the right ventricle (Figure 1, feature 9; Figure 6B). The patient began having seizures at 3 months old when she started phenobarbital treatment. At the age of 1 year, she continued to have seizures, and the phenobarbital dose was increased. At 2 years of age, seizure frequency increased to 5–12 per day, and she was started on Levetiracetam. At 2.5 years of age, seizures had not improved, so she was started on Topiramate. The patient began having cyanosis and crying during her seizures. After being seen at an emergency department, Topiramate was discontinued and the phenobarbital dose was increased.

Figure 5 A 2.5-year-old female known tuberous sclerosis complex (Case 2) with multiple brain lesions. (A) Axial T1-weighted images magnetic resonance imaging (MRI) of the brain showing multiple low signal intensity subependymal nodules (SENs; arrows). (B) Axial fluid attenuation inversion recovery (FLAIR) weighted-images MRI of the brain showing the SENs appear of high signal intensity (arrows).

Figure 6 A 2.5-year-old female known tuberous sclerosis complex (Case 2) with multiple renal lesions and mass in the right ventricle of the heart. (A) Coronal T2-weighted images magnetic resonance imaging (MRI) of the abdomen showing multiple high signal intensity bilateral renal lesions (simple cysts). (B) Axial MRI of the abdomen and lower chest showing low signal intensity mass in the right ventricle (arrow).

In terms of development, she started walking at 15 months old, and she is able to speak a few words. She currently has 5–12 seizures per day, each one lasting 10–30 seconds. She has multiple seizure types. Because of the worsening seizures, this episode was the "last straw" for her mother, who brought her in for evaluation. Based on these clinical features and radiology findings, the patient was diagnosed with TSC with developmental delay and epilepsy under treatment.

Discussion

In this article, we reported two cases of TSC and we reviewed the reported similar cases in the last 4.5 years in journals indexed in the PubMed. A total of 65 published case reports met the selection criteria and were included in the literature review. Demography of patients, major and minor features, and genotype results from these cases are shown in Table 1.

Demography

Herein, we reported two cases of TSC, one in adult man but was diagnosed during infancy and other diagnosed in an infant female. In the literature, out of 65 TSC cases, 37 were female patients and 28 were males. Umeoka et al. (1) reported that TSC can affect males and females in all ethnic groups. Similar to this, Kingswood et al. (70) and Kothare et al. (71) separately reported a slight female predominance (51–52%). In the literature, we found that 33 of patients were diagnosed in childhood and 12 cases had clinical features since childhood even though diagnoses were not made until patients were older than 18 years. Staley reported that the mean age of TSC diagnosis was 7.5 years old, ranging from birth to 73 years old (72). Similarly, Zamora et al. (73) reported that features of TSC are mostly detected in fetuses, infants, children or adolescents.

Clinical features

In this report, we documented two cases of TSC presented with seizures since infancy. In the literature, seizures were reported in 30 patients. Kothare et al. reported that 63% of TSC patients had experienced at least one seizure attack (71). The most common reported presenting symptoms of TSC were seizures, history of seizures, or infantile spasm (72). Similarly, in other studies, focal or generalized seizures were found to be the most common symptoms (72–75.3%) (74,75). This is supported by another study that found a similar percentage of patients had a type of epilepsy where more than 50% of seizures were drug-resistant for a period of time (76). Wang et al. (77) found that seizures occurred in up to 90% of patients with TSC, and the majority (63%) of seizures occurred in the first year of life and could be difficult to control.

In the literature, abdominal (mainly renal) symptoms were the second most common reported symptoms. Similarly, Dixon et al. (78) reported renal clinical manifestation in 14 (21.53%) patients, and this was the second most common clinical feature of TSC.

Brain features

This report and literature review demonstrates that cortical tubers, SENs (Figures 2,3), and SEGA (Figure 4) brain lesions were the most commonly reported major features; they were reported in 53 cases. Umeoka et al. (1) reported that the prevalence of cortical tubers (Figure 1; feature 6) and/or SENs (Figure 1; feature 7) ranges from 95% to100% in TSC patients, indicating that this feature can be an adequate clue for of TSC diagnosis on the basis of brain imaging. Northrup et al. (4) and von Ranke et al. (5) reported that cortical dysplasia and cortical tubers were present in 90% and 95% of TSC patients, respectively. In addition, 80–90% of TSC patients were reported to have cortical tubers and SENs (79).

