NORD gratefully acknowledges Harper Price, MD, Department of Dermatology, Phoenix Children’s Hospital, and Heather Etchevers, PhD, National Institutes for Health and Medical Research of France (INSERM), for the preparation of this report.
Congenital melanocytic nevi (CMN) are visible pigmented (melanocytic) proliferations in the skin that are present at birth. CMN are benign, tumor-like malformations resulting from faulty development of pigment cell (melanocyte) precursors in the embryo, and composed of an abnormal mixture of skin elements. Defined areas of these melanocytic proliferations cover surfaces at the base of the epidermis ranging from a few millimeters in diameter to large sectors of the body. In the larger forms, the CMN (single or multiple) also extend(s) vertically into the deeper dermis and more rarely, into the hypodermis or even subcutaneous tissues. The most superficial component of the CMN is the most highly pigmented, conferring brown-to-black shades to the overlying epidermis. CMN are usually classified according to their predicted largest diameter in adulthood, as if they were circular (predicted adult diameter or PAS). The most used classification assigns small CMN as less than 1.5 cm PAS, medium sized CMN between 1.5 to 19.9 cm, and large CMN 20 cm or greater. CMN measuring 50 cm or larger in PAS have been referred to as ‘giant congenital melanocytic nevi’.
CMN can be light brown to black patches or plaques, can present in variable ways, and cover nearly any size surface area or any part of the body. The incidence of CMN seems to be independent of skin color or other ethnic factors. Small to medium CMN are predicted to occur in more than one in a hundred births. Large and especially giant CMN, exceeding a predicted diameter at adult age of at least 20 cm on the body, form a much rarer subset, with prevalence estimated at around 1 in 50,000 births. Non-pigmented or small incipient congenital lesions can also be present - these are known as "tardive"; the emergence of so-called "satellite" nevi throughout the first few years of life in conjunction with larger CMN probably reflects the postnatal maturation of such precursors. On occasion, even a primary CMN can appear in a tardive manner. Treatment options currently are exclusively surgical. Neurocutaneous melanocytosis, cited in earlier literature as neurocutaneous melanosis (NCM), is a neurological and cutaneous disorder characterized by abnormal aggregations of nevomelanocytes within the central nervous system and the skin. NCM is a complication of the larger forms of CMN, or multiple smaller CMN, in a fraction of patients. Recent studies find the incidence of symptomatic and asymptomatic NCM together to range between 5 and 15 % of all persons with large and giant CMN. Melanoma develops in an estimated 1-2% of patients with LCMN or NCM, more frequently and at earlier ages than in the general population.
The first recorded descriptions of children with large CMN date from observations published by the Count of Buffon before the French Revolution. Other giant, sometimes rugous CMN were described in the early 19th century.
CMN tend to grow in a proportional fashion to the child’s growth; occasionally growth appears out of proportion to the child during periods of particularly rapid growth such as early infancy. A new size/color/texture classification, recently developed by Marghoob, Krengel and other experts in the field, may eventually help in better predicting patients at the greatest risk for developing melanoma or neurological disease by more reproducibly classifying similar patients. Nomograms can assist clinicians in easily determining the PAS of a nevus examined at any point during childhood.
Large/giant CMN are obvious at birth, most commonly covering an aspect of the trunk and less common on the head, neck and extremities. Affected areas of large CMN have been designated as “cape”, “bathing trunk”, “tippet” or “garment” CMN due to their respective distributions. Lesions may have irregular or geographic borders. In about 75% of cases, multiple small CMN will accompany the large CMN, usually in a generalized manner. “Satellite” is a commonly used description of discrete small or medium CMN or tardive nevi in the presence of a large/giant CMN, though semantically and molecularly, it is more accurate to refer to “disseminated” lesions. These additional smaller, disseminated CMN may be present at birth and/or may increase to significant numbers over the first few years of life. These multiple CMN should be noted in number, as greater numbers (>20) have been correlated with neurological anomalies.
In general, CMN can be tan, brown to dark-brown or black and rarely blue in color and may be flat, raised, or even quite thickened at birth. Color may be quite uniform throughout, or consist of multiple colors including shades of brown, black, red or blue. Texture may be smooth, highly nodular or cobblestone-like; hair may or may not be present at birth and may or may not develop as the child ages. This hair is fine (vellus) or more often coarse (terminal) in texture. A “cerebriform” or brain-like texture may be present, particularly in large scalp CMN. Areas of the nevus may be infiltrated by overgrowths of fatty or nerve tissue, so-called lipomatous or neurotized areas respectively, features that can be seen most often in larger CMN.
Over time, CMN may become darker or lighter, more or less heterogenous in color and the surface texture may change. CMN can also develop superimposed nodules, which are usually benign but require surveillance. The CMN-involved skin can be dry and develop overlying eczema, resulting in intermittent or chronic itchiness (pruritis). CMN may also have fewer sweat glands than unaffected skin, resulting in potential overheating episodes or increased sweating in other areas of the body to compensate. Areas of larger CMN may have notably less fat under the skin, particularly around the flanks, limbs and buttocks.
