Review of the spectrum of tuberous sclerosis complex: The Saudi Arabian Experience

Tuberous sclerosis complex (TSC) is a rare neurocutaneous disease; one of its remarkable features is the presence of benign tumour-like lesions known as hamartomas. Regardless of gender or race, it has autosomal dominant inheritance with a frequency of 1 in 20,000 and an estimated incidence of 1 in 6,000 to 10,000 in the general population.¹ Although TSC is inherited as an autosomal dominant characteristic, two-thirds of all TSC appear sporadically with apparent de novo mutations that need the acquisition of a second somatic hit to be diseased.^2,3 Around 10% to 15% of people who formerly met the TSC clinical criteria by traditional genetic testing were categorised as having no mutation identified in either TSC1 or TSC2.^4,5 However, the diagnosis of TSC should not be ruled out only because a causal mutation could not be found. Mosaicism and intronic mutations may be the hidden cause, according to recent research.⁶

Due to their uniqueness to TSC, numerous cortical tuber migration lines have taken the position of cortical dysplasia in the new recommendations. Importantly, a diagnosis may only be made if at least 2 significant traits or one major and 2 minor features are present. Alternately, molecular genetic testing can be used to diagnose the existence of pathogenic mutations in TSC1 or TSC2.⁷ The initial signs of TSC are epileptic spasms, neurodevelopmental delay, and cutaneous hypopigmented macules; renal angiomyolipomas appear later, in adolescence or adulthood.^8,10 One of the late indications of lymphangioleiomyomatosis (LAM), pulmonary involvement, shows a female preponderance.¹¹ Subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas are additional central nervous system diseases that affect 5%–15% of people with TSC.¹⁰ Patients with TSC 2 exhibit far more severe symptoms than those with TSC1, and they are more likely to experience epileptic spasms, kidney cancer, intellectual impairment, autism, and low intelligence quotient.^12-14

One of the most prevalent neurological symptoms of TSC is epilepsy, which is also a known source of morbidity and death in these individuals. In most cases, epilepsy develops in the first few months of life.¹⁵ In a study by Nabbout et al¹⁶, 83% of TSC patients experienced epilepsy, (of whom 67.5% had focal seizures and 38.9% had epileptic spasms). Few TSC patients with epilepsy were able to obtain a remission of their seizures following a trial of stopping antiseizure drugs (ASMs), according to the findings by Sparagana et al.¹⁷ However, patients with minor cerebrum damage are the ones who have this remission.¹⁷ Similar results from local retrospective research showed that the majority of TSC patients had seizures upon presentation. However, intriguingly, the prevalence of epilepsy among TSC patients was lower in Saudi Arabia than in Western nations.¹⁸

Even though more than 90% of TSC patients are impacted by one or more Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND) features, the expectation is that only 20% of individuals with TAND will obtain a full examination.¹⁹ One of the behavioural symptoms that have been linked to TSC is autism, although the exact mechanism underpinning this relationship is still unclear.²⁰ Autism spectrum disorder (ASD) was identified in 40.5% of individuals with TSC in research by Vignoli et al.²¹ There are limited studies in Saudi Arabia that examine the prevalence of TSC and its associated characteristics. Previous studies in Saudi Arabia focused on specific neurological symptoms of TSC, such as epilepsy,¹⁸ or examined whether children with TSC received appropriate surveillance as advised by TSC Consensus Recommendations.²² Therefore, this study aims to determine the prevalence of TSC in the paediatric Saudi population and to characterise the range of clinical symptoms, neurocutaneous findings, neuroimaging results, and complications of the disease.

Methods

Results

The present study included a total of 61 patients diagnosed with TSC. A total of 36 (59%) were males, while 25 (41%) were females. The mean age of the patients at the time of diagnosis was estimated to be 4.9 years (Table 1). The average duration of follow-up was approximately five years. Only nine (13.1%) of the patients had a first-degree relative with TSC.

In this sample, the presence of subependymal nodules was the most prevalent main criterion at 86.9% (n=53), followed by multiple cortical tubers and/or radial migration lines at 63.9% (n=39) and hypomelanotic macules at 63.9% (n=39). Multiple renal cysts were the most prevalent minor criterion at 27.9% (n=17). Based on the Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations 2021,⁹ Tables 2 and 3 display the frequency of the diagnostic criteria and the age at presentation in the cohort studied

Hypomelanotic macules were significantly more prevalent in males compared to females, accounting for 77.8% and 44%, respectively (p=0.007) (Table 4).

Multiple cortical tubers and/or radial migration lines appear earlier in males (2.7±3) than in females (6.7±6.6), as shown in Table 5. A total of 11 (18%) of the 61 patients included in this study had oral complications such as dental cavities. However, the evidence was not conclusive that any of our patients had pitted dental enamel.

Nearly nine-tenths (86.9%, or 53) of our patients had a history of epilepsy. The mean age at presentation was 3.75 years (range: 0.8-17), with an SD of 0.81 years. Of the 53 patients, 31 were males and 22 were females. The most prevalent categories of seizures were generalised motor tonic-clonic (37.7%, n=23), mixed (36.1%, n=22), and epileptic spasms (32.8%, n=20) (Table 6).

