Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis.

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Neurocutaneous Melanosis with Meningeal Melanocytosis: A Rare Case of Intracranial Hypertension and Cutaneous Manifestations.

A 50-year-old male presented to the emergency room after experiencing sudden right upper limb facial numbness and dysphasia, followed by full recovery. A brain CT scan showed hyperdense lesions within the left hemispheric sulcus, which raised suspicion of spontaneous subarachnoid hemorrhage. A T1-weighted MRI showed multiple tiny leptomeningeal enhancements in the same area, and a digital subtraction angiography showed no signs of vascular abnormality. Cerebrospinal fluid cytology revealed atypical melanin-containing cells with minimal pleomorphism. One month later, the patient developed sixth nerve palsy, which was determined to be due to intracranial hypertension. Multiple giant nevi on the legs, trunk, and scalp were also observed. A skin biopsy showed well-defined and symmetrical proliferation of melanocytic nevus cell nests in the dermis. An open biopsy was performed due to the suspicious leptomeningeal lesions, which surprisingly revealed diffuse and thick black-colored tissue infiltration of the leptomeninges. Pathology confirmed the diagnosis of meningeal melanocytosis. A ventriculoperitoneal shunt was then placed, and the patient's neurological symptoms gradually improved. Based on the presence of multiple giant nevi on the patient's skin and the finding of diffuse meningeal melanocytosis during the open biopsy, the patient was diagnosed with neurocutaneous melanosis. The patient received 6 cycles triweekly of Ipilimumab and Nivolumab 8 months after initial diagnosis. Unfortunately, the disease progressed and the patient passed away 14 months after initial diagnosis.

Persistent Intracranial Hypertension and Severe Hypoglycorrhachia in an Adult With Giant Congenital Melanocytic Naevi.

A 29-year-old female, with giant congenital melanocytic naevi (GCMN) presented with a-year history of symptoms and signs of intracranial hypertension. Investigations revealed raised cerebrospinal fluid (CSF) pressure and severe hypoglycorrhachia (low CSF glucose) without pleocytosis. Initial contrast-enhanced brain MRI was normal, but a repeat MRI after a year showed meningeal enhancement with mild communicating hydrocephalus. The raised intracranial pressure was treated with a lumbar-peritoneal shunt. Intraoperative CSF cytology revealed an abundance of squamous epithelia and degenerative cells, but no malignant cells. Her symptoms recovered with CSF diversion via shunt placement, but the hypoglycorrhachia remained. This case highlights the rare occurrence of a non-inflammatory cause of both intracranial hypertension and severe hypoglycorrhachia in a GCMN adult patient, with progressive radiological changes over time, consistent with a diagnosis of neurocutaneous melanosis.

Melanosis neurocutánea: reporte de un caso y revisión de la literatura / Neurocutaneous melanosis. Case report and literature review / Melanose neurocutânea: relato de caso e revisão da literatura

RESUMEN Introducción: la melanosis neurocutánea es un trastorno congénito no hereditario que se caracteriza por la asociación de nevus pigmentados múltiples o de gran tamaño y una excesiva proliferación de melanocitos en el sistema nervioso central. La incidencia es similar en ambos sexos, y se observa historia familiar de melanoma en un único caso. Presentación del caso: se trata de un neonato masculino que nace en Hospital General de Luanda en Angola, con mancha melánica gigante que se extiende desde el cuello, cara, tórax, abdomen, espalda y miembros superiores, requiere una vigilancia de las lesiones dérmicas y un control de las crisis convulsivas. Discusión: se realizaron revisiones de la literatura médica disponible sobre el tema, consultando el programa de genética Oxford, y se tomaron fotos de las características clínicas sobresalientes. Por lo general los síntomas neurológicos son de temprana aparición en la etapa neonatal o de lactante con presencia de convulsiones de difícil control, al crear un pronóstico reservado. Conclusiones: se considera importante el seguimiento del neurodesarrollo de forma multidisciplinario para intervención oportuna si fuera necesario.

