Introduction

PTEN hamartoma tumour syndrome (PHTS) is a group of illnesses which give rise to benign tumours and, in some cases, also malignant tumours (cancer). The cause of PHTS is a gene mutation which can either be inherited from the biological parents or spontaneously occur before birth. This gene mutation makes it extremely likely for people to develop tumours. This is referred to as a cancer predisposition syndrome, and PHTS is one of them.¹

Cause of PTEN hamartoma tumour syndrome

The mutated gene causing PTEN hamartoma tumour syndrome (PHTS) is the PTEN gene, which stands for phosphate and tensin homologue deleted on chromosome ten.¹

The PTEN gene is known as a tumour suppressor gene. As with every gene, we normally have two versions (gene copies) of each tumour suppressor gene. One is inherited from our biological mother, and one from our biological father. 

Tumour suppressor genes give rise to tumour suppressor proteins, vital in preventing healthy body cells from turning into tumour cells. Tumour suppressor proteins strictly regulate when a cell is allowed to divide to prevent cells from dividing and multiplying more than they should. This is essential because the result of excessive cell division and multiplication can be a tumour.²

One working copy of a tumour suppressor gene (e.g. PTEN) is enough to create the corresponding tumour suppressor protein to perform its function. The other working copy of a tumour suppressor gene can be considered a back-up or fail-safe. The idea is that even if one of these tumour suppressor gene copies mutates and becomes compromised over a person’s lifetime, the other copy will still be there to get the job done. Of course, losing the function of both copies of the same tumour suppressor gene is possible, but that is far less likely than just losing one copy.² This is where cancer predisposition syndromes like PHTS come in.

Unfortunately, people with PHTS are already born with one dysfunctional PTEN gene copy. They got this dysfunctional PTEN gene copy in one of two ways: 

• They inherited this compromised PTEN gene from one of their biological parents. Since inheriting one dysfunctional PTEN gene copy is enough to cause PHTS, PHTS is classified as an autosomal-dominant disorder.^1,3
• A mutation impaired one of their PTEN gene copies while they were embryos. This is called a de novo mutation.^1,3

Either way, with only one functional PTEN gene left, they will likely lose that last remaining PTEN gene in various cells across the body. If a cell's last functional PTEN gene becomes impaired, the corresponding tumour suppressor protein is lost. As a consequence, the affected cell or cells are likely to start dividing and multiplying excessively, sometimes resulting in the formation of a tumour.² Therefore, people with PHTS are at increased risk of developing tumours, some of which can be malignant (cancer).¹

Disorders of PTEN hamartoma tumour syndrome

As mentioned before, PTEN hamartoma tumour syndrome (PHTS) is a collection of different diseases. They all share the same genetic cause: deactivation of one PTEN gene copy before birth.^1,4,5

Cowden syndrome

It is estimated that one in 200,000 people is affected by Cowden syndrome. Cowden syndrome does not tend to be diagnosed until adulthood and is characterised by the appearance of numerous hamartomas.¹ 

Hamartomas are a precursor to benign tumours. Hamartomas consist of the same cell types you would normally see in the tissues found in, but hamartomas are different from these normal tissues. In hamartomas, the ratios of the different cell types can be off, the cells might be strangely organised or less mature, or a combination of any of these characteristics. In that regard, hamartomas are indeed very similar to benign tumours. The only clear difference between them is that hamartomas limit their growth (they do not tend to grow too large), while benign tumours tend to keep growing for as long as they can.⁶ 

Aside from hamartomas, features of Cowden syndrome include:¹

• Trichilemommas (small benign tumours of the hair follicle)
• Papillomatous papules (small benign growths found on the fleshy surface of the mouth)
• Acral keratoses (small benign growths on the back of hands and feet)
• Plantar keratoses (small benign growths found on the palms of the hands and soles of the feet)
• Megalencephaly (unusually big and heavy brain)
• Macrocephaly (unusually large head)
• Dolichocephaly (having a long and narrow skull)
• Gastrointestinal polyps (hamartomas in the stomach and the bowels)
• Glycogenic acanthosis (benign growths on the oesophagus)
• Lhermitte-Duclos disease (another disorder which is part of PHTS, please see below)

People with Cowden syndrome also have a heightened risk of developing benign as well as malignant tumours (= cancer) of:¹ 

• The breast (the most common)
• The thyroid (the second most common)
• The endometrium

Additionally, skin cancer, kidney cancer and brain tumours are suspected to be linked to Cowden syndrome.¹

Lhermitte–Duclos disease (LDD)

Lhermitte–Duclos disease (LDD) or dysplastic cerebellar gangliocytoma is defined by a rare benign growth of the cerebellum. The cerebellum is a part of our brains mainly focussing on controlling movement and balance. The cerebellum's rare benign growth is considered somewhere between a hamartoma and a benign tumour.⁷ As seen above, there is a very strong connection between the occurrences of Cowden syndrome and LDD.¹  

Bannayan-Riley-Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital illness, which means it is already present before or during birth. Because of that, it tends to be diagnosed at a young age. BRRS is associated with:¹ 

• Macrocephaly (unusually big head)
• Intestinal polyps (hamartomas in the bowels)
• High weight at birth
• Lipomatosis^8,9 (benign tumours composed of fatty tissue)
• Hemangiomas (benign tumours of the small blood vessels of the skin)
• Scoliosis (abnormal side curvature of the spine)
• Proximal myopathy (muscle weakness)
• Pigmented macules (coloured skin lesions) of the penis
• Pectus excavatum (breast bone grows inward)
• Joint hypermobility (having unusually flexible joints)
• Delayed development
• Intellectual shortcomings

If you would like to know more about BRRS in particular, there is an article focussing entirely on BRRS. 

