Nevoid Basal Cell Carcinoma Syndrome
- Author: Daniel Berg, MD, FRCP(C); Chief Editor: Dirk M Elston, MD more...
Background
Nevoid basal cell carcinoma syndrome (NBCCS) represents a series of multiorgan abnormalities known to be the consequence of abnormalities in the PTCH gene. The syndrome has been documented for 50 years, but more recent developments in molecular genetics have dramatically increased understanding of its pathophysiology and opened up molecular avenues for treatment in the future.
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Pathophysiology
Multiple organ systems may be impacted in nevoid basal cell carcinoma syndrome (NBCCS). Abnormalities of the skin, the skeletal system, the genitourinary system, and the central nervous system (CNS) are the most common. Other less common neoplasms and abnormalities are also associated with the disease and are well documented.[1]
Etiology
NBCCS, also known as basal cell nevus syndrome (BCNS), is an autosomal dominant syndrome caused by mutations in the PTCH (patched) gene found on chromosome arm 9q. The disease has complete penetrance and variable expressivity. Although clinical features vary more among families than within families, no clear-cut link exists between specific mutations and phenotype. Approximately one third of cases are new mutations.
Genetics
First elucidated in fruit flies, the protein product of the PTCH gene is important in determining segment polarity of wings and limbs (anterior-posterior relationships in developing embryos). In mammals, PTCH is an important inhibitor in the so-called hedgehog (HH) signaling pathway, whose downstream proteins can lead to cell growth. PTCH is frequently mutated on 1 allele in sporadic basal cell carcinomas (BCCs), and according to Epstein, "upregulation of HH signaling is the pivotal abnormality in all BCCs."[2] . Its wide-reaching activity accounts for the myriad findings in patients with NBCCS.[3, 4, 5, 6, 7]
Ultraviolet exposure
Ultraviolet (UV) light exposure appears to be an important cofactor. BCCs are much more common in sun-exposed areas and are much more common in white individuals with the syndrome. Nevertheless, molecular genetic studies looking for UV-related mutations in BCCs obtained from patients with NBCCS leave the possibility that agents other than UV-B may cause alterations to the gene.[8]
Radiation
Patients are particularly sensitive to ionizing radiation (radiation therapy; XRT), and reports have described multiple BCCs in the radiation portal developing in patients treated with XRT for medulloblastoma. Reports of more aggressive BCCs occurring in sites of previous XRT for BCC also exist. Radiobiologic studies on fibroblasts suggest an abnormal response to radiation in fibroblasts obtained from patients with NBCCS.
Epidemiology
The approximate prevalence of NBCCS is reported to be 1 case per 56,000-164,000 population. The prevalence is likely to be considerably higher in individuals younger than 20 years who present with BCCs.
The syndrome is found in all races, and men and women are affected about equally (1:1.3). However, a definite but smaller percentage of black individuals present with skin cancer and have fewer skin cancers than affected white individuals. This decreased number of skin cancers, a diagnostic hallmark, may account for the comparatively fewer patients with darker skin ascertained in reviews of the syndrome. Full expression of the non–skin cancer features of the syndrome is found in patients of all skin types.
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