Neurocutaneous melanosis is a congenital disorder characterized by the presence of

congenital melanocytic nevi The congenital melanocytic nevus is a type of melanocytic nevus (or mole) found in infants at birth. This type of birthmark occurs in an estimated 1% of infants worldwide; it is located in the area of the head and neck 15% of the time. Signs an ...

on the skin and melanocytic tumors in the

leptomeninges In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...

of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. These

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classif ...

s may occur in the

amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verte ...

, cerebellum,

cerebrum The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb ...

pons The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum. The pons is also called the pons Varolii ("bridge of Va ...

and

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...

of patients. Although typically asymptomatic,

malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

occurs in the form of leptomeningeal melanoma in over half of patients. Regardless of the presence of malignancy, patients with symptomatic neurocutaneous melanosis generally have a poor prognosis with few treatment options. The pathogenesis of neurocutaneous melanosis is believed to be related to the abnormal postzygotic development of

melanoblast A melanoblast is a precursor cell of a melanocyte. These cells migrate from the trunk neural crest cells (in terms of axial level from neck to posterior end) dorsolaterally between the ectoderm and dorsal surface of the somites. See also *Biolo ...

s and mutations of the '' NRAS'' gene.

Signs and symptoms

Neurocutaneous melanosis is associated with the presence of either giant congenital melanocytic nevi or non-giant nevi of the skin. It is estimated that neurocutaneous melanosis is present in 2% to 45% of patients with giant congenital melanocytic nevi. Patients with non-giant congenital melanocytic nevi seem to have a much lower, but undefined risk. Of these patients, only a small number are symptomatic, usually displaying symptoms before the age of 2. These symptoms are the result of melanocytic lesions being present in the leptomeninges of the central nervous system. Symptoms can include: *

Papilledema Papilledema or papilloedema is optic disc swelling that is caused by increased intracranial pressure due to any cause. The swelling is usually bilateral and can occur over a period of hours to weeks. Unilateral presentation is extremely rare. In ...

* Cranial palsies * Headache * Vomiting * Seizures Others symptoms may also exist that are related to an increase in

intracranial pressure Intracranial pressure (ICP) is the pressure exerted by fluids such as cerebrospinal fluid (CSF) inside the skull and on the brain tissue. ICP is measured in millimeters of mercury ( mmHg) and at rest, is normally 7–15 mmHg for a supine adult ...

. These symptoms seem to be present regardless of the malignancy of the melanin deposits within the central nervous system. Approximately 10% of patient with neurocutaneous melanosis also present the Dandy–Walker syndrome and associated Dandy-Walker malformation. This malformation involves an enlargement of the posterior fossae and

fourth ventricle The fourth ventricle is one of the four connected fluid-filled cavities within the human brain. These cavities, known collectively as the ventricular system, consist of the left and right lateral ventricles, the third ventricle, and the fourth ve ...

along with agenesis of the

cerebellar vermis The cerebellar vermis (from Latin ''vermis,'' "worm") is located in the medial, cortico-nuclear zone of the cerebellum, which is in the posterior fossa of the cranium. The primary fissure in the vermis curves ventrolaterally to the superior su ...

. The abnormalities of the leptomeninges during fetal development due to neurocutaneous melanosis may be the cause of this increased incidence of the Dandy-Walker malformation. The development of

hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased pressure inside the skull. Older people may have headaches, double vision, poor balance, urinary inc ...

is the most common symptom associated with a combination of neurocutaneous melanosis and a Dandy-Walker malformation, occurring in about two out of three patients.

Cause

The exact pathogenesis of neurocutaneous melanosis is not entirely clear, although several factors are thought to contribute to its development. One factor that may contribute to the development of neurocutaneous melanosis is the abnormal postzygotic development of melanoblasts. This mutation would possibly occur within the

neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...

of the ectoderm. After the mutation occurs, these cells would then migrate to the meninges as the precursors to the malignant or benign melanocytes. This mutation may be due to abnormal expression of hepatocyte growth factor/scatter factor by the mesenchymal cells within the neural crest. Another proposed cause of neurocutaneous melanosis is a mutation of the NRAS gene at codon 61. This mutation has been detected in patients with congenital melanocytic nevi, as well as those with melanocytic tumors of the central nervous system. The mutation would also likely occur within the neural crest.

Diagnosis

If a patient displays congenital melanocytic nevi or giant congenital melanocytic nevi, the criteria for diagnosis of neurocutaneous melanosis are as follows: * Melanocytic deposits exist within the central nervous system that are either malignant or benign * The cutaneous lesions, giant or otherwise, are not malignant These criteria are typically validated through

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

of the cutaneous lesions and imaging of the central nervous system. It is important to establish that the cutaneous lesions are benign. If not, then the melanocytic deposits in the central nervous system may be the result of metastasis of cutaneous melanoma and not neurocutaneous melanosis. Imaging has been shown to be the only reliable detection method for the presence of neurocutaneous melanosis that can be performed in living patients. Currently, the preferred imaging modality for diagnosis of neurocutaneous melanosis is magnetic resonance imaging, although ultrasound is another viable option. The signal due melanin deposits in the leptomeninges typical of neurocutaneous melanosis can be easily detected in MRI scans of patients under four months old. In patients above this age, there is some suggestion that normal brain myelination may partially obscure these signals. As most patients with neurocutaneous melanosis are asymptomatic, those who are diagnosed through MR imaging are not guarantied to develop symptoms. Those diagnosed who did not develop symptoms ranged from 10% to 68%. This wide range is most likely due to the large number of asymptomatic, undiagnosed patients with neurocutaneous melanosis.

Treatment

Once a patient with neurocutaneous melanosis becomes symptomatic, little can be done to improve prognosis as there is no effective treatment for the disorder. Most therapies are designed to treat the symptoms associated with the disorder, mainly those related to hydrocephalus. A ventriculoperitoneal shunt to relieve intracranial pressure is the preferred method. Chemotherapy and radiotherapy have been shown to be ineffective in cases of neurocutaneous melanosis where malignancy is present. Additionally, due to the total infiltration of the central nervous system by these lesions, surgical resection is not a viable treatment option. It has been demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM. Recently, experimental treatment with MEK162, a MEK inhibitor, has been tried in a patient with NCM and progressive symptomatic leptomeningeal melanocytosis. Pathological studies with immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies showed a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM.

Prognosis

The majority of patients with neurocutaneous melanosis are asymptomatic and therefore have a good prognosis with few complications. Most are not diagnosed, so definitive data in not available. For symptomatic patients, the prognosis is far worse. In patients without the presence of melanoma, more than 50% die within 3 years of displaying symptoms. While those with malignancy have a mortality rate of 77% with most patients displaying symptoms before the age of 2. The presence of a Dandy-Walker malformation along with neurocutaneous melanosis, as occurs in 10% of symptomatic patients, further deteriorates prognosis. The median survival time for these patients is 6.5 months after becoming symptomatic.

History

Neurocutaneous melanosis was first described in 1861 by Rokitansky. It was first named by Van Bongaert in 1948. Premortem detection is difficult without the use of MRI. This, combined with the asymptomatic nature of most cases, led to the early belief that all cases were fatal. Therefore, few symptomatic cases (around 100) have been reported to date.

References

{{reflist Congenital disorders