Familial atypical multiple birthmark and melanoma syndrome (FAMM) D48.5

Author: Prof. Dr. med. Peter Altmeyer

Last updated on: 26.11.2022

Synonym(s)

BK-Mole Syndrome; BK-Naevus Syndrome; Dysplastic melanoycytic nevi syndrome.; Dysplastic nevi syndrome; Dysplastic nevus syndrome; Familial atypical multiple mole melanoma; Familial malignant melanoma; FAMM Syndrome; Hereditary dysplastic nevus cell nevus syndrome; Large atypical mole syndrome; Melanoma malignes familial; Melanoma pancreatic cancer syndrome; Melanoma Pancreatic Cancer Syndrome; Multiple mole melanoma-pancreatic cancer syndrome; Nevus cell nevus syndrome hereditary dysplastic; Nevus Syndrome; Nevus syndrome hereditary dysplastic; OMIM 606719

History
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Norris, 1857; Clark, 1978

Definition
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Rare, autosomal-dominantly inherited syndrome associated with numerous dysplastic melanocytic nevi with a high degenerative tendency. The monogenic inheritance is doubted by some authors.

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Etiopathogenesis
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The proportion of genetic melanomas is 5-10%. This corresponds to about 500 new cases per year in Germany. It is assumed that up to 40% of autosomal dominantly inherited melanomas can be traced back to a mutation in the CDKN2A gene (cyclin dependent kinase inhibitor 2A, p16).

The gene is located on chromosome 9 and codes, among other things, for the synthesis of the guardian protein p16, whose function is to prevent uncontrolled cell division of pigment cells. Mutation of the CDKN2A gene results in decreased production of p16 and consecutive proliferation of melanocytes.

Families that have been shown to be CDNK2A mutation carriers also have a significantly increased incidence of pancreatic cancer (multiple mole melanoma-pancreatic cancer syndrome; lifetime risk is approximately 17%). The relationship is unexplained. A second gene (CDK4) also plays a (but minor) role in BK-Mole syndrome.

Localization
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Distributed over the whole integument, especially on the upper trunk.

Clinical features
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Per patient 10 to more than 100, usually 0.5-1.0 cm large (or larger), bizarrely configured, pink, brown or black melanocytic nevi appear, often with a reddish-brownish rim. One dermal component may be palpable.

Diagnosis
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Clinic, histology, sonography, endosonography, genetic detection of the gene mutation.

Therapy
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Quarterly inspection! Documentation of individual naevi (reflected light photographs, also video reflected light microscopy/follow-up). Avoid any sun exposure. Excision for suspicious pigment moles! Regular sonographic checks as screening measures after pancreatic carcinoma.

Progression/forecast
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Relatively frequent melanoma development, several melanomas per patient possible. An increased activity of BK-Naevi was observed when taking contraceptives. The risk of these patients developing pancreatic carcinoma is 22 times higher than in the normal population:-)

Note(s)
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The first evidence of a familial susceptibility to melanoma dates back to 1820. Already at that time a medical paper described a family in which over three generations melanomas occurred in a cluster, each of which had arisen from one of numerous melanocytic nevi. The term "BK-mole-syndrome" was coined by Clark. It is recommended to also examine family members for FAMM syndrome and to monitor them closely, including pancreas checks.

Literature
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Ackerman AB (2003) "Dysplastic nevus" syndrome: does a survey make it real? J Am Acad Dermatol 48: 461-463.
Bruce H et al (2009) Cutaneous manifestations of internal malignancy. Cancer J Clin 59: 73-98
Clark WH Jr et al (1978) Origin of familial malignant melanomas from heritable melanocytic lesions. The B-K mole syndrome. Arch Dermatol 114: 732-738.
Happle R (1989) Gregor Mendel and the dysplastic nevi. Dermatologist 40: 70-76
Hübinger L et al (2014) Genodermatoses associated with malignant skin tumors. Dermatologist 65: 527-535
Kint A (1986) The dysplastic nevus syndrome. Z Hautkr 61: 595-598
Lynch HT et al (1978) Familial atypical multiple mole-melanoma syndrome. J Med Genet 15: 352-356.
Naeyaert JM et al (2003) Clinical practice. Dysplastic nevi. N Engl J Med 349: 2233-2240.
Nieuwenburg SA et al (2020) Cumulative risk of skin cancer in patients with Li-Fraumeni syndrome. Fam Cancer 19:347-351.
Norris W (1820) Case of fungoid disease. Edingburgh Med Surg 16: 562-565.
Sabbaghian N et al (2011) Mutation analysis of the PALB2 cancer predisposition gene in familial melanoma. Fam Cancer 10:315-317.