Neurocutaneous melanosis

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Neurocutaneous melanosis
Other namesNeurocutaneous melanosis syndrome [1]
Neurocytaneous melanosis.jpg
A 13-year-old with a giant congenital melanocytic nevus, or "bathing trunk"

Neurocutaneous melanosis is a congenital disorder characterized by the presence of congenital melanocytic nevi on the skin and melanocytic tumors in the leptomeninges of the central nervous system. [2] These lesions may occur in the amygdala, cerebellum, cerebrum, pons and spinal cord of patients. Although typically asymptomatic, malignancy occurs in the form of leptomeningeal melanoma in over half of patients. [3] Regardless of the presence of malignancy, patients with symptomatic neurocutaneous melanosis generally have a poor prognosis with few treatment options. [4] The pathogenesis of neurocutaneous melanosis is believed to be related to the abnormal postzygotic development of melanoblasts and mutations of the NRAS gene. [5]

Contents

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. [6] These symptoms are the result of melanocytic lesions being present in the leptomeninges of the central nervous system. [3] Symptoms can include:

Others symptoms may also exist that are related to an increase in intracranial pressure. These symptoms seem to be present regardless of the malignancy of the melanin deposits within the central nervous system. [7]

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 along with agenesis of the cerebellar vermis. 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 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. [8]

Cause

The exact pathogenesis of neurocutaneous melanosis is not entirely clear.

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 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. [2]

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. [5]

Diagnosis

If a patient displays congenital melanocytic nevi or giant congenital melanocytic nevi, the criteria for diagnosis of neurocutaneous melanosis are as follows:

These criteria are typically validated through biopsy 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. [3]

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. [9] 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. [6]

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. [6]

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. [6]

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. [10]

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. [11]

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 is 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. [12]

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. [8]

History

Neurocutaneous melanosis was first described in 1861 by Rokitansky. [13] It was first named by Van Bongaert in 1948. [14] 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. [10]

See also

Related Research Articles

<span class="mw-page-title-main">Melanocytic nevus</span> Benign skin tumor of pigment-producing cells

A melanocytic nevus is usually a noncancerous condition of pigment-producing skin cells. It is a type of melanocytic tumor that contains nevus cells. A mole can be either subdermal or a pigmented growth on the skin, formed mostly of a type of cell known as a melanocyte. The high concentration of the body's pigmenting agent, melanin, is responsible for their dark color. Moles are a member of the family of skin lesions known as nevi, occurring commonly in humans. Some sources equate the term "mole" with "melanocytic nevus", but there are also sources that equate the term "mole" with any nevus form.

<span class="mw-page-title-main">Melanoma</span> Skin cancer originating in melanocytes

Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye. In women, melanomas most commonly occur on the legs; while in men, on the back. Melanoma is frequently referred to as malignant melanoma. However, the medical community stresses that there is no such thing as a 'benign melanoma' and recommends that the term 'malignant melanoma' should be avoided as redundant.

<span class="mw-page-title-main">Nevus</span> Mole or birthmark; visible, circumscribed, chronic skin lesion

Nevus is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from nævus, which is Latin for "birthmark"; however, a nevus can be either congenital or acquired. Common terms, including mole, birthmark, and beauty mark, are used to describe nevi, but these terms do not distinguish specific types of nevi from one another.

<span class="mw-page-title-main">Acral lentiginous melanoma</span> Medical condition

Acral lentiginous melanoma is a type of skin cancer. It typically begins as a uniform brownish mark before becoming darker and wider with a blurred irregular edge, most frequently seen in the foot of a person with darker skin. It may become bumpy and ulcerate. Just under the nail it typically appears as dark longitudinal streaks, and it may spread.

<span class="mw-page-title-main">Dysplastic nevus</span> Mole in the skin with an abnormal appearance

A dysplastic nevus or atypical mole is a nevus (mole) whose appearance is different from that of common moles. In 1992, the NIH recommended that the term "dysplastic nevus" be avoided in favor of the term "atypical mole". An atypical mole may also be referred to as an atypical melanocytic nevus, atypical nevus, B-K mole, Clark's nevus, dysplastic melanocytic nevus, or nevus with architectural disorder.

<span class="mw-page-title-main">Dysplastic nevus syndrome</span> Medical condition

Dysplastic nevus syndrome, also known as familial atypical multiple mole–melanoma (FAMMM) syndrome, is an inherited cutaneous condition described in certain families, and characterized by unusual nevi and multiple inherited melanomas. First described in 1820, the condition is inherited in an autosomal dominant pattern, and caused by mutations in the CDKN2A gene. In addition to melanoma, individuals with the condition are at increased risk for pancreatic cancer.

<span class="mw-page-title-main">Congenital melanocytic nevus</span> Congenital mole caused by genetic mutations

The congenital melanocytic nevus is a type of melanocytic nevus 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.

