Gorlin Syndrome – Definition
Gorlin syndrome (OMIM #109400) is a rare cancer predisposition syndrome caused by mutations in the PTCH1 or SUFU gene, which can, among other things, lead to early-onset basal cell carcinoma (BCC) and medulloblastoma along with cysts in the jaw or skeletal anomalies.
Synonyms:
Gorlin syndrome (OMIM #109400) is a rare cancer predisposition syndrome caused by mutations in the PTCH1 or SUFU gene, which can, among other things, lead to early-onset basal cell carcinoma (BCC) and medulloblastoma along with cysts in the jaw or skeletal anomalies.
Gene:
PTCH1 (Patched1) and SUFU (Suppressor of fused)
Gene products:
Protein patched homolog 1 (PTCH1) and suppressor of fused homolog (SUFU)
Function:
Part of the sonic hedgehog (SHH) signaling pathway
Patterns of inheritance:
Autosomal dominant
Prevalence:
1:30.000-1:57.000
Genotype-phenotype correlation:
The risk of developing medulloblastoma is much higher in combination with an SUFU mutation than with a PTCH1 mutation. In contrast, the incidence of basal cell carcinomas is lower in SUFU mutation carriers than in PTCH1 mutation carriers. Odontogenic keratocysts have also predominantly been described in PTCH1 mutation carriers.
Penetrance:
Nearly 100% (in relation to the syndrome as opposed to development of the neoplasia)
Gorlin Syndrome – Diagnosis
The diagnosis is confirmed if the following criteria are satisfied:
- 2 major criteria and 1 minor criterion or 1 major criterion and 3 minor criteria
- Evidence of a heterozygous germline mutation in the PTCH1 or SUFU gene
Order of genetic testing recommended:- PTCH1 sequence analysis
- PTCH1 deletion/duplication analysis
- SUFU sequence analysis
- SUFU deletion/duplication analysis
- PTCH1 RNA analysis
Major Criteria
- Multiple basal cell carcinomas (> 5) or one basal cell carcinoma before the age of 30
- First-degree relative with BCC
- Lamellar calcification of the cerebral falx before the age of 20
- Odontogenic keratocysts
- Palmar/plantar keratosis (two or more)
Minor Criteria
- Childhood medulloblastoma
- Lymphoma-mesenteric or pleural cysts
- Macrocephaly (head circumference > 97th percentile)
- Cleft lip/palate
- Vertebral/rib abnormalities
- Pre- and postaxial polydactyly
- Ovarian or cardiac fibroma
- Ocular abnormality (cataract, developmental defects, retinal pigment changes)
The following X-ray diagnostics are generally required to confirm the diagnosis:
- Cranial X-ray, AP, and lateral
- Orthopantomogram
- Thoracic X-ray
- Spinal X-ray
Blood relatives of an individual with a confirmed PTCH1 or SUFU mutation should undergo genetic testing for a PTCH1 and/or SUFU mutation as soon as possible, specifically in light of the early occurrence of medulloblastoma.
In pediatric oncology, particularly in patients with SHH-activated medulloblastoma, it is essential to rule out Gorlin syndrome – even if no other syndrome features are present.
Differential Diagnoses
| Macrocephaly | Sotos syndrome, Beckwith-Wiedemann syndrome, isolated hydrocephalus, isolated megalencephaly |
| Basal cell carcinoma | Brooke-Spiegler syndrome, Basex syndrome, Rombo syndrome |
| Medulloblastoma | 9q22.3 microdeletion syndrome |
Clinical Presentation
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Clinical manifestation |
Earliest occurrence |
| Macrocephaly (head circumference > 97th percentile) | from birth |
Congenital malformations
|
from birth |
| Gross motor development delay | from birth |
| Facial anomalies (balcony forehead, coarse facial features, milia) | from birth |
| Skeletal anomalies (e.g. fork ribs, wedge vertebrae) | from birth |
| Medulloblastoma | 1-2 years |
| Calcification of the falx cerebri | mostly from the age of 20 |
| Odontogenic keratocysts (mostly mandibular) | From the age of 10; (4 years), rarely after the age of 30 |
| Basal cell carcinomas (mostly face, back, neck) | from the age of 20; (2 years) |
| Palmo-plantar keratoses | from the age of 20 |
| Other skin manifestations: Chalazion, atheroma, dermoid cyst | |
Other tumors
|
tumor-dependent:
from birth |
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Special Features of Treatment
The use of radiotherapy leads to a massively increased risk of developing basal cell carcinomas and should, therefore, only be used if no alternative therapy is available. Irradiated skin areas should then be as small as possible.
In addition, X-ray diagnostics should be used sparingly.
Patients with Gorlin syndrome should avoid direct sunlight as much as possible.
Diagnosis of Gorlin Syndrome- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Gorlin Syndrome - What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Below you will find the recommendations according to the AACR 2024 Guidelines.
In general
- Good sun protection and avoidance of ionising radiation
PTCH1 Mutation Carriers
- Annual dermatological examination starting at 10 years of age, earlier after radiotherapy or suspicious findings
- Basic ECG in infancy, ideally <6 months, if unremarkable no further regular ECGs necessary
- Dental examination from 2 years of age, from 8 years of age digital x-ray of the jaw (OPG orthopanthogram) every 12 months, replace with MRI where possible
- Neurological examination, measurement of head circumference every 3-4 months from diagnosis until 5 years
- Ovarian sonography once at age 18, repeated if pregnant or with symptoms
- Meningioma screening only after prior radiotherapy: cranial MRI every 3-5 years from age 30
SUFU Mutation Carriers
- Annual dermatological examination starting at 10 years of age, earlier after radiotherapy or suspicious findings
- Basic ECG in infancy, ideally <6 months, if unremarkable no further regular ECGs necessary
- Ovarian ultrasound every 3 years from 5 years of age, repeated if pregnant or with symptoms
- Medulloblastoma screening: Skull MRI every 3-4 months from diagnosis until 3 years of age, then every 6 months until 5 years of age
- Meningioma screening: Cranial MRI every 3-5 years from the age of 30
