Classification of neurological abnormalities in children with congenital melanocytic naevus syndrome identifies magnetic resonance imaging as the best predictor of clinical outcome

Congenital melanocytic naevi (CMN) can be single or multiple at birth. Multiple CMN, defined as more than one CMN at birth, can be associated with neurological abnormalities of the central nervous system (CNS), traditionally termed neurocutaneous melanosis (NCM). Patients with multiple CMN also have an increased risk of primary melanoma developing in the CNS or in the skin.1 The underlying cause of multiple CMN and so‐called NCM was recently found to be mosaicism for heterozygous activating mutations in codon 61 of NRAS, a developmental gene and oncogene involved in the control of key cell signalling pathways.2 However, the onset of melanoma requires further genetic events.2 Although neurological abnormalities are well established as the most common extracutaneous manifestations of mosaicism in children with multiple CMN, with an incidence ranging from 10% to 33% in clinical studies,3, 4, 5 the blanket term ‘NCM’ has been applied to all abnormalities, with no systematic subclassification. This term was originally proposed by Rokitansky in 1861 as a description of autopsy findings in a single case with fatal melanotic leptomeningeal disease, which we would now recognize as melanoma. With the advent of magnetic resonance imaging (MRI) and the description of the characteristic signal for melanin,5, 6 the spectrum of described neurological abnormalities has expanded to include congenital and acquired, melanotic and nonmelanotic lesions, with widely varying clinical outcomes ranging from benign quiescent lesions to fatal malignancy. The most common abnormality on MRI in either asymptomatic populations or prospectively collected populations is isolated intraparenchymal melanosis (foci of melanin‐containing cells in the brain parenchyma),3, 7 previously thought to be secondary only to overlying invasive leptomeningeal disease. Although this can occur in the context of malignant disease, several histopathological studies have proven the presence of congenital melanotic parenchymal deposits without involvement of the overlying meninges. The melanin in these lesions is produced within neurons and glia rather than melanocytes, and there are subtle signs of focal cortical dysplasia within these lesions.8, 9, 10, 11, 12, 13 Other less frequent neurological diagnoses include syringomyelia, nonmalignancy‐related hydrocephalus, tumours (including ependymoma, meningioma, astrocytoma, choroid plexus papilloma and pineal germinoma) and malformations such as Dandy–Walker and Arnold–Chiari malformations.5, 6, 13, 14, 15 The risk of congenital neurological abnormalities in children with CMN increases with the size of the largest CMN and the total number of naevi.3, 4, 16 These two variables are intimately but complexly connected, with the increasing size of the largest naevus usually but not always associated with increasing numbers of total naevi. As such, these variables confound each other within logistic regression models where both are used. As both these measures are relatively inaccurate it is difficult to say with confidence which is most reliable, but, in our experience, the projected adult size of the largest lesion is a more robust measurement in statistical models. There have been other confounders in the study of neurological abnormalities in CMN. For example, CMN distribution over the posterior axis (overlying the head, neck or spine) is no longer considered to be a risk factor for neurological abnormalities but rather a confounder for size of the main CMN.3, 17, 18 Furthermore, primary CNS melanoma can develop either in the parenchyma or in the leptomeninges, and this data has usually been amalgamated with data on congenital abnormalities. Where primary melanoma occurs the clinical picture is of sudden clinical deterioration, usually with symptoms of raised intracranial pressure and/or of spinal compression. It is commonly suggested in the literature that the outcome of children with ‘symptomatic NCM’ is extremely bleak,16, 19 with near‐certain mortality. However, more recent larger studies have reported symptoms in many individuals with MRI abnormalities where the outcome has not been fatal.3, 14, 15 The original perception is based partly on reports of neurological involvement prior to the advent of MRI, all of which were at autopsy and were therefore likely malignant processes rather than congenital abnormalities, and partly on a lack of large prospective studies of children with this rare condition. The primary aim of this study was therefore to subclassify the CNS congenital radiological abnormalities on the first screening scan in a large cohort of children with CMN, and to correlate these findings with clinical outcome measures. A secondary aim was to re‐evaluate our 2008 guidelines for imaging of the CNS in order to assess whether these have proved clinically useful over the last 6 years.