Inherited syndromes that cause skin cancer: Gorlin syndrome and xeroderma pigmentosum

**Gorlin syndrome**, also called naevoid basal cell carcinoma syndrome, is autosomal dominant and is caused in most cases by a germline variant in PTCH1, the gene whose loss also drives ordinary sporadic basal cell carcinoma. In the Manchester series of people meeting the clinical criteria, 134 of 193 (69.4 percent) had an identifiable germline PTCH1 variant, 11 (5.7 percent) had a SUFU variant, and 48 (24.9 percent) had none found; no PTCH2 variant was identified, and the authors judged that gene probably rarely involved (Foulkes 2021). Birth incidence in a UK family genetic register service was estimated at 1 in 14,963 and prevalence at 1 in 30,827, with 26 percent of cases arising from a new mutation rather than an affected parent (Evans 2010). In a population-based UK study of 84 cases, basal cell carcinomas and jaw cysts each occurred in over 90 percent of patients by the age of 40 and both could appear before the age of 10; ovarian calcification or fibroma occurred in 24 percent, medulloblastoma in 5 percent, cardiac fibroma in 3 percent, cleft palate in 5 percent, and ophthalmic abnormalities such as squint or cataract in 26 percent (Evans 1993). The features are less prominent in people with a SUFU variant, and many of them never meet the clinical criteria at all (Foulkes 2021). The syndrome is the reason the hedgehog pathway was identified as the driver of basal cell carcinoma, and therefore the reason the hedgehog inhibitor drugs exist.

**Xeroderma pigmentosum** is autosomal recessive and rarer, and it is a different kind of problem: the cell cannot repair the damage ultraviolet light does to its DNA. Eight complementation groups are defined by variants in eight genes, XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5 and POLH. Estimated incidence varies from about 1 in 20,000 in Japan to about 1 in 250,000 in the United States and about 2.3 per million live births in western Europe. The consequence is extreme: people with xeroderma pigmentosum have been estimated to carry a 10,000-fold increased risk of non-melanoma skin cancer and a 2,000-fold increased risk of melanoma under the age of 20, and about a 50-fold increase in cancers inside the body, especially of the central nervous system (Lehmann 2011). Many of the complementation groups also cause progressive neurological disease. The UK has a national xeroderma pigmentosum service, at St Thomas' Hospital in London, covering the whole population.

Both syndromes have their own chapter in the WHO skin classification, under inherited or genetic tumour syndromes associated with skin malignancies, in both the fourth and the fifth editions. Neither is a cancer record here: they are conditions that cause cancers, and the cancers they cause have their own pages.