Large congenital melanocytic nevus (ORPHA:626)
A rare skin hamartoma characterized by at least one pigmented skin lesion present at birth of more than 20 cm (large congenital melanocytic nevus; LCMN) or 40 cm (giant; GCMN) projected adult diameter. The primary lesion is composed of mutated melanocytes and often locally disorganized epidermal annexes or dermis, and presents with an elevated risk of malignant transformation to melanoma or, more rarely, other neoplasms in skin or central nervous system.
Epidemiology
LCMN has a prevalence of about 1/20,000, while GCMN is estimated to occur in 1/50,000 to 1/500,000 births, becoming increasingly rare as more body surface is implicated. It is present in all ethnic groups examined to date and in both genders, with a slight female predominance.
Clinical description
CMN develop during pregnancy as at least one darkly colored, circumscribed area of the skin sometimes covered with dense hair or proliferative nodules, often accompanied by multiple small satellite nevi at birth or pigmenting during early childhood (tardive nevi). Three or more ''multiple medium CMN'' present a total surface, when summed, similar to that of other LCMN but are more frequently associated with complications. The term ''CMN syndrome'' covers these additional neurological (epilepsy, hydrocephalus, neurocutaneous or diffuse leptomeningeal melanocytosis, spinal meningeal cysts or tethered spinal cord) or endocrine symptoms. All LCMN/GCMN patients present an elevated risk of pediatric melanoma and other neuroectodermal tumors of varying severity (rhabdomyosarcoma, schwannoma, malignant peripheral nerve sheath tumor, lipoma, neurofibroma).
Etiology
CMN are disorders of embryonic neural crest development caused by somatic mutations in genes involved in the MAP kinase signaling pathway. Multiple and L/GCMN are often associated with NRAS mutations while BRAF mutations are more frequent in small to medium CMN. BRAF-mutated GCMN may be linked to higher frequency of co-morbidities (vascular malformations or benign proliferative nodules). No strict phenotype-genotype relationship has been confirmed, and further genetic heterogeneity is supported by rare reports of other activating mutations, fusion events or duplications in these and other pathway genes.
Diagnostic methods
Diagnosis is clinical, based on size, delimitation, depth and location of the lesions. Magnetic resonance imaging (MRI) and neurological evaluations are also performed in order to screen for complications. Pigmentation is darkest at the epidermal surface, in contrast to dermal (''blue'') nevi. When malignant transformation is suspected, biopsy is necessary.
Differential diagnosis
Differential diagnoses include Becker nevus syndrome, malignant melanoma, neurofibroma, nevus of Ota, Spitz nevus, blue nevus, epidermal nevus and congenital smooth muscle hamartoma.
Antenatal diagnosis
Reported cases of antenatal diagnosis are unusual.
Genetic counseling
CMN is nearly always sporadic despite rare familial reports (in siblings and cousins).
Management and treatment
Regular periodic dermatological follow-up is necessary. In some cases, excision may be advisable by an experienced plastic surgeon. Dermabrasion, curettage and laser treatments are inferior to full-thickness removal or to simple surveillance. Neurological involvement requires a multidisciplinary approach. Psychological support should be proposed to affected patients and families.
Prognosis
Most patients have normal lives. The incidence of complications increases with nevus size. Malignant transformation may occur at any age with no correlation to sun exposure, in approximately 2-3% of multiple and LCMN patients, and up to 5% of GCMN patients. Prophylactic surgery is not known to reduce cancer risk.

                            Last update: 
                            August 2023


                            - Expert reviewer(s): 
                            Dr Heather ETCHEVERS