Proteus syndrome and Proteus-like syndrome

Proteus syndrome is often congenital, which means it is present at the time of birth or even before birth. Deformations characterise Proteus syndrome due to the overgrowth of different tissues. Examples of this tissue overgrowth are connective tissue nevi and epidermal nevi (hamartomas of the skin) and hyperostosis (excess growth of bony tissue). Despite being part of the PHTS spectrum, Proteus syndrome does not generally involve the development of benign tumours and cancer, but it can happen on occasion.¹

People are diagnosed with Proteus-like syndrome if they display the typical signs of Proteus syndrome but do not meet the diagnostic criteria of Proteus syndrome.¹ 

Autism spectrum disorders with macrocephaly

People born with only one functional PTEN gene sometimes have an autism spectrum disorder with macrocephaly. As the name suggests, they develop an autism spectrum disorder and have an unusually large head (macroencephaly).¹

Diagnosis of PTEN hamartoma tumour syndrome

The diagnosis of PHTS is a rather complicated affair. It takes a certain combination of major and sometimes minor criteria to establish a PHTS diagnosis. These criteria are signs and symptoms associated with PHTS.⁴ 

Detecting a PTEN gene copy mutation makes it slightly easier because it decreases the number of major and minor criteria needed for a PHTS diagnosis. Such a PTEN gene mutation is found by taking some blood and then using it to extract and test the genetic material for these mutations.¹⁰ Because a very small group of people show obvious signs of PHTS but do not have any detectable PTEN gene mutations, this genetic test is not always successful.¹ 

Even after finally establishing a PHTS diagnosis, it still needs to be determined which PHTS illness or combination of PHTS illnesses it is. Some of them are fairly straightforward to diagnose, such as autism spectrum disorder associated with macrocephaly, LDD and BRRS. In contrast, Cowden syndrome and Proteus syndrome each have a list of criteria that need to be found to diagnose them accurately.¹ 

Treatment of PTEN hamartoma tumour syndrome

Unfortunately, there is currently no way to fix the PTEN gene copy mutations causing PHTS. Therefore, treating PHTS involves dealing with the various conditions and symptoms if and when they arise.¹ 

Generally, hamartomas and benign tumours are monitored but left alone as long as they do not cause any problems. As soon as they do, they tend to be treated with chemotherapy and surgery.¹ 

In contrast, finding and subsequently treating malignant tumours as soon as possible is imperative. To that end, regular checkups involving techniques for medical imaging (e.g. ultrasound and MRI) are recommended. The cancer treatment will strongly depend on what kind of cancer is found.¹

Summary

PTEN hamartoma tumour syndrome (PHTS) is a group of illnesses which tend to drastically increase the likelihood of developing tumours and cancer. The mutation of the PTEN gene generally causes PHTS. A biological parent inherits this mutation or spontaneously occurs before birth. Part of the PHTS group are Crowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte–Duclos disease, Proteus syndrome, Proteus-like syndrome and autism spectrum disorders associated with macrocephaly. Each one of these PHTS diseases has its conditions and symptoms. PHTS diagnosis usually involves detecting the PTEN gene mutation and several conditions and symptoms associated with PHTS. Non-cancerous tumours are generally only treated when they start causing symptoms while any occurring cancers are treated as soon as they are found.   

FAQs

What Is PTEN hamartoma tumour syndrome?

PTEN hamartoma tumour syndrome (PHTS) is a set of illnesses which tend to drastically increase the probability of developing tumours and even cancer. A mutation in the PTEN gene usually causes them.

Is PTEN hamartoma tumour syndrome a rare disease?

Yes, PTEN hamartoma tumour syndrome (PHTS) is relatively rare. It is believed that one in 200,000 people is affected by Cowden syndrome, which is part of the PTEN hamartoma tumour syndrome. 

Is PTEN hamartoma tumour syndrome related to autism?

To a certain extent. Autism spectrum disorders with macrocephaly are considered part of the PTEN hamartoma tumour syndrome (PHTS) group. 

What are the signs and symptoms of PTEN hamartoma tumour syndrome?

PTEN hamartoma tumour syndrome (PHTS) is a diverse group of illnesses, so each one tends to have signs and symptoms. In general, many of them involve tumours and the development of an unusually large head (macrocephaly).