What is PTEN hamartoma tumour syndrome?

The PTEN hamartoma tumour syndrome includes several diseases that are based on mutations with the PTEN gene. The diseases are on the one hand the Cowden syndrome (CS) and on the other hand the Bannayan-Riley-Ruvalcaba syndrome (BBRS). PTEN-associated Proteus syndrome(PS) and Proteus-like syndrome are also usually included. The PTEN hamartoma tumour syndrome is characterised by gastrointestinal polyposis, macrocephaly, mental retardation/autism spectrum disorder and vascular malformations. There is also a susceptibility to a variety of malignant carcinomas such as endometrial carcinomas, breast carcinomas, colorectal carcinomas, melanomas, thyroid carcinomas and renal cell carcinomas.

How does PTEN hamartoma tumour syndrome develop?

The PTEN hamartoma tumour syndrome is caused by genetic changes, i.e. mutations of the PTEN gene. The gene codes for the PTEN protein. This is involved in the transmission of signals between cells in the body. In certain cells, the activation of the PTEN protein specifically induces cell death and thus controls the proliferation of the cells in the body. Therefore, the PTEN protein is one of the tumour suppressors. However, if the PTEN gene is present in an altered form , the PTEN protein can no longer function properly as a tumour suppressor . For this reason, uncontrolled proliferation of cells now occurs, leading to the development of tumours and many other diseases. PTEN hamartoma tumour syndrome can certainly be passed on from parents to their children. The mode of inheritance is autosomal-dominant. It is also possible that a genetic change in the PTEN gene occurs as a new mutation or spontaneous mutation. This is then called a de novo mutation.

What are the symptoms of PTEN hamartoma tumour syndrome?

The PTEN hamartoma tumour syndrome occurs in about 1:200,000 cases and is a very complex multi-system disease. In the normal case, the patients only show some of the symptoms that are possible. This is because also reflects the great variability in the subtypes of PTEN Hamartoma Tumour Syndrome.

How is PETN hamartoma tumour syndrome diagnosed?

The diagnosis of PTEN hamartoma tumour syndrome is made at through the detection of a heterozygous germline mutation of the PTEN gene. This germline mutation is confirmed with the help of a sequence analysis or a duplication analysis. It can also be useful to use panel examinations in which several genes are recorded.

The National Comprehensive Cancer Network gives the following diagnostic criteria for the presence of Cowden syndrome:

• Lhermitte-Duclos tumours,
• Mucocutaneous lesions,
• Facial trichilemmomas (benign tumours of the hair root sheaths),
• Acral keratosis,
• Papillomatous lesions,
• Mucosal lesions.

 
Main criteria for the diagnosis of Cowden's syndrome

• Breast carcinoma,
• Epithelial thyroid carcinoma,
• Enlarged head circumference, greater than 97th percentile,
• Endometrial carcinoma.

 
Secondary criteria for the diagnosis of Cowden syndrome

• Thyroid lesions such as goiter multinodosa, adenoma,
• Mental retardation with an IQ equal to or less than 75,
• Hamartomatous intestinal polyps,
• Fibrocystic mastopathy,
• Lipomas,
• Fibromas,
• Urogenital tumours, especially renal cell carcinoma,
• Urogenital malformations,
• Uterine fibroids.

How is Bannayan-Riley-Ruvalcaba syndrome diagnosed?

Up to the present day, there are still no uniform criteria for the diagnosis of Bannayan-Riley-Ruvalcaba syndrome. However, the following findings raise suspicion of the presence of Bannayan-Riley-Ruvalcaba syndrome:

• Macrocephaly.
• Hamartomatous intestinal polyposis,
• Lipomas,
• Pigmented macules of the glans penis.

How is PTEN Hamartoma Tumour Syndrome treated?

In the context of a PTEN hamartoma tumour syndrome present benign or malignant tumour, the therapy does not differ from the corresponding therapy of a sporadically occurring tumour.

Since in Cowden syndrome there is often a manifestation on the skin and mucous membranes which are not life-threatening, the following treatment is recommended:

• if there is an asymptomatic manifestation, observation at regular intervals is quite sufficient,
• if a malignant tumour is suspected, it should be removed promptly,
• if there is a symptomatic manifestation at , it should be treated with locally acting drugs, laser therapy or surgery .

What measures can be taken for the early detection of PTEN hamartoma tumour syndrome?

For children and adolescents under 18 years of age

• an annual examination from the time of diagnosis,
• from the 8th year of age, an annual ultrasound of the thyroid gland; if a baseline examination is unremarkable, the interval can be changed to every 2 years ,
• Otherwise, no special examinations are recommended for early detection in childhood, with doctors deciding according to clinical discretion.

 
For adults:

• an annual ultrasound of the thyroid gland from the age of majority,
• an annual skin examination from the age of 30,
• A colonoscopy from the age of 35-40. Here, the frequency depends on the tissue structure and the number of polyps found,
• an ultrasound of the kidneys from the age of 40.

 
For women, additionally from the age of 30:

• a monthly breast self-examination
• an annual breast cancer screening,
• an annual MRI of the breast,
• from the age of 40, a mammography,
• Prophylactic mastectomy if a pathogenic BRCA1/BRCA2 germline variant is present.

What measures can be taken for the early detection of Cowden syndrome?

From the time of diagnosis

• an annual physical examination, mainly of the skin,
• an annual ultrasound of the thyroid gland.

 
From the age of 18, the following also applies to female patients:

• a monthly self-palping of the breast,
• from the age of 25, an annual breast examination by a gynaecologist.

 
From the age of 30 additionally for female patients applies:

• an annual MRI examination of the breast and an annual mammography,
• with regard to endometrial cancer, an annual screening examination by a gynaecologist.

 
From the age of 35 to 40, the following also applies to all patients

• a colonoscopy at least every 10 years,
• an ultrasound examination or an MRI scan of the kidneys every two years.

What measures can be taken for the early detection of Bannayan-Riley-Ruvalcaba syndrome?

There are currently no guidelines for Bannayan-Riley-Ruvalcaba syndrome, regarding early detection, so it is advised to follow the same regime as for Cowden syndrome. Nevertheless, special attention should be paid to polyps in the gastrointestinal tract .