360 REVIEW ARTICLE Skin Cancer Associated Genodermatoses: A Literature Review DV Juliane SCHIERBECK, Tine VESTERGAARD and Anette BYGUM Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark cta A Skin cancer has become the most common type of can- SIGNIFICANCE cer worldwide as a result of environmental exposure and medical treatments. A small group of patients are This article reviews hereditary skin syndromes that cause genetically predisposed to skin cancer and this article an increased risk of skin cancer development. It is im- is intended as a diagnostic tool when encountering pa- portant for physicians treating skin cancer to be aware of tients with multiple skin cancer lesions. The disorders hereditary causes, especially when examining patients with are described with clinical characteristics, genetics multiple cancerous lesions with no obvious explanation. and management. The most common syndromes asso- This article describes clinical features, genetic descriptions ciated with basal cell carcinoma are: Gorlin–Goltz syn- and management suggestions for hereditary syndromes enereologica drome, Rombo syndrome, and Bazex-Dupré-Christol associated with skin cancer, and includes clinical images V syndrome. Multiple squamous cell carcinomas can be from our practice. related to: xeroderma pigmentosum, Ferguson-Smith, Muir-Torre syndrome, Mibelli-type porokeratosis, keratitis-ichthyosis-deafness syndrome, Rothmund- This literature review focuses on hereditary causes of ermato- Thomson syndrome, Bloom syndrome, and epidermo- basal cell carcinoma (BCC), squamous cell carcinoma D dysplasia verruciformis. Malignant melanoma can be (SCC) and malignant melanoma (MM). The review will inherited, as in familial atypical multiple mole mela- serve as a tool in diagnosing and treating patients with cta noma syndrome. multiple skin cancers. A Key words: genodermatoses; skin cancer; basal cell carcinoma; squamous cell carcinoma; hereditary skin cancer. HEREDITARY BASAL CELL CARCINOMA Accepted Jan 16, 2019; E-published Jan 17, 2019 Gorlin–Goltz syndrome Acta Derm Venereol 2019; 99: 360–369. DV Gorlin–Goltz syndrome (GGS), also known as Gorlin Corr: Juliane Schierbeck, Department of Dermatology and Allergy Centre, Odense University Hospital, Vesterbro 116, 1th, DK-5000 Odense C, Den- syndrome, naevoid basal cell carcinoma syndrome or cta mark. E-mail: [email protected] multiple naevoid basal cell epithelioma, jaw cysts and A bifid rib syndrome, is an autosomal dominant condi­ kin cancer is the most common type of cancer world­ tion causing unusual facial appearances (mandibular Swide, with more than 15,000 patients annually in prognathia, lateral displacement of the inner canthus, Denmark (which has a population of ~5.8 million) (1). frontal and biparietal bossing), dental cysts, palmar pits Skin cancer is often caused by environmental exposure to and a predisposition for BCC. Other cardinal features ultraviolet radiation (UVR), immunosuppressive therapy are calcification of the falx cerebri, medulloblastoma, or radiotherapy. kyphoscoliosis, rib anomalies, cleft lip/palate, eye ano­ A small, and often overlooked, group of patients are ge­ malies, milia and syndactyly (2). Two major and 1 minor netically predisposed to develop skin cancer, sometimes criteria or 1 major and 3 minor criteria are necessary to associated with internal malignancies. These hereditary determine the diagnosis, as shown in Table I. skin conditions, or genodermatoses, are often clustered, Binkley & Johnson were the first to suggest a correla­ with multiple family members showing symptoms, al­ tion between dental cysts, partial agenesis of the corpus though de novo mutations are also not uncommon. Awa­ callosum, a bifid rib, an ovarian fibroma and epithelioma reness of these disorders is therefore essential for early adenoides cysticum in 1951 (3). It was, however, the oral diagnosis and treatment, as well as for identification of pathologist and human geneticist Robert J. Gorlin and potentially affected family members. Early identification the dermatologist Robert Goltz, who, in 1960, published and diagnosis is crucial to the outcome and prognosis. and described the specific syndrome, which consists of Skin symptoms are easier to recognize, whereas visceral multiple naevoid basal cell epitheliomas, jaw cysts and malignancies are more difficult and slower to identify. bifid ribs (4). The first healthcare practitioners to see and treat these Molecular genetics and pathophysiology. Recent studies patients are general practitioners and dermatologists, in molecular genetics have proven GGS to be caused by who have a responsibility in recognizing and facilita­ mutations in the PTCH1 gene on chromosome 9q22, the