Dysplastic nevus syndrome, also known as familial atypical multiple mole–melanoma (FAMMM) syndrome, is an inherited

cutaneous condition A skin condition, also known as cutaneous condition, is any medical condition that affects the integumentary system—the organ system that encloses the body and includes skin, nails, and related muscle and glands. The major function of this sy ...

described in certain families, and characterized by unusual nevi and multiple inherited

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

s. First described in 1820, the condition is inherited in an autosomal dominant pattern, and caused by mutations in the CDKN2A gene. In addition to melanoma, individuals with the condition are at increased risk for

pancreatic cancer Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...

. The diagnosis of dysplastic nevus syndrome is based on clinical presentation and family history. Treatment consists of resection of malignant skin lesions (melanoma). Screening for pancreatic cancer may be considered, particularly if there is a family history.

Signs and symptoms

Dysplastic nevus syndrome is characterized by unusual nevi and multiple inherited

s.Czajkowski, R., ''FAMMM Syndrome: Pathogenesis and Management'', Dermatologic Surgery, Vol. 30 Issue 2 p2, p291-296, 2004.

Genetics

The

CDKN2A CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...

gene is located on chromosome 9p21.3. Two main transcripts, isoforms '1' and '4', each contain three exons and span 7288 and 26740 bp, respectively. They encode proteins of 156 and 173 amino acids; isoform '1' encodes p16(INK4a), while isoform '4' encodes p14(ARF), a protein that is structurally unrelated to p16(INK4) but acts in cell cycle G1 control by stabilizing the tumor suppressor protein

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

. Dysplastic nevus syndrome is inherited in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner. The

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...

for melanoma in kindreds with CDKN2A mutations is estimated at 58% to 92% by 80 years of age and varies with geography. The penetrance in CDKN2A mutation carriers for pancreatic cancer has been estimated to be 17% by 75 years of age. As noted above, there is wide variation in published estimates of the penetrance of CDKN2A mutations.

Pathology

The histopathologic characteristics of melanoma in FAMMM kindreds are not different from those seen in sporadic cases of melanoma and, thus, are not useful in diagnosing the syndrome.

Superficial spreading melanoma Superficial spreading melanoma (SSM) is usually characterized as the most common form of cutaneous melanoma in Caucasians. The average age at diagnosis is in the fifth decade, and it tends to occur on sun-exposed skin, especially on the backs of ma ...

(SSM) and nodular melanoma are the most frequently encountered histological melanoma subtypes in patients with CDKN2A mutations, which is consistent with the relative early age of onset.

Diagnosis

Definition

FAMMM has been described by multiple authors and institutions, and various definitions have been adopted. According to Newton et al., a scoring system allotting one point per feature establishes FAMMM with scores greater than or equal to 3. The features include: 1) two or more clinically atypical

nevi Nevus (plural nevi) is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from ''nævus'', which is Latin for "birthmark"; however, a nevus can be either congenital (present at bir ...

, 2) more than 100 nevi in patients between 20 and 50 years of age, 3) more than 50 nevi in patients under 20 years of age or more than 50 years of age, 4) more than one nevus in buttocks or instep, 5) nevi on the anterior scalp, 6) one or more pigmented lesions in the iris. The Classical (1990) definition uses the following criteria: 1) 100 or more melanocytic nevi, 2) one or more melanocytic nevi greater than or equal to 8mm in its largest diameter, and 3) one or more clinically atypical melanocytic nevi. The

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

(NIH) Consensus 1992 definition, which is still controversial, requires a family history of melanoma, in addition to a large number of melanocytic nevi (often greater than 50) and melanocytic nevi that present certain histological features.

Management

Screening for melanoma in FAMMM kindreds should begin at age 10 with a baseline total body skin examination including scalp, eyes, oral mucosa, genital area, and nail, as family members may develop melanoma in their early teens. Monthly self-performed skin examinations and early referral to a

dermatologist Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medical ...

for monitoring are recommended interventions. Treatment approaches such as removal of the largest dysplastic nevus or all of the dysplastic nevi have not been shown to appreciably reduce the risk of developing melanoma and are not cost-effective; therefore, these approaches are not recommended. Similarly, biopsy of multiple pigmented dysplastic nevi is not recommended and biopsy should be limited to specific nevi with appearance concerning for melanoma. At

Mayo Clinic The Mayo Clinic () is a nonprofit American academic medical center focused on integrated health care, education, and research. It employs over 4,500 physicians and scientists, along with another 58,400 administrative and allied health staff, ...

, FAMMM patients with a confirmed mutation and family history of pancreatic cancer are offered screening with either high-resolution pancreatic protocol CT,

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

, or

endoscopic ultrasound Endoscopic ultrasound (EUS) or echo-endoscopy is a medical procedure in which endoscopy (insertion of a probe into a hollow organ) is combined with ultrasound to obtain images of the internal organs in the chest, abdomen and colon. It can be used t ...

starting at age 50 or 10 years younger than the earliest family member with pancreas cancer. They are counseled on the lack of evidence-based data to support screening, and on the limitations of our current technology to detect a lesion at a stage amenable to therapy.

History

In 1820 Norris reported for the first time a case of what is now recognized as FAMMM (12). He described a 59-year-old man with melanoma, a high total body mole count, and family history of the same.

References

External links

Cancer.Net: Familial Malignant Melanoma

GenoMEL: Having a family history of melanoma
{{DEFAULTSORT:Dysplastic Nevus Syndrome Melanocytic nevi and neoplasms Syndromes affecting the skin