Familial atypical multiple mole melanoma syndrome (ORPHA:404560)
Familial atypical multiple mole melanoma (FAMMM) syndrome is an inherited genodermatosis characterized by the presence of multiple melanocytic nevi (often >50) and a family history of melanoma as well as, in a subset of patients, an increased risk of developing pancreatic cancer (see this term) and other malignancies.
Epidemiology
The prevalence is unknown. An accurate estimate of the prevalence of FAMMM syndrome is difficult to make given the highly variable phenotype displayed both between and within FAMMM syndrome kindreds and the limited data available.
Clinical description
The clinical phenotype of FAMMM syndrome shows wide heterogeneity in regards to the presence of nevi and familial predisposition to melanoma and pancreatic cancer (mainly adenocarcinoma). The disease most often presents in children and teenagers but can occur at any age. The presenting feature is usually a high total body nevi count (usually more than 50). The majority will be clinically typical but some may have an atypical appearance (asymmetrical, raised, and/or different shades of tan, brown, black, or red and often of different sizes) resembling early melanoma and most frequently occur on the back, chest, buttocks, breasts, and scalp. Melanomas can arise from atypical moles or de novo and have been reported in some FAMMM syndrome patients as early as the second to third decade of life. Those with CDNK2A mutations have a 90% risk of developing melanoma by the age of 80 and a 20% increased risk of developing pancreatic cancer by the age of 75. These mutations are also associated with a younger age of onset. Other cancers that can be rarely associated with FAMMM syndrome include breast cancer, esophageal cancer and sarcoma.
Etiology
FAMMM syndrome has been associated with mutations in the 16p locus of CDKN2A  (9p21), a tumor suppressor gene involved in cell cycle inhibition. However, approximately 60% of patients with FAMMM syndrome do not have a  CDKN2A  mutation.
Diagnostic methods
Diagnostic criteria for FAMMM syndrome are as follows: high total body nevi count (usually >50), nevi with certain histologies (i.e. lentiginous pattern, nuclear atypia) and melanomas in 1 or more first or second degree relatives. Nevi are evaluated for melanoma based on the ABCDE characteristics (asymmetry, border irregularity, color variation, diameter >6 mm, and evolution or elevation). Dermatoscopy is also a non-invasive method of identifying melanomas. Molecular genetic testing identifying a CDKN2A mutation confirms diagnosis but the absence of a mutation in this gene does not exclude a diagnosis of FAMMM syndrome.
Differential diagnosis
Differential diagnoses include cutaneous neurofibromas and pancreatic ductal adenocarcinoma as well as Neurofibromatosis type 1 (see this term).
Genetic counseling
FAMMM syndrome is inherited in an autosomal dominant manner with incomplete penetrance. Genetic counseling should be offered to patients and their families.
Management and treatment
Screening for melanoma in FAMMM syndrome kindreds should begin at age 10 and include a total body skin examination with the use of dermoscopy. Follow-up clinical exams or self-exams should then be performed every 6 months to monitor any changes in nevi. In families with a history of pancreatic cancer or a CDKN2A mutation, screening by computed tomography, magnetic resonance imaging, or endoscopic ultrasound can be offered starting at age 40. Melanoma, pancreatic cancer and other cancers should follow standard treatment guidelines.
Prognosis
In those with pancreatic cancer, the prognosis is poor. Early diagnosis and treatment of melanoma tends to lead to a better prognosis.

                            Last update: 
                            February 2015


                            - Expert reviewer(s): 
                            Dr Henry LYNCH