Regarding brain lesions, cortical tubers are developmental abnormalities characterised by loss of the normal six-layer structure of the cerebral cortex and the presence of dysmorphic neurons and large astrocytes. They are the cause of neurological symptoms in TSC patients and are best detected by MRI. Cortical tubers are different from cortical dysplasia which is a congenital abnormality that occurs during development when a group of neurons fail to migrate to the proper site in the brain. SENs are benign hamartomas that are commonly calcified and are best diagnosed by CT. SEGAs consist of proliferative astrocytes and giant cells typically located in the foramen of Monro and cause obstructive hydrocephalus with no or partial calcification, gadolinium enhancement and more than 1 cm in size (1,4). Our patients did in fact have multiple brain lesions.

Skin features

In the literature, skin features were the second most common major features reported in this review. Skin features were present in 42 patients. This result is very close to the findings of Almobarak et al. (80) who found skin lesions in 64.7% of patients at the time of presentation. The result is also in line with Rosset et al. (81) who reported that skin manifestations occurred in 70% of TSC patients. Case-1 of our patients did in fact have multiple skin manifestations.

Renal features

In our report, renal features were found in both cases. In the literature, renal features were the third most common major feature reported. We found them in 33 of TSC cases. The majority were renal AMLs (Figure 1, feature 11; Figure 4) which were reported in 29 cases. Kingswood et al. (70) and Uysal et al. (79) reported that AMLs are the most common renal lesion in TSC and they are often bilateral, multiple, and asymptomatic. Von Ranke et al. found AMLs in 70–80% of patients with TSC, and they report that the most serious complication is rupture and haemorrhage frequently associated with aneurysm (5). AML is a type of benign tumour that consists of variable numbers of vascular cells, smooth-muscle cells, epithelioid cells, and fat cells (1,79). The second most common renal lesion in patients with TSC is renal cysts (Figure 1; minor feature 5+), which can be single or multiple (1). In the literature, renal cysts were the second most common renal manifestation of TSC; renal cysts were reported in 10 patients. Rarely, TSC is associated with a severe early onset polycystic kidney phenotype due to a large deletion mutation spanning parts of both TSC2 and PKD1 genes on chromosome 16p13 (78). The combination of AMLs and cysts is highly indicative of TSC (79). Our patient did in fact have multiple renal lesions.

Chest features

Cardiac rhabdomyomas, are benign muscular tumours of the heart. They are commonly located in the ventricular septum, with no clinical features at birth, and commonly regress or even disappear (1). In the literature, cardiac rhabdomyomas (Figure 1; feature 9) was reported in 17 cases, and LAM (Figure 1; feature 10) was reported in 5 cases. Northrup et al. reported that the presence of prenatal cardiac rhabdomyomas were associated with an 80% risk of TSC (4). LAM was found in 4 cases in the literature. It has been reported that pulmonary manifestations including LAM or “multifocal micro nodular pneumocyte hyperplasia” (MMPH) occur in 1–2.3% of TSC patients, but higher rates have been documented with the new radiological imaging modalities (1).

Ocular features

The literature review reveals that ocular features are among the uncommonly reported features. Retinal astrocytic hamartomas (RAHs), (Figure 1; feature 5) were reported in 9 out of 65 cases. Northrup et al. and Uysal et al. reported that retinal hamartomas are a major feature that were observed in up to 50% of TSC patients, and they also reported that retinal achromic patch is another manifestation (4,79). RAHs are a potential cause of visual deficits in TSC patients (82).

Genotype

In the literature, genetic tests were available for 23 cases. Within these cases, a TSC1 mutation was reported in 7 cases, a TSC2 mutation was reported in 14 cases, a mutation in both genes was reported in 1 case, and no mutation was reported in 1 case. Similar to this, de Vries et al. (2) study reported that 64.4% of TSC patients had a TSC2 mutation, 19.1% had a TSC1 mutation, and 14.4% had no mutation. Similarly, Almobarak et al. reported that 65.9% of patients had a TSC2 mutation, 29.5% had a TSC1 mutation, and 4.5% had no mutations (80). He et al. also reported that more patients had a TSC2 mutation compared with TSC1 (71.79% vs. 28.2%) and 10.25% had no mutations (83). Von Ranke et al. (5) and Nellist et al. (84) considered that identification of a mutation in TSC1 or TSC2 is sufficient for diagnosis of TSC.

Diagnostic clues and medical imaging

Medical imaging plays an essential role in detecting features of TSC and, thus for diagnosing patients with the disease. However, clinical features should be available for suspicion and investigation of TSC patients.

