Tuberous sclerosis in a young child: A case report

INTRODUCTION

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder with an estimated incidence of 1 in 6,000–10,000 live births.^[1] It is caused by pathogenic variants in the TSC1 or TSC2 genes, which regulate the mammalian target of rapamycin (mTOR) pathway.^[1,2] Loss of function leads to abnormal cellular proliferation and formation of hamartomas in multiple organs, including the brain, skin, kidneys and heart.

Clinical manifestations are highly variable, ranging from isolated dermatological findings to severe neurological involvement such as epilepsy and developmental delay.^[3] Seizures are often the earliest presenting feature and may precede other clinical signs.

Early identification of subtle cutaneous lesions and recognition of seizure semiology are critical for timely diagnosis, targeted therapy and structured surveillance.^[1,4]

CASE REPORT

A 2-year-old boy, the second child of non-consanguineous parents, presented with a history of seizures beginning at 15 months of age. He was well until that time, following which he developed brief episodes of sudden head drops occurring 4–5 times daily. Initially, these episodes were not associated with loss of consciousness, limb posturing or eye deviation. Over the next 3 months, the events evolved in frequency and semiology, with episodes occurring predominantly after awakening and associated with transient loss of awareness and eye rolling. There was no history of fever, trauma, vomiting or regression of developmental milestones. Parents also noted multiple hypopigmented patches over the trunk since early infancy. There was no family history of epilepsy or neurocutaneous disorders.

The child was born at term by normal vaginal delivery with a birth weight of 2.5 kg and had an uneventful neonatal period except for transient jaundice requiring phototherapy. Developmental assessment revealed mild global delay, with neck holding achieved at 4 months, sitting without support at 9 months and independent walking at 20 months. At 2 years of age, he was speaking only monosyllables without disyllabic word formation, although social interaction was appropriate for his age. On examination, he was haemodynamically stable with pallor. Dermatological examination revealed multiple hypopigmented ash-leaf macules over the trunk [Figure 1]. There were no facial angiofibromas, shagreen patches or periungual fibromas. Neurological examination showed normal tone, power and reflexes without focal deficits, and fundus examination was normal.

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Figure 1: (a) Persistent mongoloid spots and (b) Ash leaf macules (red arrows).

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Laboratory investigations revealed microcytic hypochromic anaemia with haemoglobin of 8.1 g/dL and low ferritin levels. Liver and renal function tests were within normal limits except for elevated alkaline phosphatase. Metabolic parameters, including serum electrolytes, lactate, ammonia and homocysteine, were normal. Electroencephalography demonstrated generalised epileptiform discharges. Magnetic resonance imaging of the brain showed multiple cortical tubers and subependymal nodules, consistent with TSC [Figure 2]. Genetic testing confirmed a heterozygous pathogenic mutation in the TSC1 gene. An additional variant in the GABRD gene was identified, the clinical significance of which was considered in the context of seizure susceptibility, early onset of seizures and refractoriness and not in the causation of tuberous sclerosis. Screening for systemic involvement, including abdominal ultrasonography and echocardiography, was normal.

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Figure 2: Magnetic resonance imaging of the brain showed multiple cortical tubers and subependymal nodules (red arrow).

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The child was initially managed with valproate and clobazam, followed by the addition of cannabidiol in view of persistent seizures. Despite this, seizure frequency remained suboptimal and given the evolution of events with features suggestive of epileptic spasms spectrum disorder, intravenous methylprednisolone was initiated. The decision to escalate to steroid therapy was based on clinical suspicion of epileptic encephalopathy and inadequate response to conventional antiseizure medications. Following pulse methylprednisolone therapy, there was a significant reduction in seizure frequency. The child was discharged on valproate, clobazam and supportive therapy, with a plan for a repeat steroid cycle and continued follow-up. Parents were counselled regarding the chronic nature of the disease, seizure precautions and the need for long-term multidisciplinary surveillance.

DISCUSSION

TSC is a genetic neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, leading to dysregulation of the mTOR pathway^[1] and resulting in multisystem hamartoma formation. The clinical presentation is highly variable, and early diagnosis can be challenging, particularly in the absence of classical features. Seizures are among the earliest and most common manifestations and may present in diverse forms, including focal seizures, infantile spasms and epileptic drop attacks.^[4,5] In the present case, the initial presentation with isolated head drops posed a diagnostic challenge, as it mimicked epileptic drop attacks rather than classical infantile spasms. The subsequent evolution of seizure semiology and partial response to steroid therapy suggests that this case likely represents an overlapping epileptic spasms spectrum, highlighting the importance of early electroclinical correlation.

The presence of hypomelanotic macules in early infancy served as a critical diagnostic clue, reinforcing the importance of careful dermatological examination in children presenting with seizures.^[1] Neuroimaging findings of cortical tubers and subependymal nodules further supported the diagnosis, which was confirmed by identification of a pathogenic TSC1 mutation.^[1] Although TSC1 mutations are generally associated with a milder phenotype compared to TSC2, significant neurological involvement can still occur, as observed in this child.^[4] The additional GABRD variant identified in this case is of interest, as it encodes a subunit of the GABA-A receptor involved in inhibitory neurotransmission. While not causative of TSC, such variants have been implicated in epilepsy susceptibility and may contribute to variability in seizure severity and treatment response, although definitive clinical correlations remain limited.^[4]

Management of seizures in TSC is often challenging and requires a stepwise approach. First-line antiseizure medications may not achieve adequate control, necessitating escalation of therapy. In this case, the addition of cannabidiol was based on evidence supporting its efficacy in TSC-associated drug-resistant epilepsy; however, its role remains primarily antiseizure rather than disease-modifying, with limited evidence for direct mTOR pathway modulation.^[3] The subsequent introduction of corticosteroid therapy was guided by clinical suspicion of epileptic spasms or an evolving epileptic encephalopathy, particularly in the context of persistent seizures despite multiple medications.^[5] The observed clinical improvement following steroid therapy supports this reasoning and underscores the importance of early recognition and treatment of epileptic spasms, which are associated with adverse neurodevelopmental outcomes if untreated.^[5]

In recent years, targeted therapy with mTOR inhibitors such as everolimus has emerged as an important therapeutic option in TSC.^[2] Everolimus has demonstrated efficacy in reducing seizure frequency in patients with drug-resistant epilepsy and is also indicated for subependymal giant cell astrocytomas and renal angiomyolipomas.^[2] Although not used in the present case, it remains a potential option in patients with refractory seizures or progressive disease. Long-term management of TSC requires structured surveillance, including periodic neuroimaging to monitor for subependymal giant cell astrocytomas, renal imaging for angiomyolipomas, cardiac evaluation in early childhood and ongoing developmental and behavioural assessments.^[1,6] Early diagnosis and multidisciplinary care are essential to optimise outcomes and reduce morbidity.

This case highlights the importance of recognising atypical seizure presentations in young children and maintaining a high index of suspicion for neurocutaneous syndromes.

CONCLUSION

Early recognition of subtle dermatological signs and evolving seizure patterns is essential. It also emphasises the need for dynamic clinical reasoning in the management of epilepsy, including timely escalation of therapy and consideration of evolving treatment modalities. Structured surveillance remains critical to optimise long-term outcomes.