Tuberous sclerosis complex — branching viva

Opening framework

My framework has four layers. First, the diagnosis — this baby with infantile spasms, hypomelanotic macules and hypsarrhythmia has tuberous sclerosis complex, which I confirm with the 2012 consensus criteria. Second, the mechanism — a loss-of-function variant in TSC1 or TSC2 that abolishes the hamartin-tuberin complex, the GTPase-activating protein that brakes Rheb and mTORC1. Third, the management — vigabatrin first-line for the spasms, then lifelong organ-by-organ surveillance. Fourth, the family — cascade testing and counselling on the 50 per cent autosomal-dominant recurrence risk. [1]

Applying the criteria

The 2012 International Consensus criteria define definite TSC as two major features, or one major plus two minor features, or a pathogenic TSC1 or TSC2 variant. Hypomelanotic macules are a major feature, and cortical tubers on MRI would be a second major feature, confirming the diagnosis. A pathogenic variant alone is now sufficient, which is why molecular testing is requested early — it enables prenatal and preimplantation testing and cascade testing of relatives. The combined-feature rule is a detail worth naming: lymphangioleiomyomatosis and angiomyolipoma together count as one major feature, not two. [3]

The molecular basis and recurrence risk

TSC1 on chromosome 9 encodes hamartin and TSC2 on chromosome 16 encodes tuberin; together they form a complex that converts active Rheb-GTP to inactive Rheb-GDP, restraining mTORC1. When the complex is lost, Rheb stays active, mTORC1 overdrives, and cells proliferate without the brake, forming the hamartomas of skin, brain, kidney, heart and lung. The same mechanism explains therapy: mTOR inhibitors act downstream to restore control. TSC is autosomal dominant with complete penetrance and variable expressivity, so an affected parent transmits the variant to half their children, though severity varies. About two-thirds of cases are de novo, so a negative family history never excludes it. [1] [2]

Branch: the growing subependymal giant cell astrocytoma

A SEGA abutting the foramen of Monro threatens obstructive hydrocephalus, so I would monitor for signs of raised intracranial pressure and arrange urgent imaging if any emerge. The first-line systemic therapy is the mTOR inhibitor everolimus, which in the EXIST-1 trial reduced SEGA volume in the majority of patients, reserving surgery for obstruction or non-response. Everolimus is continued long-term with monitoring of glucose, lipids, blood count and renal function. If his focal seizures are also refractory, adjunctive everolimus has evidence from the EXIST-3 trial. [5] [6]

Branch: the fetus with a cardiac rhabdomyoma

A cardiac rhabdomyoma is the most common cardiac tumour of infancy and a frequent presenting clue to TSC, so I would screen the fetus and family with a skin examination, family history and ultimately molecular testing. Most rhabdomyomas regress spontaneously over the first years, so management is surveillance rather than surgery unless there is haemodynamic compromise. Identifying the familial variant prenatally enables cascade testing and informs reproductive counselling for future pregnancies. The key teaching point is that a fetus or neonate with a rhabdomyoma should be assumed to have TSC until proven otherwise. [4] [2]