Key Points
Disease summary:
The genetics of hereditary skin cancer susceptibility syndromes is complex and expression is influenced by confounding environmental factors, including solar ultraviolet radiation, as well as other genetic factors.
Hereditary melanoma is characterized by the presence of multiple diagnoses of cutaneous melanoma within a family. In addition, an increased risk for other types of cancer, including pancreatic cancer, has been observed in some families with hereditary melanoma.
Hereditary basis:
Germline mutations in the CDKN2A gene are estimated to account for approximately 20% to 40% of hereditary melanoma. Mutations in the CDK4 gene are uncommon and have been detected in a small number of hereditary melanoma families.,
Although the penetrance is complicated by environmental and confounding genetic factors, CDKN2A and CDK4 gene mutations are generally considered to be associated with an autosomal dominant pattern of inheritance with variable penetrance.
Geographic location has been associated with variable CDKN2A expression. A study of CDKN2A carriers with positive family histories of melanoma estimated the risk of developing melanoma by age 80 in CDKN2A carriers to be 58% in Europe, 76% in the United States, and 91% in Australia. This difference has been attributed to environmental influences as well as other inherited factors.
Other cancer susceptibility syndromes associated with high skin cancer risk:
In addition to CDKN2A and CDK4, other hereditary syndromes have been associated with a highly increased susceptibility for skin cancer (Table 107-1).
| Syndrome | Associated Gene Symbols | Inheritance | Associated Findings | Clinical Phenotype | Genetic Testing |
|---|---|---|---|---|---|
Xeroderma pigmentosum (XP) | XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V) | Autosomal recessive | Sun sensitivity, melanoma and nonmelanoma skin and ocular cancers, neurologic abnormalities | Cutaneous: melanoma and nonmelanoma skin cancer at UV-exposed areas of the body, severe sunburn, persistent erythema, facial freckling < age 2, xerosis, poikiloderma Noncutaneous: Ocular: photophobia, keratitis, increased eye lid pigmentation, atrophy of the eye lid skin Nervous system: progressive sensorineural hearing loss, cognitive impairment, abnormal deep tendon stretch reflexes, acquired microcephaly | Clinical testing available for XPA and XPC Limited availability for other XP-related genetic testing outside of research testing. |
Nevoid basal cell carcinoma syndrome (BCNS; see Chap. 113) | PTCH1 PTCH2a SUFUa | Autosomal dominant, approximately 40% of cases are de novo4 | Basal cell carcinoma, jaw keratocysts, skeletal abnormalities, characteristic facial features, ectopic calcification, cardiac and ovarian fibromas, medulloblastoma | One major criteria and molecular confirmation, two major criteria, or one major and two minor criteria (adapted from): Major criteria: Basal cell carcinoma (BCC) < age 20 or excessive number of BCCs; odontogenic keratocysts of the jaw (histologically proven) < age 20; palmar or plantar pits; lamellar calcification of the falx cerebri; medulloblastoma; first-degree relative with BCNS. Minor criteria: rib abnormalities; macrocephaly; ocular abnormalities; cleft lip/palate; other skeletal abnormalities (including vertebral abnormalities, kyphoscoliosis, polydactyly); ovarian or cardiac fibromas; lymphomesenteric cysts |
Diagnostic Criteria and Clinical Characteristics
Due to the variable expressivity, standard diagnostic criteria do not exist for hereditary melanoma. Genetic counseling for hereditary melanoma predisposition syndromes should be considered for the individuals who meet the criteria below.
Criteria for individuals in areas with a high incidence of melanoma (including the United States):
Three or more relatives on the same side of the family with melanoma
Greater than or equal to three primary melanomas in one individual
Pancreatic cancer and melanoma on the same side of the family
Criteria for individuals in areas with a low incidence of melanoma:
Two or more relatives on the same side of the family with melanoma
Greater than or equal to two primary melanomas in one individual
Pancreatic cancer and melanoma on the same side of the family
Although sometimes observed in hereditary melanoma families, the following features are unlikely to be associated with a hereditary melanoma susceptibility syndrome in the absence of a family history of melanoma:
Early age of onset of melanoma
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