PTCH1 or SUFU (Gorlin) – risk management

Gorlin syndrome/nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant multisystem disorder usually caused by a germline pathogenic variant in the PTCH1 gene.^r A second gene, SUFU, is responsible for a smaller proportion of diagnosed cases. NBCCS is characterised by the early onset of multiple basal cell carcinomas (BCC) and a range of other features including jaw keratocysts, calcification of the falx cerebri, palmar pits, paediatric medulloblastoma and skeletal abnormalities.

• Known or obligate carrier of a pathogenic variant in the PTCH1 or SUFU gene
• Individuals meeting the clinical diagnostic criteria for NBCCS 
• Individuals at 50% risk of being a PTCH1 or SUFU pathogenic variant carrier

Exclusion criteria

• Individuals with multiple BCCs without other clinical features of NBCCS
• Individuals with a variant of uncertain significance

Cancer/tumour type	Risk for PTCH1 pathogenic variant carrier	General population risk to age 85 years
Basal cell carcinoma (BCC)	80% have 1 or more by age 30 yearsrr	Unable to obtain
Medulloblastoma (childhood)	PTCH1: 2-5%  SUFU: unclear, estimated to be 12-16 times PTCH1 riskr	<1%

Type	Recommendations
Odontogenic keratocysts of the jaw	PTCH1	Specialist dental review from age 8 years Jaw x-ray every 12-18 months from age 8 years Cease surveillance at age 30 years if no keratocysts have developed
Cardiac fibroma	PTCH1 and SUFU	One-off echocardiogram in infancyr
Ovarian fibroma	PTCH1 and SUFU	Investigation of unexplained pelvic or abdominal pain

Odontogenic keratocysts 

Up to 90% of individuals with PTCH1-related NBCCS develop jaw keratocysts. They can occur as early as age 5 years, peak occurrence is in the teenage years and they rarely occur after age 30. Jaw keratocysts may present as painless swellings. They require specialist dental review and may need surgery. If left untreated, they can lead to major tooth disruption and fracture of the jaw.^r

Jaw keratocysts have not been reported in SUFU pathogenic variant carriers.^r

Cardiac fibromas

Approximately 2% of infants have cardiac fibroma. They can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow. When symptomatic, they usually present at birth or soon after. These require specialist cardiology review.

Ovarian fibromas

Ovarian fibromas occur in approximately 20% of individuals and may cause torsion of the ovary. Some specialists recommend one-off screening at age 18 years,^r however there is no evidence of benefit in asymptomatic individuals. If asymptomatic ovarian fibromas are detected, there is a lack of evidence that intervention is required.

Prenatal detection of abnormalities

Prenatal ultrasound may detect macrocephaly, cleft palate or cardiac tumour.^r

Basal cell carcinoma (BCC)

Surgical

Management of BCCs may vary according to type, size and site. Surgical excision, cryotherapy, photodynamic therapy and topical fluorouracil may be used.^rr

Surveillance

There is no evidence to support annual skin examination, but this is recommended on the basis that early detection may maximise the opportunity of early treatment.^rrr

Risk reducing medications

There is some evidence that retinoids (isotretinoin and etretinate) prevent BCCs, however long term use is not practical due to side effects.^r Further studies are needed on photodynamic therapy as chemoprevention.^r

Prevention

Although frequent sun exposure may not be required for the development of BCCs in Gorlin syndrome, more BCCs are observed in sun exposed areas, suggesting UV exposure may exacerbate development of BCCs.^r Expert consensus is to minimise UV exposure by adopting sun protective behaviours. Vitamin D deficiency from reduced sun exposure can be ameliorated with supplementation. Untreated vitamin D deficiency is associated with several health problems.^r

There is evidence that radiation may induce BCCs and therapeutic and diagnostic radiation should be avoided where possible.^r

Medulloblastoma

The risk of medulloblastoma appears higher for SUFU pathogenic variant carriers though data is based on small numbers (less than 20 cases). Where it occurs, medulloblastoma usually develops by age 3 (90% of known cases).

Surveillance

There is concern about the risk of inducing skin cancers with the use of routine CT screening.^r For SUFU pathogenic variant carriers, expert opinion is to consider regular brain MRI from infancy until mid-childhood as early diagnosis may be associated with a higher probability of surgical cure.^r For PTCH1 pathogenic variant carriers, surveillance for medulloblastoma is not recommended based on the low frequency of tumours and the need for sedation for MRIs in children.^r

An alternative is to promptly investigate any symptoms or signs such as developmental delay, neurological signs or new onset of macrocephaly.^r

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Bibliography

Southwick, G. J. and R. A. Schwartz. 1979. "The basal cell nevus syndrome: disasters occurring among a series of 36 patients." Cancer 44(6):2294-2305.

