Abstract
Background:Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option.Methods:Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis.Results:All four had an improvement in symptoms and objectively in signs. These varied from mild improvement for 1 month, to a sustained symptom-free period of 9 months in one case. In all cases there was eventual disease progression through treatment, followed by rapid death after discontinuation. There were no clinically-significant side effects.Conclusions:Trametinib is the first therapy to show any objective or measurable effect in NRAS-mutated primary CNS melanoma, with few side effects in this small series. The role of this therapy should be explored further in this rare paediatric tumour.
Highlights
Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations
congenital melanocytic naevus (CMN) syndrome is the association of congenital moles with extracutaneous features such as congenital neurological malformations (Kadonaga et al, 1992; Barkovich et al, 1994; Acosta et al, 2005; Kinsler et al, 2008) and characteristic facies (Kinsler et al, 2012) (Figure 1)
In postnatal life affected individuals are at increased risk of cutaneous and CNS melanoma, with the peak incidence in childhood (Krengel et al, 2006; Kinsler et al, 2017a)
Summary
Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis. Trametinib was used initially at a dose of 0.0125 mg kg À 1 per day in two patients (patients 1 and 2, Table 1); both had symptomatic benefit (reversal of neurological signs) this was of short duration prior to rapid disease progression. Prior to starting Trametinib all patients had echocardiogram, ECG, ophthalmological exam and blood tests for full blood count, urea and electrolytes, liver function tests, gamma GT and creatinine kinase
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