Phenotypic Variation and Systemic Cancer in the FAMMM Syndrome

Abstract

Familial atypical multiple mole melanoma (FAMMM) syndrome, a cancer‐associated genodermatosis, is a dominantly inherited heterogeneous disorder with variable expressivity of both its cutaneous and cancer phenotypes. By using a verified historical review technique of cancer documentation (idout patient health records, pathology reports/slides, autopsy reports/slides, and death certificates) of all anatomic sites in all members of a modified nuclear pedigree (first‐degree relatives plus maternal and paternal grandparents, aunts, and uncles) over several generations, we showed that the FAMMM syndrome is similar to the majority of autosomal dominant inherited cancer‐associated genodermatoses and has excessive risk for cancer of multiple anatomic sites. With respect to the FAMMM syndrome, these cancers involved the breast, respiratory tract, gastrointestinal system, the eye (intraocular melanoma), and the lymphatic system. These FAMMM pedigrees showed some of the following distinctive characteristics of hereditary cancer: 1) integral patterns of cancer within and between pedigrees; 2) early age of onset of cancer; 3) prolonged survival of some pedigree members with cancer; and 4) an excess of multiple primary melanomas and cancers of variable anatomic sites. The presence of these features indicates that these cancers of variable anatomic sites may be etiologically associated with the FAMMM syndrome. Heterogeneity should be investigated in FAMMM pedigrees with attention to consistent differences in size and distribution of atypical lesions, age at cancer onset, and pattern of tumor occurrences. The occurrence of FAMMM pedigrees in the general population or among pedigrees of probands with atypical nevi is not known. The occurrence of systemic cancers in these FAMMM pedigrees requires the development of cancer surveillance programs that are specifically modified to the particular cancer pattern of each pedigree.