In the literature, neurological manifestations were the main clues that led to investigation and diagnosis of TSC in 22 patients. Neurological features included seizures in 18 cases, developmental delay in 2 cases, weakness in 1 case, and headache in 1 case. The second most common indication to investigate for TSC was abdominal manifestations which were found in 16 cases, including renal clinical manifestations, such as flank pain and hematuria, in 11 cases, and other abdominal clinical manifestations in 5 cases. Antenatal follow-up by ultrasonography was the feature that led to TSC diagnosis in 11 out of 65 cases. The main clue features that initiated investigation of disease were skin manifestations, chest manifestations, ocular manifestations, gingival and teeth manifestations, and tachycardia after birth in 4, 3, 2, 2, and 1 cases, respectively. The remained 4 cases were incidentally diagnosed, 2 cases during abdominal imaging, 1 case during chest imaging, and 1 case during follow-up pregnancy imaging.

Kija et al. (74) found that skin manifestations led to diagnosis in 33% of TSC patients. However, in the literature, skin manifestations were the diagnostic clue in only 4 cases. This gap can be explained by that skin lesions were omitted by the patients because they were not causing of alarming manifestations.

Regarding imaging modalities, Umeoka et al. and von Ranke et al. reported that CT is an effective modality for detection of SENs, because they are commonly associated with calcification. CT can detect cortical tubers, but MRI was found to be more effective than CT in detecting cortical tubers and SEGAs. CT can diagnose AMLs by measuring intratumoral fat density (density < ‒20 HU) with homogenous enhancement after administration of intravenous contrast media. Chest manifestations including LAM and MMPH can also be diagnosed easily by chest CT (1,5).

Echocardiography is the primary diagnostic tool used to investigate cardiac rhabdomyomas. However, MRI or CT can provide further information regarding tumour size and extension (5). Cardiac rhabdomyomas can be detected during antenatal ultrasonography at or after the 22^nd week of gestation (79). Gu et al. (85) reported that identification of cardiac tumours by antenatal ultrasonography is often the first feature of TSC, and Davis et al. (86) reported that 35% of infants with TSC presented with cardiac rhabdomyomas during the antenatal period, as observed by medical imaging.

Pathophysiology of TSC lesions

Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase that controls eukaryotic cell growth and metabolism. Loss of function mutations in TSC1 or TSC2 lead to hyperactive mTOR which causes abnormal cell proliferation and increases in cell size; this causes formation of brain lesions that occur in TSC patients. Somatic mutations that activate the mTOR complex-1 pathway cause a plethora of neurological diseases (87,88). Brain lesions in TSC are formed during the embryonic period as a consequence of increased activation of mTOR and these lesions can be detected by fetal ultrasonography or brain MRI (89).

Regarding the occurrence of AMLs, Niida et al. (90) reported that loss of heterozygosity of the remaining wild type TSC1 or TSC2 allele was detected in some patients, whereas in other patients, additional yet uncovered mechanisms may be pathogenic.

TSC1 encodes the protein hamartin and TSC2 gene encodes the protein tuberin. These two proteins act as tumor suppressors by forming the TSC1-TSC2 heterodimer which activates the GTPase-activating protein complex resulting in inhibition of the mTOR. In TSC patients, mutations of TSC1 and TSC2 activate mTOR, leading to abnormal cell proliferation and differentiation and multiple hamartomatous growths in the brain, heart, kidneys, eyes and skin (91).

Oral mTOR inhibitors are effective in treatment of TSC manifestations, for example, Cardis and DeKlotz reported that rapamycin and its analogues inhibit mTOR and impede its overactivation, preventing tumor growth in TSC. Oral mTOR inhibitors are effective in treatment of TSC manifestations. Oral rapamycin is approved by the American Food and Drug administration and by the European Medicines Agency for treatment of pulmonary LAM in TSC. Additionally, topical mTOR inhibitors are effective in treatment of angiofibromas as indicated by consensus guidelines (92).

Conclusions

TSC can affect males and females in any age and ethnic group. Medical imaging plays an essential role in detecting features and diagnosing TSC. However, clinical features are the main factor that leads to suspected TSC cases and investigation of disease in patients. We reported two cases of TSC. Case 1 presented with seizures from 6 months of age and was diagnosed by multiple calcified subependymal nodules, and Case 2 presented with seizures from 3 months of age and was diagnosed prenatally by a tumour in the heart. In the literature, neurological manifestations, including seizures, were the most common clues that led to investigation and diagnosis of TSC. Abdominal manifestations, including renal manifestations, were the second most common clues for diagnosis, and antenatal follow-up by ultrasonography was the third most common clue for diagnosis. Skin, chest, ocular and gingival manifestations were less-common clues. Tachycardia following birth was the least common clue that led to TSC diagnosis. TSC may be incidentally discovered by medical imaging for any purpose.

Acknowledgments

The authors would like to thank scribendi.com for their effort in English language editing.

Funding: None.

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/qims-21-412). 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. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient or legal guardian.

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