Lack of behavioural improvement with sirolimus in a patient with MTOR-related macrocephaly with pigmentary mosaicism: A new case report

Postzygotic activating MTOR variants result in neurocutaneous mosaic phenotypes including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism (hypomelanosis of Ito), whereas germline activating variants cause Smith-Kinsgmore syndrome. The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. As rapamycin downregulates the increased activity caused by the mosaic mTOR variant, it may result in improvement of clinical outcomes, as shown for refractory epilepsy in tuberous sclerosis, another genetic disease of the mTOR pathway. However, results of treatment have been reported in only three genotyped patients so far, one with pigmentary mosaicism, megalencephaly and epilepsy, and two with focal cortical dysplasia, with conflicting results. Here we report on a 12-year-old male patient with megalencephaly-pigmentary mosaicism and a mTOR mosaic gain-of-function variant (p.(Ser2413Ile)) in 23 % of affected skin cells, who received compassionate off-label sirolimus for severe behavioural disorder. Sirolimus was initiated at 1.3 mg twice a day with regular blood monitoring. After a 6-months period, no improvement was observed, neither on family environment-reported outcomes nor on neuropsychology scales, leading to treatment discontinuation. Despite physiopathological rationale, case reports have failed so far to suggest efficacy on the outcomes studied, which questioned the implementation of clinical trials.