Dysplastic nevus syndrome (DNS)

1999-10-01 Claude Viguié Affiliation

Identity

Name

Alias

Familial atypical mole-malignant melanoma syndrome (FAMMM) , B-K mole syndrome

Inheritance

autosomal dominant with high penetrance and variable expressivity; the frequency of DNS is difficult to evaluate because a number of cases without malignant evolution are not recorded; DNS defines patients with numerous dysplastic nevi. FAMMM defines families where coexist numerous nevi with malignant melanoma (MM)
sporadic forms of dysplastic nevi are not considered as DNS

Omim

155600 , 155601

Mesh

D004416

Orphanet

404560 Familial atypical multiple mole melanoma syndrome

Umls

Clinics

Note

the familial dysplastic nevus syndrome is a good example of a genetic disorder which leads to the practice of self prevention and prevention at the family level; the risk is the evolution towards MM

multiple dysplastic naevi on the skin of the bac, with (left) a surgically resected malignant melanoma on the scalp - Courtesy Daniel Wallach

Phenotype and clinics

predominant in patients with a clear complexion, blue eyes and\/or presence of numerous nevi; the dysplastic nevus or \"nevus of Clark\" or \"atypical melanocytic nevus\" is a large mole with a variable size (5 to 15 mm), an irregular border and a color varying from dark brown to depigmentation; lesions are located mainly on the upper trunk, back, limbs, abdomen and arms; the number of moles is variable, from 10 to up to 100

histologic studies show the dysplastic nature of these nevi: junctional hyperplasia with isolated or clustered melanocytes, cells with large, irregular, hyperchromatic, and non mitotic nucleus; this aspect is intermediate between benign nevus and MM

Neoplastic risk

the main risk is to develop a MM but there is also a possible increased incidence of pancreatic cancer, breast cancer, and myeloma; MM usually arises from a dysplastic nevus (DN) but it can also appear de novo or from a benign nevus; it occurs most often in the skin but it may also involve other sites, mainly the eye or the central nervous system; the risk of MM depends on three factors:

1- the number of nevi: MM occurs in 2 to 7% of the population; without DN the risk is multiplied by 2 if the total number of nevi is higher than 25; the risk is multiplied by 4 if they are more than 5 nevi with a diameter higher than 5 cm; the risk is multiplied by 2 with one DN and by 12 with 10 DN; 40% of MM occur on dysplastic nevi, more frequently in superficial than nodular forms

2- the existence of at least one case of MM in the family (risk x 2); the risk of MM is 100% in case of FAMMM; the patients with DNS who develop MM are notably younger than patients with sporadic forms; the age of onset in FAMMM regresses from generation to generation

3- the role of UV as a promoting factor is discussed; the number of DN increases with sun exposure

Treatment

clinical vigilance and tumour exeresis

Evolution

the number of DN can increase during life with an increase in MM risk

Prognosis

according to the tumour expansion at the time of exeresis

Cytogenetics

Inborn condition

a chromosome instability disorder was observed in cell cultures from the normal skin and dysplastic nevi over three-generations in DNS families, leading to translocations, duplications and deletions; in another study on MM, translocations involving bands 11q24, 1q25 and Xq13 were observed in patients with DNS, in dysplastic nevi and in the normal skin as well; a loss of chromosome 9 was found in 2 out of 4 DN, suggesting that deletion \/ inactivation of a gene on 9p may be a primary event in melanocyte transformation; loss of heterozygocity (LOH) for markers flanking the CDKN2A on 9p was described in primary MM and in a metastasis; other putative tumor suppressor genes which could be involved in the process are located in 1p13, 10p, 10q, 11q and 6q15-q23
DNS is characterized cytogeneticaly by an UV-induced elevated level of sister chromatid exchange (SCE); the post-UV plasmid hypermutability test is a laboratory marker for FAMMM patients, suggesting a defective repair mechanism of UV-induced DNA damage; deficient DNA repair in lymphocyte studies also characterizes some patients with sporadic dysplastic nevi or non familial MM

Genes involved and Proteins

Note

locus in 1p36 (called CMM1 for cutaneous malignant melanoma): this locus segregates with MM and DNS, but no gene is yet cloned

Note

locus in 1p32; this locus has been found mutated in the germline from patients with MM and other tumors

Note

CDKN2A\/p16\/MTS1\/CDK4 inhibitor (cyclin-dependent kinase inhibitor 2A)ocus in 9p21; this locus has been designated as CMM2; germline mutations were found in this locus in 30 to 40% of patients with FAMMM, and in some patients with two cutaneous and\/or mucous MM; P16 is a candidate gene for MM susceptibility; there is a p16 mutation in 10 to 14% of patients suffering from sporadic multifocal MM; P16 is also involved in several other types of cancers; other tumor suppressor genes located at 9p are hypothetically involved in MM progression

Note

locus in 12q14; 2 germline mutations found in 3 FAMMM families

Note

locus in 6q: a 6q allelic loss was identified in 21 of 53 informative loci; the chromosomal region bearing the highest frequency of 6q allelic loss was defined by the markers MYB and ESR located at 6q22-q23 and 6q24-q27, respectively; this may indicate genetic heterogeneity

Note

locus in 16q24.3; defined as possible susceptibility gene

Note

mutations were found in benign and dysplastic nevi from patients with previous personal or familial history of MM; however, these mutations are considered to be late events and cannot be used as a marker to identify patients at high risk of MM

To be noted

Hgmd

335362 CDKN2A

Article Bibliography

Pubmed ID	Last Year	Title	Authors
9835460	1998	Characteristics of familial and non-familial melanoma in Australia.	Ang CG et al
8970585	1996	A review of inherited predisposition to melanoma.	Cannon-Albright LA et al
7982177	1994	Dysplastic nevi as a melanoma risk factor in patients with familial melanoma.	Carey WP Jr et al
1673858	1991	Cytogenetic analysis in melanoma and nevi.	Cowan JM et al
8116618	1994	Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity.	Goldstein AM et al
3964923	1985	Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome.	Greene MH et al
1392119	1992	Dysplastic nevus syndrome: intrafamilial identification of carriers by cytogenetics.	Hürlimann AF et al
9328469	1997	Germline mutations of the CDKN2 gene in UK melanoma families.	Harland M et al
3180013	1988	Chromosome rearrangements in dysplastic nevus syndrome predisposing to malignant melanoma.	Hecht F et al
8485708	1993	Overexpression of p53 is a late event in the development of malignant melanoma.	Lassam NJ et al
10388950	1999	Melanoma precursors in children.	Lefkowitz A et al
7671235	1995	Detection of p53 mutations in benign and dysplastic nevi.	Levin DB et al
9377580	1997	Hypermutability of UV-treated plasmids in dysplastic nevus/familial melanoma cell lines.	Moriwaki SI et al
7673498	1995	Melanocytic nevi, dysplastic nevi, and malignant melanoma in children from melanoma-prone families.	Novakovic B et al
8536232	1995	Cytogenetic study of neoplastic and nonneoplastic cells of the skin.	Pavarino EC et al
9724087	1998	Screening of germline mutations in the CDK4, CDKN2C and TP53 genes in familial melanoma: a clinic-based population study.	Platz A et al
9439668	1997	Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene.	Puig S et al
9326388	1997	Radiation-induced chromatid breaks and DNA repair in blood lymphocytes of patients with dysplastic nevi and/or cutaneous melanoma.	Sanford KK et al
8467253	1993	Dysplastic nevi in relation to superficial spreading melanoma.	Titus-Ernstoff L et al