The EEG was performed for 51 (83%) patients and found to be abnormal in 37 (60.7%) patients, with focal abnormalities being the most prevalent at 31.1% (n=19) (Table 6).

The EEG showed diffuse slowing of the background in some patients, while it showed focal and multifocal epileptiform discharges in others, with maximum epileptiform discharges over the frontal and temporal head regions.

Epilepsy management was dominated by medical treatment. The majority of the patients (73.8% (n=45)) received ASMs, with levetiracetam (36.1%; n=22) and valproate (31.1%; n=19) being the most commonly used medications. Four patients with refractory seizures underwent surgery, three were treated with mTOR inhibitors, and one underwent VNS. No patients were treated with a ketogenic diet. Table 6 displays the prevalence of the various epilepsy management strategies used by our participants.

Neuroimaging was performed on 93% (n=57) of our patients, of whom 91.8% (n=56) showed abnormalities. Moreover, 55.7% (n=43) of our patients were subjected to genetic testing. Of these, 14.8% (n=9) were diagnosed with TSC1, while 37.7% (n=23) were diagnosed with TSC2. Although males had a higher prevalence of TSC1 and TSC2, the difference was not statistically significant (p=0.613 and p=0.819, respectively).

The overall frequencies of TAND manifestations in the studied cohort are depicted in Table 6.

No significant difference was seen between the presence of TAND and gender. The TAND was present among 66.7% of those with TSC1 and 73.9% of those with TSC2.

In this study, 29.5% (n=18) of our cohort had cardiovascular manifestations, 9.8% (n=6) of which were arrhythmias. Mitral regurgitation was 3.3% (n=2), hypertension was 1.6% (n=1), and atrial septal defect was 1.6% (n=1). Only one patient (1.6%) with rhabdomyoma underwent cardiac surgery. Table 6 outlines the treatment options available for TSC complications.

Discussion

In this study, the current mean age was 11 years, and the mean age at diagnosis was 4.9 years. In contrast, in a previously published study, Staley et al²⁶ noticed that the mean age at diagnosis was 7.5 years. This may reflect the progress made in the detection of TSC in recent years.

Almubarak et al¹⁸ found that those who were genetically evaluated were more likely to carry TSC2 mutations than TSC1 mutations.¹⁸ This mirrors the findings of our current investigation, where we identified that 14.8% of the patients were diagnosed with TSC1, while 37.7% were diagnosed with TSC2. This demonstrates that the Saudi population matches what has been reported in the literature. One of the initial symptoms of TSC is epilepsy, which manifests primarily as epileptic spasms. According to the 2012 International Tuberous Sclerosis Complex Consensus Group, approximately 85% of TSC patients are affected by this.⁷ This was aligning with the findings of our study, where we identified that 86.9% of our patients had a history of epilepsy.

Despite epilepsy being one of the earliest manifestations of TSC, nearly 19% of patients were treated for it for 6 weeks to 36 years before receiving a formal diagnosis of TSC.²⁶ However, the prevalence of epilepsy among TSC patients remains variable, as Almubarak et al. have reported lower rates.¹⁸ In both investigations, motor tonic-clonic seizure was found to be the predominant seizure semiology, affecting 37% of both cohorts. In contrast to the study of Almubarak et al¹⁸ in which the rate of epileptic spasms was 15.9%, a higher rate of 32.8% was observed in our study.

The identification of epileptic spasms is crucial, and prompt treatment is essential as the cognitive prognosis is poor.²⁷ The majority of TSC-related epilepsy patients are resistant to treatment with standard ASMs and require multiple therapies management. Lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.9%), vigabatrin (19.0%), and levetiracetam (17.9%) were the ASMs most commonly used in the German population, according to a study.²⁸ In comparison to our sample, levetiracetam was the most commonly used ASM at 36.1%, followed by valproate at 31.0%.

Neurocutaneous stigmata are essential for the diagnosis of TSC, and a comprehensive clinical dermatological examination is essential, as they constitute four major and 3 minor criteria. Although they appear early on, the onset of these cutaneous characteristics varies depending on age and gender. In our study, hypomelanotic macules were significantly more prevalent in males compared to females, accounting for 77.8% and 44%, respectively (p=0.007). Similar to our findings, hypomelanotic macules have been reported to affect more than 90% of TSC patients in many large studies.²⁹ In addition, the advent of the other cutaneous manifestations was consistent with the literature, albeit at a lower frequency than anticipated. This was likewise noted in the article by Almubarak et al.¹⁸ Approximately half of TSC patients are afflicted by shagreen regions, according to one study.³⁰ In the current investigation and the study by Almubarak et al¹⁸ the prevalence of shagreen regions was 26.2% and 13.6%, respectively.¹⁸

Lesions of angiofibroma progress with advancing age. Approximately 8% of TSC patients younger than 2 years old exhibit angiofibroma, compared to 75% of those older than nine years.³¹ Around 24.6% of our cohort was initially diagnosed with angiofibroma at an average age of 9 years. Consistent with what Almubarak et al¹⁸ reported, only one patient in our study manifested with ungual fibroma.