dvances in dermatology and venereology ting further genetic investigations and primary care, as PTCH2 gene on chromosome 1p32, or the SUFU gene A described below. on chromosome 10q24-q25, encoding for proteins in the doi: 10.2340/00015555-3123 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2019; 99: 360–369 Journal Compilation © 2019 Acta Dermato-Venereologica. Skin cancer associated genodermatoses 361 Table I. Diagnostic criteria for Gorlin–Goltz syndrome vessels. Defective or completely missing eyelashes and Major criteria eyebrows are also seen in adulthood. BCCs develop in the • Excessive numbers of basal cell carcinomas out of proportion with prior sun rd th exposure and skin type or <20 years of age 3 or 4 decade of life and are a consistent complication DV • Odontogenic keratocysts of the jaws prior to 20 years of age throughout life (8) (Fig. 1 C). • Palmar or plantar pitting • Lamellar calcification of the falx cerebri • Medulloblastoma, typically desmoplastic cta • First-degree relative with Gorlin–Goltz syndrome Bazex-Dupré-Christol syndrome A Minor criteria • Rib anomalies In 1964 Bazex, Dupré & Christol first described the • Other specific skeletal malformations and radiological changes (i.e. vertebral condition Bazex-Dupré-Christol syndrome (BDCS) as anomalies, kyphoscoliosis, short fourth metacarpals, postaxial polydactyly) • Macrocephaly an X­linked dominant syndrome affecting hair follicles • Cleft lip and/or palate • Ovarian/cardiac fibroma and skin, along with an increased risk of developing • Lymphomesenteric cysts BCCs. The condition is very rare; only approximately • Ocular abnormalities (i.e. strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma) 20 families have been reported (9). Molecular genetics and pathophysiology. A recent study hedgehog signalling pathway, controlling growth and tis­ has revealed that BDCS might be caused by mutations enereologica sue development. The condition is autosomal dominant in the ARCT1 gene, resulting in an aberrant activation of V with complete penetrance, although approximately 10% the Hedgehog signalling pathway (10). BCCs have been of patients with GGS do not develop BCCs (5). The described in the first decade of life, although they most prevalence is reported to be 1 in 56,000–164,000 people, commonly present in the second decade onwards. The with an even sex distribution. female to male ratio is 2:1 (11). ermato- Characteristics. Patients with BDCS are generally diag­ D Characteristics. Patients with GGS often start develo­ ping BCCs between puberty and the age of 35 years, nosed based on a combination of hypotrichosis, multiple milia primarily on the face, follicular atrophoderma and cta but other cutaneous characteristics, such as palmar pits, multiple BCCs. Hypohidrosis and facial hyperpigmen­ A should also raise suspicion. The primary diagnostic criteria are odontogenic keratocysts, palmoplantar pits, tation are also described as early­onset manifestations. calcification of the falx cerebri, medulloblastoma, a The follicular atrophoderma is located mainly on the first-degree relative with GGS and multiple BCCs (2). dorsa of the hands, giving a characteristic orange­peel Minor criteria include rib anomalies, other specific appearance. BCCs are reported as early as the age of 3 skeletal malformations including macrocephaly, cleft years, but often develop in the second or third decade DV lip and/or palate, ovarian/cardiac fibroma, lymphome­ of life, typically in sun­exposed areas, such as the head and neck (9, 12) (Fig. 1 D). cta senteric cysts and ocular abnormalities. Palmar pits in childhood are considered a very strong indicator, along A with skeletal abnormalities, such as bifid ribs, frontal bossing and hypertelorism. Patients with GGS may develop from a few BCCs to several hundreds of BCCs during their lifetime (Fig. 1 A, B). Rombo syndrome Michaelsson, Olsson & Westermark were the first to describe Rombo syndrome (RS), in 1981, when they described a family with vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, BCCs and peripheral vasodilation with cyanosis (6). The condition is extremely rare and only a few cases have been reported since then. Molecular genetics and pathophysiology. The genetic mutation in RS has yet to be determined, but male­to­ male transmission has been described in a family with transmission through 4 generations, suggesting autoso­ mal dominant inheritance (7). Characteristics. The syndrome presents in childhood with a reticular pattern of skin atrophy on the cheeks, preauricular area and forehead, along with cyanotic Fig. 1. (A, B) Patient with Gorlin–Goltz syndrome and multiple basal cell carcinomas (BCC) of the scalp and neck. This patient