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

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## TL;DR

Two rare inherited conditions cause skin cancer decades earlier and in far greater numbers than sun exposure alone. Gorlin syndrome causes many basal cell carcinomas from a young age through a fault in the same pathway the hedgehog inhibitor drugs block. Xeroderma pigmentosum leaves cells unable to repair ultraviolet damage at all.

## Summary

**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.

## Fields

- Kind: Term
- Last checked: 2026-09-25
- Also known as: Gorlin syndrome; Gorlin-Goltz syndrome; naevoid basal cell carcinoma syndrome; nevoid basal cell carcinoma syndrome; NBCCS; BCNS; basal cell naevus syndrome; PTCH1; SUFU; xeroderma pigmentosum; XP; inherited skin cancer syndrome; genetic skin cancer syndrome

## Notes

- Why a rare syndrome mattered to everybody with this cancer. Identifying PTCH1 as the Gorlin syndrome gene tied basal cell carcinoma to the hedgehog developmental pathway, and the drugs that block that pathway, vismodegib and sonidegib, followed from it. It is one of the clearest cases in oncology of a rare inherited condition explaining the common sporadic disease, and it is why a person with an advanced basal cell carcinoma today has a tablet to take.
- Immunosuppression and genetic susceptibility change the referral route as well as the risk. The UK reporting dataset lists immunocompromised patients among those whose basal cell carcinoma requires local skin cancer multidisciplinary team referral, and people with a genetic susceptibility among those requiring specialist team referral, whatever the tumour looks like (RCPath G123).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Nevoid_basal_cell_carcinoma_syndrome
- Foulkes, Kamihara, Evans et al., Familial Cancer 2021;20(4):317 to 325: current recommendations for cancer surveillance in Gorlin syndrome, a report from the SIOPE host genome working group: https://doi.org/10.1007/s10689-021-00247-z
- Evans et al., American Journal of Medical Genetics A 2010;152A(2):327 to 332: birth incidence and prevalence of tumour-prone syndromes, estimates from a UK family genetic register service: https://doi.org/10.1002/ajmg.a.33139
- Evans, Ladusans, Rimmer, Burnell, Thakker and Farndon, Journal of Medical Genetics 1993;30(6):460 to 464: complications of the naevoid basal cell carcinoma syndrome, results of a population-based study of 84 UK cases: https://doi.org/10.1136/jmg.30.6.460
- Lehmann, McGibbon and Stefanini, Orphanet Journal of Rare Diseases 2011;6:70: xeroderma pigmentosum: https://doi.org/10.1186/1750-1172-6-70
- WHO Classification of Tumours Editorial Board: Skin tumours, 5th edition, volume 12 (IARC, Lyon, 2025), ISBN 978-92-832-4535-3: https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/Skin-Tumours-2025
- Elder, Massi, Scolyer and Willemze (eds): WHO Classification of Skin Tumours, 4th edition, volume 11 (IARC, Lyon, 2018): https://publications.iarc.who.int/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Skin-Tumours-2018

## Connected records

- technologies: [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/)
- pathways: [Field cancerisation](https://onco.cc/pathways/field-cancerisation/)
- terms: [Actinic keratosis (solar keratosis): sun damage, not cancer](https://onco.cc/terms/actinic-keratosis/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [Keratinocyte cancer (and why 'non-melanoma skin cancer' is being retired)](https://onco.cc/terms/keratinocyte-cancer/), [The growth pattern on a basal cell carcinoma report: nodular, superficial, infiltrative, basosquamous](https://onco.cc/terms/bcc-growth-pattern/), [What makes a skin cancer high risk: the UK feature lists](https://onco.cc/terms/skin-cancer-high-risk-features/)
- cancers: [Basal cell carcinoma](https://onco.cc/cancers/basal-cell-carcinoma/), [Bowen's disease (squamous cell carcinoma in situ)](https://onco.cc/cancers/bowens-disease/), [Cutaneous squamous cell carcinoma](https://onco.cc/cancers/cutaneous-scc/), [Locally advanced and metastatic basal cell carcinoma](https://onco.cc/cancers/locally-advanced-bcc/), [Melanoma](https://onco.cc/cancers/melanoma/), [Skin cancer (all types)](https://onco.cc/cancers/skin-cancer/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Prevention & Risk](https://onco.cc/fronts/prevention/)

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