Read abstract

We have reviewed a series of 36 patients with the basal cell nevus syndrome seen at Roswell Park Memorial Institute from 1950 to 1978. Among these patients a number of disastrous complications occurred. These include extensive uncontrolled basal cell epithelioma of the face resulting in one death from direct cerebral invasion via the orbit, one facial nerve palsy, two bilateral and two unilateral eye enucleations, and several severe facial mutilations in young patients. There were three patients who developed severe bradycardia and hypotension during induction of general anesthesia required postponement of the intended operation, and one patient with congenital hemiparesis who on investigation was found to have an absent internal carotid artery. A review of the syndrome complex is presented with a plan for recognition and management.

Version 10

Date	Summary of changes
15/09/2023	New eviQ cancer genetics risk management template changes applied - PDF of changes. Version number changed to V.10.

Version 9

Date

Summary of changes

13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template: Summary: Template sentence updated. Target population: Added to exclusion criteria "Individual with a variant of uncertain significance". Cancer/tumour risk management guidelines: Template sentence updated.  Lifestyle factors sentence moved above table. Management of associated health problems: Accordion title changed to "Management of associated health issues". Version number increased to V.9.

Version 8

Date

Summary of changes

22/04/2022

Document reviewed by cancer genetics reference committee out of session on MS Teams. Approved for publication with the following changes made: Summary: minor wording changes Target population: Bullet 1: added Bullet 2 and 3: Minor wording changes Cancer risk management guidelines: minor wording and formatting changes Management of associated health problems:  Jaw keratocysts, Cardiac fibromas, Ovarian fibromas and Prenatal detection of abnormalities: information moved up from evidence section Evidence for risk management guidelines: minor wording changes Version increased to V.8. Review in 2 years. Approved on 22/04/2022, published on 06/05/2022.

Version 7

Date	Summary of changes
20/12/2019	"Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.7.
18/12/2020	The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template: Related pages: added link to "Cancer predisposition genes: population carrier frequency" Summary: template sentence added Lifetime risk of cancer: heading changed to "Lifetime risk of cancer/tumour" Cancer risk management guidelines: Heading changed to "Cancer/tumour risk management guidelines" Sentence added above table "The choice of risk management strategy should take current age, other health issues and residual cancer risk into account"  Other table formatting changes Support and information: template wording updated.

Version 6

Date	Summary of changes
28/08/2019	Protocol title changed from 'Risk management for Gorlin syndrome/nevoid basal cell carcinoma syndrome' to 'PTCH1 or SUFU (Gorlin) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.

Version 5

Date

Summary of changes

18/04/2018

Protocol reviewed and presented at November 2017 RCM. Discussion continued via email and approved for publication with the following amendments:  inclusion of the SUFU gene  lifetime risk of cancer statistics updated cancer risk management guidelines revised to include both PTCH1 and SUFU mutations  non-cancer risk management guidelines updated  evidence updated  reference list updated  Version change to V.5.

Version 4

Date	Summary of changes
31/05/2017	Transferred to new eviQ website. Version number changed to V.4.

Version 3

Date	Summary of changes
28/09/2015	Discussed at October 2014 reference committee meeting and the following changes made: Definition - reference added and link to book chapter. Cancer risk management table - updated. Evidence for risk management guidelines - updated. References - updated. Version number increased to V.3
07/01/2016	Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed".
14/04/2016	Sentence added to risk management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up".

Version 2

Date	Summary of changes
05/09/2012	Discussed at national cancer genetics reference committee on April 19, 2012 and the following changes were made: Definition updated Target group - point 1 updated Risk management - guidelines updated Non-cancer risk management guidelines added Management of associated health problems and side effects - updated.     - Odontogenic keratocysts including age for commencement of specialist dental review added. Evidence for risk management guidelines information for screening for medulloblastoma added. Reference list updated Southwick et al moved to history tab. Version number increased to V.2.
07/04/2014	Frequency of review discussed at March 6, 2013 reference committee meeting and discussion continued via email: Review 2nd yearly.
31/07/2015	Link to AGSA changed to Genetic Alliance Australia.

Version 1

Date	Summary of changes
04/04/2011	Approved at cancer genetics reference committee on March 24, 2011 and published on eviQ as version 1.