ABSTRACT Introduction: neurocutaneous melanosis is a non-hereditary congenital disorder characterized by the association of multiple or large pigmented nevi and an excessive proliferation of melanocytes in the central nervous system. The incidence is similar in both sexes, and a family history of melanoma is observed in a single case. Case presentation: this is a male neonate born at the General Hospital of Luanda in Angola, with a giant melanic spot that extends from the neck, face, chest, abdomen, back and upper limbs, requires surveillance of dermal lesions and control of seizures. Discussion: reviews of the available medical literature on the subject were conducted, consulting the Oxford genetics program, and photos of outstanding clinical features were taken. Usually the neurological symptoms are of early onset in the neonatal or infant stage with the presence of seizures that are difficult to control, creating a reserved prognosis. Conclusions: it is considered important to monitor neurodevelopment in a multidisciplinary way for timely intervention if necessary.

RESUMO Introdução: a melanose neurocutânea é uma doença congênita não hereditária caracterizada pela associação de nevi pigmentado múltiplo ou grande e uma proliferação excessiva de melanócitos no sistema nervoso central. A incidência é semelhante em ambos os sexos, e um histórico familiar de melanoma é observado em um único caso. Apresentação do caso: trata-se de um recém-nascido no Hospital Geral de Luanda, em Angola, com um ponto melanico gigante que se estende do pescoço, rosto, tórax, abdômen, costas e membros superiores, requer vigilância de lesões dérmicas e controle de convulsões. Discussão: foram realizadas revisões da literatura médica disponível sobre o tema, consultando o programa de genética de Oxford e fotos de características clínicas de destaque. Geralmente os sintomas neurológicos são de início precoce no estágio neonatal ou infantil com a presença de convulsões de difícil controle, criando um prognóstico reservado. Conclusões: é considerado importante monitorar o neurodesenvolvimento de forma multidisciplinar para intervenção oportuna, se necessário.

Neurocutaneous melanosis with an intracranial cystic-solid meningeal melanoma in an adult: A case report and review of literature.

BACKGROUND: Neurocutaneous melanosis (NCM) is a rare congenital, nonhereditary neurocutaneous syndrome that mainly occurs in children; adult NCM is very rare. Due to its rarity, the clinical features and treatment strategies for NCM remain unclear. The purpose of this study was to explore the clinical features, diagnosis, treatment and prognosis of NCM in adults. Most intracranial meningeal melanomas are solid masses, and cystic-solid malignant melanomas are very rare. Due to the lack of data, the cause of cystic changes and the effect on prognosis are unknown. CASE SUMMARY: A 41-year-old woman was admitted to the hospital with intermittent headache for 1 mo. Magnetic resonance imaging (MRI) showed a 4.7 cm × 3.6 cm cystic-solid mass in the left temporal lobe with peritumoral edema. The entire mass was removed, and postoperative pathology indicated malignant melanoma. CONCLUSION: MRI is the first-choice imaging approach for diagnosing central nervous system diseases in NCM patients, although cerebrospinal fluid may also be used. At present, there is no optimal treatment plan; gross total resection combined with BRAF inhibitors and MEK inhibitors might be the most beneficial treatment.

Central nervous system magnetic resonance imaging abnormalities and neurologic outcomes in pediatric patients with congenital nevi: A 10-year multi-institutional retrospective study.

