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BACKGROUND: Neurocutaneous melanocytosis (NCM) is a poorly understood disease due to its rarity. This study aimed to summarize the characteristics of adult NCM and improve the awareness of this disease. METHODS: The clinical data of 13 adult patients with NCM were retrospectively reviewed, including neuroimages, cerebrospinal fluid (CSF), and histological features. RESULTS: There were 9 males and 4 females. The mean age at symptom onset was 36.5 years. The initial symptoms included intracranial hypertension in 8 patients and seizure in 4 patients. Ten patients had large and/or multiple congenital melanocytic nevi. MRI revealed hydrocephalus and diffuse thickening of the leptomeninges with T1 shortening in all patients. Post-contrast T1-weighted images showed diffuse linear enhancement of the leptomeninges. Lumbar punctures showed increased open pressure, and elevated protein levels and decreased glucose concentrations in CSF. Cells with intracytoplasmic coarse black granules were found in the CSF and were positive for S100, HMB45, and vimentin. Histopathology of the cutaneous lesions and meninges showed melanocytes but no evidence of malignant melanoma. CONCLUSION: Adult NCM patients present a diversity of clinical manifestations. Brain MRI showing diffuse thickening of the leptomeninges with T1 shortening is useful in diagnosing NCM. Heterocellular melanin may be of great value for early diagnosis of NCM in challenging cases.

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Phacomatoses are a special group of familial hamartomatous syndromes with unique neuro-cutaneous manifestations as well as disease characteristic tumors. Neurofibromatosis 2 (NF2) and tuberous sclerosis complex (TSC) are representatives of this family. Vestibular schwannoma (VS) and subependymal giant cell tumor (SGCT) are two of the most common intracranial tumors associated with NF2 and TSC, respectively. These tumors can present with obstructive hydrocephalus due to their location adjacent to or in the ventricles. However, both tumors are also known to have a unique association with an elevated protein concentration in the cerebrospinal fluid (CSF), sometimes in association with non-obstructive (communicating) hydrocephalus (HCP), the causality of which has been unclear. Furthermore, SGCTs have repeatedly been shown to have a predisposition for CSF clotting, causing debilitating obstructions and recurrent malfunctions in shunted patients. However, the exact relation between high protein levels and spontaneous clotting of the CSF is not clear, nor is the mechanism understood by which CSF may clot in SGCTs. Elevated protein levels in the CSF are thought to be caused by increased vascular permeability and dysregulation of the blood-brain barrier. The two presumed underlying pathophysiologic mechanisms for that, in the context of tumorigenesis, are angiogenesis and inflammation. Both mechanisms are correlated to the Pi3K/Akt/mTOR pathway which is a major tumorigenesis pathway in nearly all phacomatoses. In this review, we discuss the influence of angiogenesis and inflammation on vascular permeability in VSs and SGCTs at the phenotypic level as well as their possible genetic and molecular determinants. Part I describes the historical perspectives and clinical aspects of the relationship between vascular permeability, abnormal CSF protein levels, clotting of the CSF, and communicating HCP. Part II describes different cellular and molecular pathways involved in angiogenesis and inflammation in these two tumors and the correlation between inflammation and coagulation. Interestingly, while increased angiogenesis can be observed in both VS and SGCT, inflammatory processes seem more prominent in SGCT. Both pathologies are characterized by different subgroups of tumor-associated macrophages (TAM): the pro-inflammatory, M1 type is predominating in SGCTs while pro-angiogenetic, M2 type is predominating in VSs. We suggest that lack of NF2 protein in VS and lack of TSC1/2 proteins in SGCT determine this fundamental difference between the two tumor types, by defining the predominant TAM type. Since inflammatory reactions and coagulation processes are tightly connected, a "pro-inflammatory state" of SGCT can be used to explain the observed associated enhanced CSF clotting process. These distinct cellular and molecular differences may have direct therapeutic implications on tumors that are unique to certain phacomatoses or those with similar genetics.

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Neurocutaneous melanosis (NCM) is a rare phakomatosis characterized by a focal or diffuse proliferation of melanin-producing cells in both the skin and the leptomeninges. This syndrome is believed to result from an error in the morphogenesis of embryonal neuroectoderm. Two-thirds of patients with NCM have giant congenital melanocytic nevi, and the remaining one-third have numerous lesions but no giant lesions. Patients may present with neurologic manifestations early in life secondary to intracranial hemorrhages, impairment of cerebrospinal fluid circulation, or malignant transformation of the melanocytes. The prognosis of patients with symptomatic NCM is poor.

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Neurocutaneous melanosis (NCM) is a rare neuroectodermal dysplasia characterized by large or multiple cutaneous congenital pigmented nevi and benign or malignant melanocytic tumors of the leptomeninges. Although the MR manifestations of this disease have been reported in a small series of cases, the usefulness of fluid-attenuated inversion recovery (FLAIR) MR findings has not been documented. We present a case of NCM that showed diffuse leptomeningeal hyperintensity on FLAIR images. This FLAIR finding may be a clue to the detection of leptomeningeal abnormalities in NCM.

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Neurological symptoms in a patient with large congenital melanocytic naevus are highly suggestive of cerebromeningeal melanoma metastasis. The presence of melanocytic cells in cerebrospinal fluid confirms this diagnosis If their malignant nature is shared with cutaneous naevocytic cells. Conversely, neurocutaneous melanosis is diagnosed when benign melanocytosis meningitis is found in patients with multiple and/or large congenital melanocytic naevus, whether cutaneous naevus cells are benign or not, or when cerebrospinal fluid cells are malignant with benign cutaneous melanocytic naevus. We report the case of a young man aged 19 presenting with multiple and large congenital melanocytic naevus who experienced transcient neurological signs and increased intracranial pressure. Cerebral neuroimaging evoked meningeal infiltration which benign melanocytic nature was supposed on CSF analysis and confirmed by necropsy findings, only 3 month after neurological onset, leading to neurocutaneous melanosis diagnosis. This rare neuroectodermal dysembryoplasia finds expression in various neurological signs, depending on patient's age and leptomeningeal and/or cerebral proliferation localization. Lumbar puncture, cerebral scanography and MRI may help diagnosis, but only histological examination can prove neurocutaneous melanosis, more often by necropsy because of poor prognosis.

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