Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

Abstract

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

A Case of Gorlin-Goltz Syndrome Without the Characteristic Physical Features That Was Diagnosed After the Development of a Fifth Cancer

“…Another literature reported that a SUFU mutation was found in 8 of 43 children with medulloblastoma below 3 years of age at diagnosis, whereas no mutation was identified in any of the 88 patients age above 3 years at diagnosis 12. A more recent report described that the identification of a predisposition syndrome for medulloblastoma caused by germline pathogenic variants in SUFU or PTCH1 gene is fundamental, because the presence of an underlying genetic anomaly can have an impact on the therapeutic management, because of the different behavior of SUFU or PTCH1 -related medulloblastomas 13. Radiation therapy for hereditary diseases such as GGS in medulloblastoma causes basal cell carcinoma and intracranial and sinus tumors 14.…”

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum

“…While it seems that mild JS and Gorlin syndrome represent SUFU-related allelic conditions, nevertheless genetic counselling should take into account the possibility of an increased risk for cancer and discuss the opportunity of appropriate surveillance, as tumours may also occur in adulthood. 28 The mechanisms underlying such phenotypical diversity associated with SUFU loss of function variants, as well as their reduced penetrance, remain to be explained. We can speculate that additional molecular mechanisms, such as a mutational burden involving heterozygous hypomorphic variants in other JS or cancer genes, or second hits within specific cell types may be implicated in the development of either phenotype.…”

Basal Cell Carcinoma: Pathology, Current Clinical Treatment, and Potential Use of Lipid Nanoparticles

“…For early detection of BCC, dermatologic examination should start at around 10 years old Radiotherapy treatment is contraindicated because of the increased risk of new BCC lesions in the irradiated area [ 11 , 12 ].…”