Overview

Gorlin syndrome, a rare genetic condition, often manifests with basal cell carcinoma (BCC), a type of skin cancer. Additionally, individuals with Gorlin syndrome may face various other medical conditions. 

Gorlin syndrome, or nevoid basal cell carcinoma syndrome (NBCCS), is a rare inherited disease. Roughly 80% of individuals with this condition will develop multiple basal cell skin cancers in adolescence or early adulthood. They also face a risk of developing a form of brain cancer called medulloblastoma, as well as other types of cancer. About 70-80% of those affected inherit a genetic mutation from a parent, while others have a random (de novo) gene mutation. The syndrome impacts all genders equally and can lead to a variety of different medical conditions.^1,2  Although there’s no cure for Gorlin syndrome, most individuals can expect an average lifespan with proper treatment.

The article provides an overview of the symptoms, causes and management of Gorlin syndrome.

What is gorlin syndrome?

Gorlin syndrome, also called nevoid basal cell carcinoma or Gorlin-Goltz syndrome, is a rare autosomal dominant genetic condition. People with this condition are susceptible to developing both benign and malignant tumours.

Around  80% of those affected develop multiple basal cell cancers of the skin, most frequently on the face, back, and neck. Cancers generally begin to develop from a young age, usually during puberty, though occasionally starting earlier in childhood.

Gorlin syndrome occurs in about one in 1/31,000 in the United States of America, 1/164,000 in Australia and the United Kingdom, 1/256,000 in Italy and 1/235,800 in Japan.³

The most common symptoms include:

• Occurrence of several basal cell carcinomas before turning 20
• Cysts on the jaw – keratocystic odontogenic tumours (KOTs) that usually emerge during the teenage years
• Pits or small indentations on the palms and soles of the feet

 Those affected can also have different medical conditions:

• Rib, skull or vertebral abnormalities
• Calcification of the falx cerebri (visible on X-rays)
• Benign (non-cancerous) ovarian tumours
• Benign tumours of the heart (cardiac fibromas)
• Increased risk of medulloblastoma during childhood
• Distinct facial features
• Large head (macrocephaly)
• Large forehead (frontal bossing)
• Eye problems like strabismus, cataracts or small eyes (microphthalmia)
• Wide-set distance between the eyes (hypertelorism)
• Cleft lip or palate
• White skin bumps or cysts (facial milia)
• Developmental abnormalities¹ 

Risk of developing medulloblastoma     

Approximately 5% of people with Gorlin syndrome develop medulloblastoma. Medulloblastoma is the most common type of brain tumour that usually affects children between the ages of 2 and 5, which is significantly younger than in patients with sporadic medulloblastoma.²  

It begins in or near a part of the brain called the cerebellum. Only a small percentage of children with medulloblastoma also have Gorlin syndrome. Although people with Gorlin syndrome have an increased risk of developing medulloblastoma, this risk is considered small. Children with medulloblastoma and Gorlin syndrome would receive the same treatment as other children with medulloblastoma.

Causes

What causes gorlin syndrome?

The genes associated with Gorlin Syndrome are PTCH1, PTCH2, and SUFU. Gorlin syndrome occurs due to a mutation in one of these three tumour suppressor genes. Tumour suppressor genes protect cells from becoming cancerous.³ 

Among these, mutations in the PTCH1 gene, which acts as a key regulator of the hedgehog signalling pathway critical for controlling cell growth and division, have been identified as the primary cause of Gorlin syndrome.

Each person has two copies of each tumour suppressor gene, one inherited from their mother and one from their father. Both gene copies must be mutated for cancer to occur. In Gorlin syndrome, the initial genetic alteration usually originates from either parent in 70-80% of cases. 

In 20-30% of cases, the first mutation is not inherited but arises for the first time (de novo) in the affected individual. The development of cancer in a person with a germline mutation, as well as its specific location, depends on the cell type where the second mutation occurs. For instance, if the second mutation occurs in skin cells, it may result in skin cancer.

Diagnosis and tests

How is gorlin syndrome diagnosed?

Gorlin syndrome is diagnosed through genetic tests that identify specific mutations as well as imaging tests such as MRI and ultrasounds.

Because exposure to X-rays involves small doses of radiation, which can elevate the risk of basal cell carcinoma in individuals affected by the condition, doctors may opt not to recommend them.

Management and treatment

How is gorlin syndrome treated?

Treatment for basal cell skin cancers

Those with Gorlin syndrome require regular skin monitoring by a dermatologist every 6-12 months. However, if there are any changes between appointments, individuals with Gorlin syndrome should inform their doctor.

Basal cell skin cancers usually develop slowly and rarely metastasise. Surgery is the primary treatment for basal cell skin cancer, though additional treatments may be required in some cases.

Surgery

A tumour or jaw cyst may be surgically removed. For a small basal cell carcinoma, the affected area is surgically excised along with a small border of healthy tissue. For larger skin cancers, a wider area of skin is excised, and sometimes a skin graft may be necessary. Mohs surgery is commonly used to remove damaged skin tissue in layers.

Other treatments may include:

• Imiquimod cream
• Applying chemotherapy cream such as fluorouracil (5-FU) to the skin (topical chemotherapy)
• Photodynamic therapy
• Freezing of skin lesions (cryosurgery)

People with Gorlin syndrome undergo treatment similar to others with skin cancer, generally yielding effective results. However, they are very sensitive to radiation, and radiotherapy can elevate the risk of skin cancers in the treated area. Doctors generally advise against using radiotherapy.

Individuals with Gorlin syndrome have a higher risk of developing skin cancer. Like everyone, the risk of skin cancer can be reduced by limiting sun exposure and using a combination of shade, ultraviolet (UV) protecting clothing and sunscreen.

What is the prognosis for individuals with gorlin syndrome?

There is currently no treatment to cure Gorlin syndrome; however, many of the associated conditions are manageable. By following a healthcare provider’s recommendations, individuals affected by the syndrome can live well.

Summary

Gorlin syndrome is a rare genetic condition. About 80% of individuals with this syndrome will develop multiple basal cell carcinomas in adolescence or early adulthood, along with a risk of medulloblastoma and other cancers. 

The syndrome arises from genetic alterations in one of three genes: PTCH1, PTCH2, or SUFU. Around 70-80% of those affected inherit a mutation from a parent, while others have a random gene mutation (de novo). It affects both men and women equally. 

People with Gorlin syndrome may experience various medical issues. Tumours or jaw cysts can be surgically removed, and for small basal cell carcinomas, the tumour and some healthy tissue are excised. Larger cancers may require more extensive removal and skin grafts. Mohs surgery is commonly used to remove damaged skin in layers. Other treatment options include topical chemotherapy, photodynamic therapy, and cryosurgery. While there is no cure for Gorlin syndrome, most individuals who follow their doctors' recommendations can expect an average lifespan.