BACKGROUND: High-risk congenital melanocytic nevi (CMN) are associated with abnormalities of the central nervous system (CNS), prompting magnetic resonance imaging (MRI) screening guidelines. OBJECTIVE: Describe MRI brain and spine abnormalities in children with CMN and report trends between nevus features, MRI findings, and neurologic outcomes. METHODS: Retrospective review of individuals aged ≤18 years with an MRI of the brain and/or spine and at least 1 dermatologist-diagnosed CMN. RESULTS: Three hundred fifty-two patients were identified. Forty-six children had CMN that prompted an MRI of the brain and/or spine (50% male, average age at first image, 354.8 days). In these children, 8 (17%) had melanin detected in the CNS, of whom all had >4 CMN. One developed brain melanoma (fatal). In patients without CNS melanin, 4 had concerning imaging. Concerning MRI patients had more neurodevelopmental problems, seizures, neurosurgery, and death than individuals with unremarkable imaging. Three hundred six patients received MRIs for other reasons; none detected melanin. No children with only multiple small CMN (n = 15) had concerning imaging. LIMITATIONS: Lack of a control group, cohort size, and retrospective methods. CONCLUSION: MRI of the brain and spine is useful for detecting intervenable abnormalities in high-risk children. Healthy infants with few small CMN may not require screening MRI.

Neurosurgical management of patients with neurocutaneous melanosis: a systematic review.

OBJECTIVE: Neurocutaneous melanocytosis (NCM), also referred to as neurocutaneous melanosis, is a rare neurocutaneous disorder characterized by excess melanocytic proliferation in the skin, leptomeninges, and cranial parenchyma. NCM most often presents in pediatric patients within the first 2 years of life and is associated with high mortality due to proliferation of melanocytes in the brain. Prognosis is poor, as patients typically die within 3 years of symptom onset. Due to the rarity of NCM, there are no specific guidelines for management. The aims of this systematic review were to investigate approaches toward diagnosis and examine modern neurosurgical management of NCM. METHODS: A systematic review was performed using the PubMed database between April and December 2021 to identify relevant articles using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Search criteria were created and checked independently among the authors. Inclusion criteria specified unique studies and case reports of NCM patients in which relevant neurosurgical management was considered and/or applied. Exclusion criteria included studies that did not report associated neurological diagnoses and neuroimaging findings, clinical reports without novel observations, and those unavailable in the English language. All articles that met the study inclusion criteria were included and analyzed. RESULTS: A total of 26 extracted articles met inclusion criteria and were used for quantitative analysis, yielding a cumulative of 74 patients with NCM. These included 21 case reports, 1 case series, 2 retrospective cohort studies, 1 prospective cohort study, and 1 review. The mean patient age was 16.66 years (range 0.25-67 years), and most were male (76%). Seizures were the most frequently reported symptom (55%, 41/74 cases). Neurological diagnoses associated with NCM included epilepsy (45%, 33/74 cases), hydrocephalus (24%, 18/74 cases), Dandy-Walker malformation (24%, 18/74 cases), and primary CNS melanocytic tumors (23%, 17/74 cases). The most common surgical technique was CSF shunting (43%, 24/56 operations), with tethered cord release (4%, 2/56 operations) being the least frequently performed. CONCLUSIONS: Current management of NCM includes CSF shunting to reduce intracranial pressure, surgery, chemotherapy, radiotherapy, immunotherapy, and palliative care. Neurosurgical intervention can aid in the diagnosis of NCM through tissue biopsy and resection of lesions with surgical decompression. Further evidence is required to establish the clinical outcomes of this rare entity and to describe the diverse spectrum of intracranial and intraspinal abnormalities present.

Primary leptomeningeal melanoma in association with neurocutaneous melanosis: A case report.

Background: Primary melanocytic tumors of the central nervous system accounts for approximately 1% of all melanoma with a peak incidence in the fourth decade. The tumor originates from leptomeningeal melanocytes with a variable degree of belligerence. The proliferation of these melanocytes in large amounts in the dermis and nervous system can raise suspicion of neurocutaneous melanosis (NCM), which is an association between malignant melanoma and the presence of a giant intradermal nevus. Case Description: We present a case of a 62-year-old South Asian male with a large congenital melanocytic nevus (>20 cm in size) in the left hemifacial, and head region who presented with complaints of a single episode of grand-mal seizure followed by neuropsychiatric symptoms. The patient was thoroughly evaluated both clinically and surgically leading to a rare diagnosis of primary leptomeningeal melanoma of the left temporal lobe. The patient subsequently underwent a neuronavigation guided left temporal craniotomy with gross total resection of the lesion. Conclusion: Primary leptomeningeal melanoma with a clinical association with NCM is rarely ever reported within the literature. To date, our case is one of the very few instances where such an association is being reported in this age group along with rare neuropsychiatric symptoms.

