Tuberous sclerosis, caused by germline mutations in the TSC1 or TSC2 genes, is associated with aberrant upregulation of the mammalian target of rapamycin (mTOR) signalling pathway, resulting in growth of tumours, including renal angiomyolipomas (AMLs). AMLs may cause hypertension, renal failure and spontaneous life-threatening haemorrhage. Previously, invasive interventions were required to treat AMLs. More recently, mTOR inhibitors have been used as molecularly targeted treatment to treat AMLs. We present here the case of a paediatric patient with TSC in whom sirolimus has been used successfully to halt growth of renal AMLs.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, with 95% penetrance and a birth incidence of 1 in 6000–11 000.1 TSC is caused by germline mutations in either the TSC1 gene on chromosome 9q34 encoding the protein hamartin or the TSC2 gene on chromosome 16p13 encoding tuberin.1 Tuberin and hamartin form a complex that regulates signalling through the mammalian target of rapamycin (Rheb/mTOR/p70S6K) pathway, which controls processes such as growth, cell cycle progression and apoptosis.2 Mutations of these proteins permit aberrant upregulation of the mTOR signalling pathway and cellular proliferations (subependymal giant cell astrocytomas, cutaneous angiofibromas, cardiac rhabdomyomas, lymphangioleiomyomatosis (LAM), pulmonary multifocal micronodular hyperplasia and renal angiomyolipomas).3 4
Eighty per cent of children with TSC have renal lesions by 10.5 years of age: 75% of these lesions are angiomyolipomas (AMLs) and 17% are renal cysts.1 AMLs increase in size and/or number in around 60% of children; thus, follow-up is required even if an initial renal ultrasound is normal. AMLs are benign mesenchymal tumours composed of smooth muscle cells, fibrous tissue, adipose tissue and thick-walled disorganised vascular channels. AMLs cause hypertension and renal failure and, importantly, may cause spontaneous life-threatening haemorrhage, particularly lesions more than 4 cm in diameter.
Previously, invasive interventions, such as embolisation or surgery, were required to treat AMLs. Sirolimus, an mTOR inhibitor, is a macrocyclic lactone isolated from a Streptomyces hygroscopicus strain with immunosuppressive activity. Sirolimus is commonly used following renal transplantation and has been approved for treatment of renal cell carcinoma and acute myeloid leukaemia.4 More recently, sirolimus has been used as molecularly targeted treatment in both patients with TSC and lymphangioleiomyomatosis.3 5 We present here the case of a paediatric patient with TSC and renal AML in whom sirolimus has been used successfully to halt growth of the renal AMLs.
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Competing interests None.
Ethics approval This study was conducted with the approval of the Guy's and St Thomas' NHS Trust Local Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent Obtained.
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