Tuberous sclerosis complex — formative SAQs

Question 1 (10 marks)

A seven-month-old boy presents with clusters of flexor spasms and developmental regression. On examination under a Wood's lamp he has three hypomelanotic macules, and his EEG shows hypsarrhythmia. His father has a single ash-leaf patch and was "a slow learner" at school. (a) What is the most likely diagnosis and which diagnostic criteria do you apply? (b) Outline the immediate management of his seizures and the developmental surveillance plan. (c) Explain the molecular basis and the recurrence risk. [2]

Model answer

(a) The most likely diagnosis is tuberous sclerosis complex presenting as West syndrome (infantile spasms). The 2012 International Consensus criteria apply: definite TSC requires two major features, or one major plus two minor, or a pathogenic TSC1/TSC2 variant. Hypomelanotic macules are a major feature, infantile spasms strongly suggest cortical tubers (a second major feature), and I would confirm with brain MRI and molecular testing. Examining the father may reveal familial disease. [3]

(b) The immediate management is vigabatrin first-line for TSC-associated infantile spasms, started promptly because early seizure control protects the developing brain, with serial EEG to assess response and ophthalmic surveillance for visual-field toxicity. The developmental surveillance plan is a structured baseline assessment of cognition, behaviour and autism risk at diagnosis, with annual review, early intervention services, and educational support, because neurocognitive comorbidity dominates quality of life. [4] [8]

(c) TSC is an autosomal-dominant mTOR-opathy caused by loss-of-function variants in TSC1 (chromosome 9, hamartin) or TSC2 (chromosome 16, tuberin). The hamartin-tuberin complex is a GTPase-activating protein that restrains Rheb and brakes mTORC1; its loss drives uncontrolled cell growth. The recurrence risk to each child of an affected parent is 50 per cent, though expressivity varies widely. Cascade testing of the father and first-degree relatives is mandatory, and genetic counselling addresses reproductive options. [1]

Question 2 (10 marks)

A six-year-old girl with known TSC is found on routine surveillance MRI to have a subependymal giant cell astrocytoma that has enlarged since her previous scan and now abuts the foramen of Monro. (a) What is the significance of this finding and what complication do you watch for? (b) Outline the management options. (c) Her focal seizures remain refractory to two anti-seizure medicines — what systemic therapy has evidence in this setting? [4]

Model answer

(a) A growing subependymal giant cell astrocytoma abutting the foramen of Monro threatens obstructive hydrocephalus, the most dangerous complication of a SEGA. I would monitor closely for headache, vomiting, visual change or deteriorating consciousness, and arrange urgent imaging if any of these emerge. Serial MRI every one to three years through childhood and adolescence is the surveillance schedule designed to detect growth before obstruction occurs. [4]

(b) The first-line systemic therapy is the mTOR inhibitor everolimus, which in the EXIST-1 trial reduced SEGA volume in the majority of patients and offers a medical alternative to surgery for a growing lesion. Surgery is reserved for obstructive hydrocephalus, acute deterioration, or non-response to medical therapy. Everolimus is typically continued long-term, with monitoring of glucose, lipids, full blood count and renal function. [4]

(c) For refractory focal-onset seizures associated with TSC, adjunctive everolimus has evidence from the EXIST-3 trial, which showed reduced seizure frequency, with a paediatric post-hoc analysis confirming benefit in children and adolescents. Other options include epilepsy surgery for a focal resectable lesion, which is considered early because TSC is a surgically amenable aetiology. The shared mechanism — mTOR inhibition restoring control downstream of the broken brake — underpins both the SEGA and the epilepsy benefit. [6] [2]