The most burdensome aspect of TSC is its association with neuropsychiatric conditions. In our study, we did not identify any statistically significant difference between males and females in terms of the prevalence of TAND. This was consistent with the findings of a previous study that examined the prevalence of TAND among the pediatric population, which showed comparable findings.³³ A study of TAND revealed that 88% of patients with TSC were affected by at least one TAND entity, while 78% had more than four TAND entities.³⁴ In addition, the earlier the onset of seizures in TSC patients, the greater the likelihood that the patient will develop multiple neuropsychiatric disorders. The mutation in TSC2 was associated with a higher incidence of intellectual disability and autism spectrum disorders.^35,36 Epilepsy, epileptic spasms, and TSC2 mutations were risk factors for the development of ASD in TSC patients, according to one study.²¹ TAND was detected in 66.7%, 73.9%, and 67.6% of TSC1 patients, TSC2 patients, and DRE patients, respectively. One study supported the applicability of a TAND detection protocol in TSC patients.³⁷ Therefore, the use of screening tools is necessary to guarantee a prompt diagnosis of TAND and, consequently, an improved prognosis for the disease.

Cardiac rhabdomyomas are strongly linked to TSC. Although benign, if sufficiently large, these hamartomatous lesions can cause significant mass effects, resulting in arrhythmia and cardiac failure.³⁸ In our study, cardiac rhabdomyomas were observed in 15 patients, or approximately 25%. Six of these 15 patients developed cardiac arrhythmias due to the lesions. The mean age of diagnosis for these cardiac lesions was 1.6±2.8 years, making it the earliest clinical manifestation of TSC among our participants. Although cardiac rhabdomyomas are an early finding in TSC, they typically regress spontaneously in the early stages of the disease. Compared to our findings, the prevalence of cardiac rhabdomyomas in TSC patients is higher in other studies.^39,40 The age at which TSC was diagnosed in our participants may be one plausible explanation for this lower prevalence. In addition, the fact that not all of our asymptomatic patients have undergone an echocardiogram is a potential explanation for this decreased prevalence. In contrast to other clinical manifestations of TSC, these cardiac lesions are detectable in utero.³⁸ Patients with cardiac rhabdomyoma require echocardiogram and electrocardiogram monitoring for early detection of complications, including electrical disturbances, as observed in 6 of our patients.⁴¹

Renal manifestations are prevalent among TSC patients and are regarded as a major cause of morbidity and mortality.⁴² In our study, the prevalence of AMLs (39.3%) exceeded that of multiple renal cysts (27.9%). This is consistent with the results of other investigations of a similar nature.^39,42 Renal AMLs are associated with renal dysfunction and impairment. Around 16% of TSC patients with AMLs who were observed for 12 years by a cohort study developed Stage 3 or higher chronic kidney disease (CKD).⁴³ This decline in renal function due to AMLs was observed in one of the patients who developed Stage 5 CKD in our study. This emphasises the need for vigilant surveillance of renal function in TSC patients.

To achieve optimal results, TSC administration necessitates the incorporation of numerous specialities. The complexity of TSC necessitates a multidisciplinary team (MDT) approach. This improves the outcome by ensuring that all specialists are efficiently interconnected. In addition, the MDT approach would facilitate the transition from adolescent to adult care. Existing gaps in the literature necessitate additional research on the establishment of TSC multidisciplinary team plans and guidelines with an emphasis on the role of each specialist.

Our study has certain limitations. First, this is a retrospective study based on a review of patient records. The original intent of these infographics was not data collection. Therefore, information may be lacking or inadequately documented. Second, cutaneous and dental manifestations may have been underreported because not all of our patients underwent comprehensive dental and dermatological examinations. Our study also included TSC patients from a single centre, which is NGHA. One potential bias that may arise among patients is related to the specificity of the NGHA facility. This bias stems from the fact that patients who are linked to the Saudi Arabian National Guard and their relatives often have priority access to NGHA facilities. This may result in disparities in healthcare access when compared to the broader population. Moreover, the distinctiveness of NGHA services may result in patients obtaining exceptionally specialized care, hence offering advantages to individuals with specific medical needs in those particular domains. Therefore, our findings should be interpreted carefully.

Conclusion

The TSC is a medical condition characterized by a range of neurological, cutaneous, and radiological manifestations. Males were substantially more likely than females to have hypomelanotic macules. Furthermore, it was shown that males had a notable development of cortical tubers and/or radial migration lines at an earlier stage compared to females. Almost half of the sample was subjected to genetic testing, which revealed a higher prevalence of TSC2. Neuropsychiatric disorders and a history of epilepsy were documented in the majority of our patients, and nearly half of those with epilepsy had intractable epilepsy.