Skip to Main Content

107: Hereditary Melanoma and Other High-Risk Skin Cancer Susceptibility Syndromes

Michele Gabree; Hensin Tsao

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).

Table 107-1Other High-Risk Hereditary Skin Cancer Susceptibility Syndromes4,5
View Table||Download (.pdf)
Table 107-1 Other High-Risk Hereditary Skin Cancer Susceptibility Syndromes4,5
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.

...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

This site uses cookies to provide, maintain and improve your experience. MH Privacy Center Close