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At a glance

Genetic disorder characterized by the presence of abnormal nevi that predispose to melanoma development.

Synonyms

BK Mole Syndrome; Familial Atypical Mole Melanoma (FAMM) Syndrome; Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome; Hereditary Dysplastic Nevus Syndrome; Nevoid Melanoma Syndrome.

History

First reported in 1820 by W. Norris.

Incidence

Prevalence in white population of America and Europe is approximately 2 to 5%. In Sweden, 18% of white adults have atypical moles clinically but only 8% have the typical histologic features. No sex predilection. Atypical moles are rare in black, Asian, and Middle Eastern populations.

Genetic inheritance

Clinical history and family examinations suggest an autosomal dominant mode of inheritance. A first proposed assignment of a melanoma gene (CMM1) chromosome 1p36 was not confirmed. A second proposed gene (cell cycle regulator CDKN2A [P16], a cyclin-dependent kinase) has been mapped to chromosome 9p21, and this gene assignment has been confirmed. Germline mutations in this gene occur in approximately 20% of kindreds with Familial Atypical Mole Syndrome. Penetrance is variable. Exposure to ultraviolet light plays a role in the phenotypic expression of the syndrome.

Pathophysiology

Dysplastic nevi appear to be histogenetic precursors of melanomas.

Diagnosis

Clinically based on the presence and specific appearance of nevi. The National Institutes of Health Consensus Conference requires the following criteria to establish the diagnosis:

  1. First-degree (eg, parent, sibling, or child) or second-degree relative (eg, grandparent, grandchild, aunt, uncle) with malignant melanoma

  2. Large number of nevi, often more than 50, some of which are atypical nevi

  3. Nevi that demonstrate certain microscopic features

Histologic examination of dysplastic nevi shows compound nevi with evidence of abnormal growth. Nevus cell nests within the epidermis may be enlarged and show abnormal coalescence with adjacent nests. As part of this process, single nevus cells begin to replace the normal basal cell layer along the dermoepidermal junction. Cytologically, the atypical features consist of irregular, often angulated, nuclear contours frequently combined with hyperchromasia. Associated alterations occur in the superficial dermis, with sparse lymphocytic infiltrate, loss of melanin pigment from presumably destroyed nevus cells, phagocytosis of melanin pigment by dermal macrophages, and linear fibrosis surrounding the involved epidermal rete ridges. This Atypical Nevus Syndrome phenotype is the most potent risk factor for melanoma in families and in the general population. Although most dysplastic nevi are stable lesions, transition to melanoma is well known and can occur within a few months. Atypical Mole Syndrome (AMS) represents the highest risk factor known for malignant melanoma. A 7-year follow-up of 14 families indicated affected individuals having at least two relatives with malignant melanoma have a 100% lifetime risk of developing a melanoma, whereas all other affected persons have a lifetime risk of approximately 18%. ...

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