Course:MEDG550/Student Activities/Gorlin Syndrome

Gorlin Syndrome

Overview

Gorlin Syndrome (Gorlin-Goltz Syndrome, Nevoid Basal Cell Carcinoma Syndrome, Basal Cell Nevus Syndrome) is a genetic condition that can affect the head, face, eyes, and bones. An individual with Gorlin syndrome is also more likely than the average person to develop growths like tumours and specific kinds of cancers.

Clinical Features

There are a variety of different physical features and symptoms that can be associated with Gorlin syndrome. Gorlin syndrome is variable which means that one individual diagnosed with Gorlin syndrome might have different features than another individual with Gorlin syndrome. Not every individual with Gorlin syndrome will have all of the features listed below but they will have at least some of these features.

An adult male diagnosed with Gorlin Syndrome who has some of the classic features of the face.

Features of the Head and Face:

• Very large head (macrocephaly)
• Hole in the roof of the mouth and/or split in the upper lip at birth (cleft palate and/or lip)
• Eyes placed far apart on the face (hypertelorism)
• Forehead sticks out or is prominent (frontal bossing)
• Larger and rounded features such as big, bushy eyebrows; wide nose; and thick lips (coarse facial features)
• Small, hard, white bumps on the face in early childhood (facial milia)

Findings in the Eyes:

• Eyes don't look in the same direction at the same time (strabismus)
• Eyes move like they're shaking a little which can't be controlled (nystagmus)
• Part of the eye becomes cloudy and affects the ability to see properly (cataract)
• Hole or gap in one part of the eye (coloboma)

Features of the Bones and Skeleton:

• Differences in the structure of the ribs or spine such as one rib splits into two (bifid ribs)
• Shoulders slope downwards
• Salts made out of calcium build up in the bones or soft tissues (ectopic calcification)
• Extra fingers (polydactyly)

Multiple skin cancers (basal cell carcinomas) on a child with Gorlin Syndrome. A scar from surgery to treat brain cancer (medulloblastoma) can also be seen.

Features of the Hands and Feet:

• Small pits in the skin of the hands and/or feet (palmar/plantar pits)

Tumours, Growths and Cancers:

• Skin cancer that looks like a small, red spot mainly on the face and neck (basal cell carcinoma)
• Growth or cyst in the jaw mainly occurring in the teenage years (jaw keratocyst)
• Cancer tumour in the jaw (ameloblastoma)
• Brain cancer in the lower, back part of the brain called the cerebellum which occurs mainly in young children (medulloblastoma)
• Brain tumour in the outer part of the brain near the skull bone (meningioma)
• Growth or tumour in the heart which is usually present at birth or soon after birth (cardiac fibroma)
• Growth or tumour in the ovaries also known as the reproductive organs of individuals assigned female at birth (gonadal tumour)
• Cysts in the lymph nodes (part of the immune system) located in the belly (lymphomesenteric cysts)

It has been suggested in the past that individuals with Gorlin syndrome might have a shorter lifespan than the average lifespan of a human due to the extra risk of developing cancer, but this has not been confirmed to be true.

Genetics

Gorlin syndrome is a genetic condition. Genes are like the instruction manuals for our bodies, everybody has genes that are passed on in the form of DNA. If you think of DNA like a book, genes are like the chapters of the book and each chapter is an instruction. Genes tell our bodies what to do and how to function. We use a 26-letter alphabet to read a book and our body uses a 4-letter alphabet to read our gene instructions. Sometimes, there are spelling mistakes in our genes. Everybody has small spelling mistakes in their genes, those differences contribute to making us all unique. These spelling mistakes or variations in our genes are usually harmless, our body can read right through the variation. However, some variations are significant enough that our body doesn't understand what to do with the gene or isn't able to read the instruction at all. In those cases, that's when genetic conditions can occur. Specifically, Gorlin syndrome is caused by variations in a gene called the PTCH1 gene or variations in a gene called the SUFU gene. Variations in the spelling of these genes can stop the PTCH1 gene or the SUFU gene from working like they typically should.

Inheritance:

Autosomal Dominant Inheritance

The way Gorlin syndrome is inherited is in what's called an autosomal dominant pattern.

Individuals will typically have two copies of every gene. You inherit one copy of every gene from your biological mother and the other copy of every gene from your biological father. Therefore, a child typically gets half of their DNA from their biological mother, and the other half from their biological father. For an autosomal dominant genetic condition, only one out of the two copies of a gene will have a variation which will cause symptoms of the condition. Basically, one copy of the gene is not working as it typically would, and the other copy can't do the job alone. Therefore, an individual with Gorlin syndrome will have a variation in one copy of their PTCH1 gene or a variation in one copy of their SUFU gene. The presentation of the condition can vary from person-to-person but almost everyone who is found to have a significant variation in the PTCH1 or SUFU genes will show some symptoms of the condition. Gorlin syndrome is more likely to be caused by variations in the PTCH1 gene rather than variations in the SUFU gene.

