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
PTCH1 Mutation Carriers
- Annual dermatological examination starting at 10 years of age and every 2-3 months from the first BCC
- Regular ECGs during infancy and early childhood
- Dental examination with an X-ray of the jaw every 12-18 months, starting at age 8
- Ovarian ultrasound from 18 years of age
- Due to the low risk of medulloblastoma, no radiological screening unless there are neurological anomalies or if the head circumference increases
SUFU Mutation Carriers
- The same as with carriers of a PTCH1 mutation, but without performing an X-ray of the jaw
- Additional medulloblastoma screening: cranial MRI every 4 months until the age of 3 and then every 6 months until the age of 5
