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Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors

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Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease.

Introduction

Nonmelanoma skin cancers (NMSCs) represent the most common malignancies in the United States, making up 96% of all skin cancers and accounting for 2 to 3 million cases each year.1 Like melanoma, cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) represent complex diseases influenced by both the external environment and inherent genetics. While tumor development in both often occurs sporadically and is strongly associated with risk factors such as ultraviolet radiation, immunosuppression, viral infections, and radiotherapy, there is a subset of cases in which it occurs in the context of hereditary cancer syndromes. In general, these genetic syndromes fall under several broad categories: those associated with immunodeficiency, those that affect pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. This article is an overview of the clinical features, epidemiology, evaluation, genetics, and management of the major hereditary genodermatoses with NMSC predisposition (Table I). While the risk of NMSC is increased in many hereditary conditions associated with immunodeficiency, this article focuses on those with the most direct risk of skin cancer.

Section snippets

Familial cancer syndromes and nonmelanoma skin cancer risk: Increased risk of basal cell carcinoma

Key points

  1. •

    Basal cell nevus syndrome is an autosomal dominant syndrome driven by aberrant activation of the sonic hedgehog pathway; it is characterized by developmental defects and multiple neoplasms, including the development of numerous basal cell carcinomas

  2. •

    Developmental defects in patients with basal cell nevus syndrome include palmar and plantar pits, craniofacial anomalies, corpus collosum dysgenesis, falx cerebri calcification, coarse facies, cleft palate, and spina bifida occulta

  3. •

    Extracutaneous

Familial cancer syndromes and nonmelanoma skin cancer risk: Increased risk of squamous cell carcinoma

Key points

  1. •

    There are numerous genodermatoses leading to an increased risk of squamous cell carcinoma; they primarily fall into 1 of the following categories: germline defects in DNA repair leading to increased genomic instability, defects in pigmentation, or defects in key signaling pathways involved in squamous cell carcinoma development

  2. •

    Many of the genetic syndromes leading to an increased risk of squamous cell carcinoma are also characterized by an increased risk of other malignancies; therefore, a

Familial cancer syndromes and nonmelanoma skin cancer risk: Increased risk of other nonmelanoma skin cancers

Key points

  1. •

    Adenosine deaminase severe combined immunodeficiency is a rare immunodeficiency syndrome that is associated with a high incidence of dermatofibrosarcoma protuberans; unlike dermatofibrosarcoma protuberans in the general population, dermatofibrosarcoma protuberans in patients with adenosine deaminase severe combined immunodeficiency typically demonstrates multicentricity and occurrence at an early age

  2. •

    Muir–Torre syndrome is an autosomal dominant condition caused by germline mutations in mismatch

Conclusion

In conclusion, NMSCs are uncommon in pediatric patients, and the diagnosis of skin cancer at a young age often points to an underlying genetic condition. Recent advances in genomics promise to change the way in which these conditions are diagnosed and managed, and dermatologists play a critical role in this process. In general, genetic testing is used in 2 situations: (1) to confirm the clinical diagnosis of a genetic disease or (2) to predict the probability of a genetic condition in an

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      Xeroderma pigmentosum, a group of inherited disorders characterized by impaired DNA repair and hypersensitivity to UV-induced mutagenesis, have an 1000-fold increased risk of cutaneous malignancies, including BCC. KCs begin to develop at median age of 8.5 years.136 Other genetic disorders characterized by increased BCC risk (but not necessarily as a prominent and specific finding) include diseases of DNA replication/repair functions (Werner, Rothmund–Thomson, Bloom, Werner, and Muir–Torre syndromes), immune response (cartilage-hair hypoplasia, epidermodysplasia verruciformis), folliculosebaceus unit (Brooke–Spiegler, Schöpf-Schulz-Passarge, and Cowden syndromes), melanin biosynthesis (oculocutaneous albinism and Hermansky–Pudlak syndrome), and epidermal nevus syndromes.141

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    Supported by a Stanford University Medical Scholars Research Fellowship (Ms Jaju) and the Howard Hughes Medical Institute (Ms Ransohoff).

    Conflicts of interest: None declared.

    Date of release: March 2016

    Expiration date: March 2019

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