The PTCH1 Gene:

The PTCH1 gene is also known as the Patched1 gene. This gene plays an important role as our bodies grow and develop. Due to the role of PTCH1 in the body, this gene falls into the category of what is called a tumour suppressor gene. It's called a tumour suppressor gene because it helps to stop the cells in our bodies from growing and multiplying more than they should. Too much growth and multiplication of cells is what leads to the development of tumours. The connection between the PTCH1 gene and controlling the growth of cells is why Gorlin syndrome is associated with growths, tumours, and cancers in the body. When the PTCH1 gene has variations that prevent it from working as it typically would to balance growth and suppress tumours, individuals have an increased risk to develop cancer tumours.

Model for Inherited Cancer Risk

Someone with Gorlin syndrome who is born with a variation in one copy of the PTCH1 gene is more likely to have a variation introduced into their other copy of PTCH1 just by chance. This introduction of variation occurs often in our genes, but usually these random variation events are fixed before they cause changes. Although, if someone already has a variation present in all their cells at birth, and then they get another variation randomly, this makes it harder for the cell to fix leading to extra growth and cancer development. This extra risk for developing cancer is known as a hereditary risk for cancer (see image) because you can inherit the risk from a biological parent and you only need one more random variation to develop cancer. The average person will need two random variations in the same gene (called somatic mutations in the image) to develop cancer.

The differences in the head, face, eyes, and bones of an individual with Gorlin syndrome are due to differences in the balance of growth caused by PTCH1 variations affecting their early development as a baby in their mother's belly. Individuals with a variant in PTCH1 are more likely to have differences to their facial features than those with variations in SUFU. They are also more likely to develop jaw cysts, and more likely to have differences in their bone structure. However, individuals with Gorlin syndrome due to PTCH1 variations are less likely to have brain cancer in the back of the brain during childhood (medulloblastoma).

The SUFU Gene:

The SUFU gene stands for the SUppressor of FUsed gene. This gene is very similar to the PTCH1 gene and works with that gene to keep the balance as our bodies grow and develop. You can see details in the first and second paragraphs above for the role of the PTCH1 gene which also apply to the SUFU gene. Individuals with a variation in the SUFU gene are more likely to develop brain cancer (medulloblastoma or meningioma) than those with a PTCH1 variation, but usually they have less of the other symptoms like jaw cysts and differences in the face and bones.

Recurrence:

Since Gorlin syndrome is an autosomal dominant condition, an individual with Gorlin syndrome has a 50% chance (or 1/2 chance) of passing on the condition to every biological child that they have. As touched on above, individuals who have Gorlin syndrome have a variation in one copy of either their PTCH1 gene or their SUFU gene and one typical copy of the gene. Biological parents typically pass on half of their genetic information to their children which means they will either pass on one copy of all their genes, or the other copy of all their genes. An individual with Gorlin syndrome will either pass on their variant copy of PTCH1 or SUFU, or they will pass on their typical copy of the gene. There is no way to predict or influence which one of the two copies will get passed on to children, it is always a 50/50 chance with each new pregnancy.

Not all individuals who have Gorlin syndrome will have gotten the condition from a biological parent. Only 70-80% of Gorlin syndrome cases occur because a variation in the PTCH1 gene or SUFU gene was passed on to a child from a biological parent. In 20-30% of Gorlin syndrome cases, the variation in PTCH1 gene or SUFU gene occurred for the first time in that individual and was not given to them from a parent. This occurs by random chance and is due to a mistake as the DNA from both biological parents is passed on to their child.

Prevalence:

Gorlin syndrome is considered to be a rare genetic condition. It's thought that somewhere between one in every 19,000 (1/19,000) to one in every 30,000 (1/30,000) individuals will be diagnosed with Gorlin syndrome.

Diagnosis

At the time this was written, there are no standard guidelines on the exact criteria that need to be met to diagnose Gorlin syndrome. Some suggest that in order to receive a confirmed diagnosis of Gorlin syndrome, an individual has to have a certain number of features associated with the condition. These features are outlined below and it's suggested that an individual must have two major features or one major feature plus two minor features to receive the Gorlin syndrome diagnosis.

Major Features:

• Multiple skin cancers (specifically basal cell carcinomas) in patients less than 20 years of age or many basal cell carcinomas over a lifetime
• A cyst in the jaw (jaw keratocyst)
• Multiple pits in the hands and/or feet (palmar/plantar pits)
• Salts made out of calcium built up in the middle part of the brain called the falx (lamellar falx calcification)
• A very closely related biological relative like a parent or sibling diagnosed with Gorlin syndrome

Minor Features:

• Brain cancer in the lower, back part of the brain called the cerebellum that occurs mainly in young children (medulloblastoma)*
• Cysts in the lymph nodes (part of the immune system) located in the belly (lymphomesenteric cysts)
• A difference in the structure of the skeleton, mainly in the ribs
• Very large head (macrocephaly)
• Hole in the roof of the mouth and/or split in the upper lip at birth (cleft palate and/or lip)
• Extra fingers (polydactyly)
• Growth or tumour in the heart and/or in the ovaries (cardiac and/or ovarian fibroma)
• Differences in the eyes (strabismus, nystagmus, cataract, or coloboma)

*Please note it has not been decided if a medulloblastoma should be considered and major or minor feature.

