Cowden syndrome and PTEN hamartoma tumour syndrome: genetics and cancer surveillance

Cowden syndrome is a genetic condition in which the body develops multiple hamartomas, which are benign, tissue-like overgrowths, and has a higher chance of some cancers. It is now usually described as part of PTEN hamartoma tumour syndrome (PHTS), the name used by clinicians for all of the conditions caused by changes in the PTEN gene.

The NHS Genomics Education Programme says PTEN syndrome is characterised by multiple hamartomas and a high chance of developing benign and malignant tumours of the thyroid, breast, endometrium and kidney. Affected individuals usually have macrocephaly and specific skin features, and may have neurodevelopmental delay.

Not everyone with a PTEN change is affected in the same way. The programme explains that the features are very variable, and that is why diagnosis can arrive by many routes.

The programme lists the main features. These include a large head circumference, characteristic skin and mucous membrane changes such as facial trichilemmomas, acral keratoses and cobblestone-like papillomatous lesions, as well as lipomas, vascular malformations and a pigmented macule on the glans penis.

Tumours of the thyroid, breast, endometrium and kidney are described, with most cancers presenting in adulthood although thyroid cancer has been reported in childhood. Mixed bowel polyps can occur, and developmental delay, particularly motor, and autism spectrum disorders are over-represented. Adult-onset Lhermitte-Duclos disease, a growth in the cerebellum, is characteristic of PTEN-related conditions.

Many of these are individually common in the general population, which is why the combination, rather than any one feature, prompts a genetic test.

PTEN stands for phosphatase and tensin homolog. The programme describes it as a tumour suppressor gene on the long arm of chromosome 10, which restrains a signalling pathway responsible for cell growth and survival and also functions to repair errors in DNA. Deletions and nonsense, missense and splicing variants can all cause the syndrome.

The condition is autosomal dominant. Someone with a PTEN variant has one working copy and one changed copy, and the chance of passing the changed copy to a child is 1 in 2, or 50 per cent. The programme notes that incomplete penetrance occurs, meaning not everyone who has the variant develops the disease.

While over half of cases are caused by new variants, 10 to 50 per cent of affected individuals inherited the variant from a parent. When neither parent is found to carry the variant seen in an affected child, the chance of recurrence in future pregnancies is less than 1 per cent. The exception is PTEN-related Proteus syndrome, which almost always arises newly.

The programme says that because of the broad spectrum of features, PTEN syndrome may be diagnosed in many different ways. Some features are highly suggestive, leading directly to testing of the PTEN gene. Others, such as breast cancer, are much less specific, so broader genomic testing for a presentation such as familial breast cancer may reveal a diagnosis that comes as a relative surprise to clinicians and patients.

The programme points clinicians to the NHS Genomic Medicine Service panels and the National Genomic Test Directory for NHS genetic testing. Because inheritance is dominant and presentation is variable, first-degree relatives are considered carefully, and predictive testing can be discussed with them once the family variant is known.

A result can alter care for other family members as well as the person tested, so genetic counselling is part of the process.

The programme describes management as based on early detection and prevention of associated cancers, principally from adulthood, with approaches for children published by several authors.

A cancer surveillance guideline for PHTS, written by a group of clinicians in genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and surgery together with affected individuals, and hosted by the University of Cambridge repository, sets out firm recommendations for surveillance of breast, thyroid and renal cancers and more limited recommendations for endometrial, colon and skin. It stresses that there is no international consensus, that current guidelines are based on expert opinion and that the evidence base is limited.

The guideline also says the recommendations require a coordinated multidisciplinary approach and significant commitment from patients, so surveillance is usually organised through a specialist genetics service with local clinics. The details of when to start and how often to be checked are best taken from the person's own genetics team.

The programme lists a UK and Ireland PTEN patient group among resources for patients. A GP should be told about the diagnosis so that new symptoms, such as a lump in the neck or breast, unusual bleeding or persistent bowel changes, are assessed promptly rather than attributed to something minor, and urgent symptoms are always a reason to contact the GP or NHS 111.