[An adult case of neurocutaneous melanosis with acute exacerbation after a long asymptomatic period following excision of a melanocytic nevus].

Neurocutaneous melanosis is caused by postzygotic NRAS mutations in neural crest cells, resulting in large or multiple nevi in the skin and proliferation of leptomeningeal melanocytes in the central nervous system. The onset of neurological symptoms is usually before the age of 2 years, but it can also occur in adults. A 35-year-old male had been asymptomatic for a long time after excision of a large congenital melanocytic nevus, but he developed headache, disturbance of consciousness, and seizure. Methotrexate was ineffective, cerebral pressure was decreased by spinal drainage, and steroid pulse therapy was temporarily effective. Seizures and disturbance of consciousness worsened and the patient died on the 92nd day. Cerebrospinal fluid human melanin black-45 immunostaining and serum 5-S-cysteinyldopa (5-S-CD) were useful in diagnosing melanocytic proliferation, and serum 5-S-CD may be useful in predicting prognosis.

Giant Congenital Melanocytic Nevi in a Pakistani Newborn.

Congenital melanocytic nevi arise from overgrowth or disrupted migration of melanocyte precursor in the neural crest. They are also known as coat-sleeve, stocking, bathing trunk or garment nevi. The colour ranges from brown to black, with the lesions presenting as flat to raised nevi. Lesions presenting at birth with a diameter greater than 20cm are labelled giant congenital melanocytic nevi. Risk increases with an increase in the number of satellite lesions near the giant nevus. Management includes regular clinical follow-up monitoring of changes in the lesion and surgical procedures in cases with risk of melanoma and psychological support. The purpose of this case presentation is to describe a rare issue of giant congenital melanocytic nevi in a newborn, along with a literature review and discussion on possible management options.

Imaging and Clinical Features of Neurocutaneous Melanosis in the Pediatric Population.

BACKGROUND: Neurocutaneous Melanosis (NCM) is a rare nonfamilial phakomatosis characterized by the presence of congenital melanocytic nevi and abnormal melanocyte infiltration of the leptomeninges. OBJECTIVE AND METHODS: This paper shows the importance of early diagnosis and the most important imaging features of the disease on CT and MR scans. PubMed database was searched from January 1972 to September 2020. Papers including imaging findings of NCM, clinical, follow-up, and treatment features were collected, selecting only 89 studies. DISCUSSION: NCM is a term used for the first time by van Bogaert in 1948. It refers to a condition caused by an error during morphogenesis and migration leading to leptomeningeal melanocytic accumulation. Although histological findings are the gold standard for diagnosis confirmation, neuroimaging and clinical features strongly support the suspect of NCM. Localization and extension of the lesions are predictive of neurological manifestations related to increased intracranial pressure, mass lesions, or spinal cord compression. CT demonstrates sites of increased density in the anterior temporal lobe, mainly the amygdala, thalami, cerebellum, and frontal lobes base. However, MRI is the best imaging method to diagnose central nervous system lesions, often appearing as T1-short signal areas of the cerebral parenchyma, indicative of central nervous system melanosis. MRI can also reveal associated intracranial and intraspinal abnormalities. CONCLUSION: Early imaging, when available, is helpful if NCM suspect is raised and may be of guidance in comparing later studies. NCM requires a multidisciplinary approach since it is a multisystem disease with a genetic component.

Giant cerebriform melanocytic nevus of the scalp: A case report.

Giant melanocytic nevus is a rare condition caused by benign proliferation of melanocytes. There is a slight risk of malignancy in these lesions which should be noticed especially when they become larger. GCMN can be removed by plastic surgery.

Congenital Melanocytic Nevus: Considerations for Neonatal Clinicians and a Parent Perspective.