<span class="mw-page-title-main">Dandy–Walker malformation</span> Congenital malformation of the cerebellar vermis

Dandy–Walker malformation (DWM), also known as Dandy–Walker syndrome (DWS), is a rare congenital brain malformation in which the part joining the two hemispheres of the cerebellum does not fully form, and the fourth ventricle and space behind the cerebellum are enlarged with cerebrospinal fluid. Most of those affected develop hydrocephalus within the first year of life, which can present as increasing head size, vomiting, excessive sleepiness, irritability, downward deviation of the eyes and seizures. Other, less common symptoms are generally associated with comorbid genetic conditions and can include congenital heart defects, eye abnormalities, intellectual disability, congenital tumours, other brain defects such as agenesis of the corpus callosum, skeletal abnormalities, an occipital encephalocele or underdeveloped genitalia or kidneys. It is sometimes discovered in adolescents or adults due to mental health problems.

<span class="mw-page-title-main">Becker's nevus</span> Irregularly pigmented area of skin with hair growth

Becker's nevus is a benign skin disorder predominantly affecting males. The nevus can be present at birth, but more often shows up around puberty. It generally first appears as an irregular pigmentation on the torso or upper arm, and gradually enlarges irregularly, becoming thickened and often hairy (hypertrichosis). The nevus is due to an overgrowth of the epidermis, pigment cells (melanocytes), and hair follicles. This form of nevus was first documented in 1948 by American dermatologist Samuel William Becker (1894–1964).

<span class="mw-page-title-main">Uveal melanoma</span> Type of eye cancer

Uveal melanoma is a type of eye cancer in the uvea of the eye. It is traditionally classed as originating in the iris, choroid, and ciliary body, but can also be divided into class I and class II. Symptoms include blurred vision, loss of vision, and photopsia, but there may be no symptoms.

<span class="mw-page-title-main">Blue nevus</span> Type of melanocytic tumor

A blue nevus is a type of coloured mole, typically a single well-defined blue-black bump.

<span class="mw-page-title-main">Diastematomyelia</span> Birth defect in which part of the spinal cord is split

In neurology, diastematomyelia is a congenital disorder in which a part of the spinal cord is split, usually at the level of the upper lumbar vertebra in the longitudinal (sagittal) direction. Females are affected much more commonly than males. This condition occurs in the presence of an osseous, cartilaginous or fibrous septum in the central portion of the spinal canal which then produces a complete or incomplete sagittal division of the spinal cord into two hemicords. When the split does not reunite distally to the spur, the condition is referred to as diplomyelia, which is true duplication of the spinal cord.

<span class="mw-page-title-main">Schimmelpenning syndrome</span> Medical condition

Schimmelpenning syndrome is a neurocutaneous condition characterized by one or more sebaceous nevi, usually appearing on the face or scalp, associated with anomalies of the central nervous system, ocular system, skeletal system, cardiovascular system and genitourinary system.

Nevi and melanomas are a group of neoplasia.

<span class="mw-page-title-main">Benign melanocytic nevus</span> Medical condition

A benign melanocytic nevus is a cutaneous condition characterised by well-circumscribed, pigmented, round or ovoid lesions, generally measuring from 2 to 6 mm in diameter. A benign melanocytic nevus may feature hair or pigmentation as well.

Oral pigmentation is asymptomatic and does not usually cause any alteration to the texture or thickness of the affected area. The colour can be uniform or speckled and can appear solitary or as multiple lesions. Depending on the site, depth, and quantity of pigment, the appearance can vary considerably.

<span class="mw-page-title-main">Bonnet–Dechaume–Blanc syndrome</span> Medical condition

Bonnet–Dechaume–Blanc syndrome, also known as Wyburn-Mason syndrome, is a rare congenital disorder characterized by arteriovenous malformations of the brain, retina or facial nevi. The syndrome has a number of possible symptoms and can, more rarely, affect the skin, bones, kidneys, muscles, and gastrointestinal tract. When the syndrome affects the brain, people can experience severe headaches, seizures, acute stroke, meningism, and progressive neurological deficits due to acute or chronic ischaemia caused by arteriovenous shunting.

<span class="mw-page-title-main">Macrocephaly-capillary malformation</span> Medical condition

Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation, body asymmetry, polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.

<span class="mw-page-title-main">Cavernous hemangioma</span> Region with a lack of blood flow due to vein malformation

Cavernous hemangioma, also called cavernous angioma, venous malformation, or cavernoma, is a type of venous malformation due to endothelial dysmorphogenesis from a lesion which is present at birth. A cavernoma in the brain is called a cerebral cavernous malformation or CCM. Despite its designation as a hemangioma, a cavernous hemangioma is not a tumor as it does not display endothelial hyperplasia. The abnormal tissue causes a slowing of blood flow through the cavities, or "caverns". The blood vessels do not form the necessary junctions with surrounding cells, and the structural support from the smooth muscle is hindered, causing leakage into the surrounding tissue. It is the leakage of blood, referred to as hemorrhage, that causes a variety of symptoms known to be associated with the condition.

<span class="mw-page-title-main">Veronica Kinsler</span> British physician scientist

Veronica Kinsler is a British physician scientist specialising in paediatric dermatology and molecular genetics. She is Professor of Paediatric Dermatology and Dermatogenetics at the Great Ormond Street Hospital for Children (GOSH) and the University College London GOS Institute of Child Health.

References

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