A diagnosis can also be made using a combination of the physical features and symptoms above as well as genetic testing that looks for significant variations in the PTCH1 gene or SUFU gene of the individual thought to have Gorlin syndrome.

Methods of Investigation and Diagnosis:

Genetic testing can typically be done on a sample of blood or saliva from the individual being tested. In order to asses the differences in the bone structure that can be associated with Gorlin syndrome, X-rays of the chest and head can be done. As for the cysts in the jaw, that feature can be assessed using a specific X-ray of the jaw which gives a wider view which is called an orthopantogram. This is a common type of X-ray that dentists use.

Management and Treatment

The recommended management for individuals with Gorlin syndrome mainly involves regular checks for the development of cancers or problematic growths.

Skin Care:

Due to the increased risks of developing skin cancer (basal cell carcinoma) for individuals with Gorlin syndrome, it is recommended that they have an appointment with a skin doctor (dermatologist) at least every year. These appointments with a dermatologist may be as frequent as every 3-4 months. It is also recommended for individuals with Gorlin syndrome to protect themselves from the sun as much as possible since the harmful sun rays can increase the risk of developing skin cancer even more. When skin cancers do occur, individuals with Gorlin syndrome would be treated similarly to how anyone with skin cancer could be treated such as surgical removal of the cancer, laser treatments, and special light therapy treatments.

Jaw and Dental Care:

To assess for potential cysts in the jaw (jaw keratocysts), it's recommended that an dental X-ray (orthopantogram) is done every year starting at the age of 8 years old. To treat these cysts, they typically need to be removed through surgery.

Monitoring Tumours and Growths:

Heart

Tumours and other growths in the heart can be found and monitored by imaging the heart using a method called an echocardiogram. An echocardiogram is a method of taking pictures of the heart. This is most often done during the first year of life for babies diagnosed with Gorlin syndrome as recommended by a children's heart specialist doctor (pediatric cardiologist).

Ovaries

The presence of tumours on the ovaries or reproductive organs of individuals with Gorlin syndrome who are assigned female at birth can be found and monitored by taking pictures of these organs in the lower belly by ultrasound. An ultrasound is a method of taking pictures of internal organs. It's recommended that this is done for individuals with Gorlin syndrome who are assigned female at birth when they turn 18 years old. Treatment for ovarian tumours might include surgically removing them as well as removing all or part of the ovary depending on how large the tumour is.

Brain

Monitoring an individual with Gorlin syndrome for brain cancers is recommended mainly for those who have Gorlin syndrome due to a variation in their SUFU gene. However, it's recommended that any child diagnosed with Gorlin syndrome should be checked for changes in their development every 6 months starting at birth until they are 5 years old. These checks can help identify when they might be showing signs of brain cancer. As for individuals who specifically have a SUFU gene variant, it's recommended that they have imaging of their brain done by a scan called an MRI which will take pictures of the brain. These MRIs should start every 3-4 months from birth until the child is 4 years old, then every 6 months until they are 5 years old, and then once per year until they are 8 years old. If a child with Gorlin syndrome does develop brain cancer specifically in the back of the brain (medulloblastoma), they will be treated as per the recommendations of a children's brain specialist doctor (pediatric neurologist) as well as a children's cancer specialist doctor (pediatric oncologist). Those specialized doctors may also recommend more frequent imaging of the brain to be done if a child does develop brain cancer in early childhood. Again for those with a SUFU gene variant, imaging of the brain done by an MRI is recommended to start again every 3-5 years when they turn 30 years old.

Other Care:

There are no specific recommendations for the management and treatment of the other findings of the face, eyes, and bones that may or may not be present in individuals with Gorlin syndrome. These features may require no treatments, or may be treated and managed through surgery or therapy. Doctors specializing in the eyes (ophthalmologist); ears, nose and throat (ENT), and bones (orthopedist) would be responsible for the management and treatment of these features.

Patient Resources

Gorlin Syndrome Alliance: Provides more information on Gorlin syndrome including current research in the field what it's like to live with Gorlin syndrome. There are also opportunities for support and to connect with others affected by the condition. https://gorlinsyndrome.org/

Gorlin Syndrome Group: Based in the UK, provides guidance and support to individuals and families affected by Gorlin syndrome. This organization has opportunities for support and connection to others impacted by Gorlin syndrome. https://gorlingroup.org/