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Familial melanoma in short

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

Prevalence: Unknown

Inheritance: Autosomal dominant, Multigenic/multifactorial

Age of onset: Adult

Epidemiology

Familial melanoma (FM) represents approximately 10% of all cutaneous melanoma cases. The condition predominantly affects individuals of European descent. Higher incidence rates are observed in regions with increased sun exposure, particularly in the southern United States, Australia, and New Zealand. In 2012, the European incidence rate was estimated at 1 case per 90,000 individuals.

Familial melanoma typically manifests earlier than sporadic melanoma cases.
While non-familial melanoma commonly appears between ages 50 and 60 in the general population, FM’s average onset occurs between ages 30 and 40, though both earlier and later presentations have been documented in certain families. Patients often develop multiple primary melanomas.
The condition typically presents as a pigmented skin lesion characterized by asymmetry, irregular borders, and varied coloration. These lesions usually exceed 6 mm in diameter.
Common sites include the trunk, lower extremities, and back. All four major clinicopathologic variants (superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma) are encountered.
Disease progression varies, with potential for metastatic spread to other organs. Atypical moles frequently occur in FM-affected families.

Familial melanoma risk is associated with various genetic alterations in susceptibility genes and is modulated by phenotypic factors including pigmentation, freckling, nevi patterns, and sun sensitivity, along with UV radiation exposure. The condition’s development is believed to result from complex gene-environment interactions.
The CDKN2A gene represents the primary high-penetrance susceptibility gene, accounting for roughly 20% of FM cases. The high-risk CDK4 gene is less frequently involved.
Recent discoveries include mutations in BAP1, POT1, TERF2IP, ACD, and TERT, though their penetrance remains unclear. MITF and MC1R are classified as medium-penetrance genes. Additionally, approximately twenty common genetic variants influence melanoma risk in families with low clustering.

Familial melanoma is considered when melanoma affects two or more close relatives. Evaluation of new or changing moles focuses on alterations in color, border, size, and symmetry.

Key differential diagnoses include

In affected families, inheritance patterns vary, with some showing autosomal dominant transmission, while most cases suggest a polygenic inheritance model. Patients should be made aware that having one close relative with melanoma typically doubles their risk. The risk increases substantially when multiple relatives are affected and when individuals display specific phenotypic traits, such as multiple atypical pigmented melanocytic growths.

For high-risk individuals and FM families, ongoing surveillance is essential. This includes comprehensive skin examinations by a dermatology specialist twice yearly. Regular self-examination of the skin is strongly recommended. The therapeutic approach mirrors that of sporadic melanoma, primarily focusing on surgical intervention in early stages.

Patient outcomes vary significantly based on several factors: detection timing, lesion depth, ulceration presence, mitotic rate, lymph node involvement, and metastatic spread. Early detection, particularly when lesions are thin (low Breslow thickness), correlates with high cure rates.
The primary goal of monitoring melanoma-prone families is early melanoma detection through skin surveillance, which generally leads to better outcomes.