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Familial melanoma

ORPHA618
Synonym(s) -
Prevalence Unknown
Inheritance Autosomal dominant
or Multigenic/multifactorial
Age of onset Adult
ICD-10
  • C43
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Familial melanoma (FM) is a rare inherited form of melanoma characterized by development of histologically confirmed melanoma in two first degrees relatives or more relatives in an affected family.

FM is thought to account for about 10% of all cases of cutaneous melanoma. Melanoma primarily affects populations of European origin. Incidence is higher in geographical regions with greater sun exposure (southern USA, Australia, New Zealand). Incidence was estimated at 1/90,000 in Europe in 2012.

Familial melanoma tends to occur earlier than non-familial melanoma. The average age of onset is often between 30 and 40 years, while non-familial melanoma typically occurs in the general population between 50 and 60. Earlier and later onset is nonetheless reported in some families. A higher frequency of multiple primary melanomas is also found. Melanoma generally presents as a pigmented lesion on the skin. It is often asymmetrical with irregular borders and color variegation. The diameter is often greater than 6 mm. The most common sites are the trunk, lower legs and back. All four main clinicopathologic subtypes of primary cutaneous melanoma described (spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma) are observed. A variety of growth patterns are found with progression to a potential for metastasis to other organs. Atypical moles are often found in families with FM.

The risk of familial melanoma is closely related to a wide range of genetic alterations in susceptibility genes but also appears to be influenced by phenotypic risk factors, such as pigmentation, freckling and nevi and sun reactions but also exposure to UV radiation. Complex interactions between genetic and environmental factors are therefore thought to underlie FM. The most common high-penetrance susceptibility gene implicated in FM is CDKN2A, accounting for predisposition in approximately 20% of FM. CDK4, another high risk gene, is rarely involved. Mutations of BAP1,POT1, TERF2IP, ACD,and TERT have recently been reported and penetrance remains to be determined. Medium penetrance genes include MC1R.Some twenty common genetic variants modulate risk for melanoma in low clustering families.

FM is suspected in individuals when two or more close relatives have developed melanoma. A new or changing skin mole should be assessed to identify melanoma. Changes include color, border, size, and symmetry.

The main differential diagnoses are seborrheic keratosis, atypical mole, familial atypical multiple mole melanoma (see this term) and skin carcinoma.

In some affected families, susceptibility is consistent with autosomal dominant inheritance but in most cases, a polygenic mode of inheritance appears likely. Patients should be informed that a family history of melanoma in one close relative is associated with an average 2-fold increased risk. History in more than one relative and relevant personal phenotypic characteristics such as multiple pigmented atypical melanocytic lesions result in a significantly higher risk.

Long-term screening of individuals at high risk and monitoring in FM families is recommended. This involves a total-body skin examination by a qualified dermatologist every six months. Self-examination of skin should be encouraged. Treatment is similar to sporadic melanoma and is largely based on surgery at initial stages.

Long-term screening of individuals at high risk and monitoring in FM families is recommended. This involves a total-body skin examination by a qualified dermatologist every six months. Self-examination of skin should be encouraged. Treatment is similar to sporadic melanoma and is largely based on surgery at initial stages.

Expert reviewer(s)

  • Pr Marie-Françoise AVRIL
  • Dr Eve MAUBEC

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