At birth or within the first few weeks of life, transient erosions or ulcerations may develop over large CMN due to incomplete maturation of the skin during this period. Healing usually occurs over days to weeks. Also notable during the infantile period are rapidly growing ‘proliferative nodules’ within the CMN that mimic melanoma but show benign features when examined. Evaluation of these nodules by a dermatopathologist with expertise in pigmented lesions is recommended to avoid unnecessary surgery and possible toxic adjuvant therapy if misdiagnosed as melanoma. Significant lightening of color in large CMN can also been seen in the first few years of life, especially those that involve the scalp.
Both CMN and acquired melanocytic nevi are associated with somatic mutations in intracellular proteins of the microtubule-associated protein signal transduction pathway. For 4 in 5 cases, a single mutation in the DNA encoding the NRAS enzyme can be found, and for up to one in 6 cases, a single mutation in the DNA for the BRAF enzyme. The currently identified mutations cause the enzymes to become permanently active, and have been found in many apparently unrelated cancers as well, perhaps driving cells to proliferate. These findings imply that other, less common and not yet identified, mutations may also contribute to cause CMN.
Both CMN and normal pigment cells (melanocytes) come from an embryonic cell population that separates from the future central nervous system before the end of the first month of pregnancy, and as it multiplies, the population colonizes all the tissues of the body. Within the skin, these cells then become pigment cell precursors that are both between and at the base of hair follicles. Constant activation of NRAS or BRAF may drive the prenatal proliferation of this cell population. A second mutation that occurs in the other copy of the NRAS or BRAF gene in a CMN cell may be responsible for the onset of malignant melanoma, which happens more frequently in children affected with large/giant CMN than in the general pediatric population, where melanoma is exceedingly rare. Recent results indicate that the same NRAS mutations may also be responsible for nevomelanocyte proliferation within the central nervous system, causing NCM.
Large/giant CMN are usually sporadic, but familial occurrence has been rarely reported. One of the first reports that families of patients with giant CMN had relatives with multiple small pigmented nevi was made over 40 years ago, and this observation has been made many times since. Affected siblings and first cousins have also been observed. Autosomal dominant inheritance with reduced penetrance and/or multifactorial inheritance are possible explanations for the familial cases.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause the disease. The gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. Some individuals who have the abnormal gene may not display symptoms of the condition (reduced penetrance).
Multifactorial inheritance means that many factors, including a combination of genes from both parents, in addition to unknown environmental factors, cause the condition.
People of all races and colors of skin can be affected with large/giant CMN. A slight female preponderance has been noted in large/ giant CMN (male/female ratio of 1 to 1.4), but is not observed in the smaller population of people affected by NCM.
Making the diagnosis of a CMN is most often done by examining clinical and dermoscopic features. The larger CMN can easily be diagnosed based solely on their size. For smaller CMN, their history of presence since birth, surface topography, presence of hair or globular dermoscopic pattern can assist in diagnosis. When biopsied, the histological features of CMN are similar to those found in common acquired nevi which arise later in life; however, CMN tend have a greater cellularity with deeper extension of nevus cells into the deep dermis and subcutis, and cells extend along adnexal structures such as hair follicles and around blood vessels and nerves. Histological criteria alone cannot be used to dictate with absolute certainty whether a nevus is congenital or acquired.
Clinical Testing and Workup
Magnetic resonance imaging (MRI) with contrast of the brain and spine is recommended for any individual with multiple CMN, or a large CMN with > 20 satellite nevi, as those with 20 or more satellite nevi are 5 more times likely to have NCM than those with fewer, and some of these will become symptomatic. Any patient with new onset of neurological symptoms, such as enuresia (extended night-time bed-wetting) or tiptoeing which indicate the possibility of a tethered spinal cord, epilepsy, or "sunset eyes" (indicative of increased intracranial pressure due to hydrocephalus) should also undergo a neurologic evaluation and appropriate imaging. Patients with asymptomatic NCM should also be followed by a neurologist, on a yearly basis or more frequently if concerns exist. The need for subsequent MRIs in those asymptomatic patients is not clear; however, most experts will not recommend further MRI unless symptoms arise. Patients with significant symptomatic NCM should consider foregoing elective surgical removal of the CMN until prognosis is clear.
Lifelong monitoring in patients with extensive CMN is mandatory regardless of the treatment employed, both with self-skin examinations and in an experienced dermatologist’s office. Serial photographs, the use of dermoscopy, palpation of nevus and scars, examination of lymph nodes and a thorough review of systems may aid physicians in early detection of melanoma. Suspicious lesions should be removed and examined histologically by an experienced pathologist.
Treatments currently rely on the arsenal of plastic surgical techniques. While partial-thickness grafts or ablations, using dermabrasion or curettage, have been used in the past and are still occasionally relevant, the gold standard is to replace the skin in its full thickness. Replacement skin can be generated from other zones by natural forced expansion from adjacent areas, or implanting expanders either adjacent to or in a donor graft site. Artificial dermis is currently an inadequate replacement for most nevi. Simple surveillance is an option for extensive, technically inaccessible and homogeneous nevi. Psychological accompaniment is highly recommended for both patients and families, irrespective of physical treatment options. Each treatment regimen is unique as a result of the highly individual distributions and combinations of textures, nodules and other attributes of CMN.
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