Congenital melanocytic nevus (CMN) or nevi, also known as dark moles, are present at birth. While small CMN are quite common, large and giant nevi are rare and can be associated with significant psychological distress and the potential for further clinical sequelae. Neonatal clinicians can offer anticipatory guidance to families through distribution of resources and navigation to additional consultants.

Neurocutaneous Melanosis with Hydrocephalus and Dandy-Walker Variant.

Neurocutaneous melanosis (NCM) is one of the rare, congenital, noninheritable phakomatoses characterized by the presence of large and/or multiple congenital melanocytic cutaneous nevi associated with intracranial leptomeningeal melanocytosis. NCM usually presents before 2 years of age. So far 302 cases have been reported in literature. We report a case of NCM presenting with obstructive hydrocephalus and Dandy-Walker Variant in a young adult.

Primary meningeal melanoma masquerading as neurofibromatosis type 2: illustrative case.

BACKGROUND: Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS: The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS: This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.

Clinical Follow-Up of Patients with Neurocutaneous Melanosis in a Tertiary Center; Proposed Modification in Diagnostic Criteria.

INTRODUCTION: Neurocutaneous melanosis (NCM) is a rare congenital syndrome. Except for some retrospective studies, information on clinical follow-up and management of these patients are limited. This study aimed to review our experience on diagnostic protocol and clinical follow-up of patients with NCM in a referral children's hospital in Iran. METHODS: Between 2012 and 2019, eight patients with NCM were consecutively managed in our center. Brain magnetic resonance imaging and cutaneous biopsy were done in all patients at diagnosis. Follow-up surveillance and characteristics of the disease are described. RESULTS: The mean follow-up period was 25.75 ± 13.81 months, and 75% of patients were male. Most magnetic resonance imaging findings were hypersignal lesions in the temporal lobe (75%), cerebellum (62.5%), brainstem (50%), and thalamus (12.5%). Dandy-Walker syndrome was found in 4 patients (50%), and shunt-dependent hydrocephalus was found in 3 patients (37.5%). Cutaneous malignant melanoma and malignant involvement of the central nervous system were found in 2 (25%) and 3 cases (37.5%), respectively. The mortality rate was 37.5%. CONCLUSIONS: There are no specific guidelines for management of NCM due to the rarity of the disease. This study proposed modifications in diagnostic criteria, as well as recommendations for follow-up surveillance.

Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.

PURPOSE: Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by giant melanocytic cutaneous nevi and melanosis within the central nervous system (CNS), often sparing leptomeninges and concentrated in the brain parenchyma. Epilepsy and neurodevelopmental abnormalities are the only complications reported in children with isolated parenchymal melanosis. A minority of patients experience drug-resistant epilepsy, and up to now, no predictors of epilepsy prognosis have been identified. METHODS: In this systematic review, according to preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, we aggregated clinical cases of patients with isolated parenchymal melanosis affected by epilepsy, in order to recognize predictors of clinical outcome and to clarify indications of available therapeutic approaches. RESULTS: Sixteen articles (19 patients) were included in the final analysis from initial database research; 4 articles (4 patients) were selected from reference lists and 1 from conference abstracts (1 patient). In our series, distribution of parenchymal melanosis was the best predictor of epilepsy outcome: frequencies of seizure-free patients were different between cases of isolated/bilateral amygdale melanosis and those of multiple localizations (p = 0.037). Failure of antiepileptic drugs (AEDs) and/or surgical epilepsy therapy were associated with poor cognitive outcome (p = 0.03). CONCLUSION: Antiepileptic drugs were effective in the majority of patients with epilepsy with parenchymal melanosis. In case of multifocal distribution, more than one-third of patients presented a drug-resistant epilepsy. Epilepsy surgery is the best choice in patients with isolated amygdala localization. We propose the recognition of a multifactorial nature of cognitive impairment in neuromelanosis, emphasizing the role of drug-resistant epilepsy.