PTEN syndrome

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 dermatological features, and may have neurodevelopmental delay.

Clinical features of PTEN syndrome include:

• macrocephaly (typically two standard deviations above the mean);
• pathognomonic mucocutaneous changes (facial trichilemmomas, acral keratoses and papillomatous ‘cobblestone-like’ lesions) as well as lipomas, vascular malformations and pigmented macule of the glans penis;
• benign and malignant tumours of the thyroid, breast, endometrium and kidney (the majority of cancerous presentations are in adulthood, though thyroid cancer has been reported in childhood);
• mixed bowel polyps, including hamartomatous, ganglioneuromatous, juvenile and adenomatous;
• developmental delay (particularly motor) and autistic spectrum disorders (overrepresented in this population); and
• adult-onset Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum, characteristic of PTEN-related conditions).

PTEN-related Proteus syndrome is a highly variable condition involving congenital malformations and hamartomatous overgrowth of multiple tissues.

The syndrome is caused by deletions or nonsense, missense and splicing variants in the PTEN gene (phosphatase and tensin homolog), a tumour suppressor gene located on the long arm of chromosome 10. PTEN negatively regulates the cytoplasmic receptor tyrosine kinase pathway, which is responsible for cell growth and survival, and also functions to repair errors in DNA.

Due to the broad spectrum of associated clinical features, PTEN syndrome may be diagnosed in many different ways. Some associated features are highly suggestive, or even pathognomonic, therefore clinicians may have a high degree of clinical suspicion leading to direct genetic testing of the PTEN gene. Other complications, such as breast cancer, are much less specific. Therefore broader genomic testing for presentations, such as familial breast cancer, may reveal a diagnosis which may come as a relative surprise to clinicians and patients.

As PTEN is inherited in an autosomal dominant pattern, and can have a very variable presentation, careful consideration must be given to first-degree family members who could also be affected.

The Cleveland Clinic offers a PTEN risk calculator that can help clarify the likelihood of a PTEN diagnosis. For more information about diagnosis please see Presentation: Clinical suspicion of PTEN hamartoma tumour syndrome.

PTEN syndrome is an autosomal dominant condition:

• Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
• The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur when not everyone who has the variant develops the disease.

While over half of cases are caused by de novo variants, 10%–50% of affected individuals will have inherited the variant from their parents. The exception is those with PTEN-related Proteus syndrome, which almost always arises de novo.

In cases where neither parent is found to carry the variant present in their affected child, the chance of recurrence for future pregnancies will be less than 1%.

Management of individuals with PTEN syndrome is based on the early detection and prevention of associated malignancies, principally from adulthood. Suggested approaches for managing children have been published by several authors – see our list of resources.

For clinicians

• GeneReviews: PTEN hamartoma tumor syndrome
• Genetic and Rare Diseases Information Center: PTEN hamartoma tumor syndrome
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Comprehensive Cancer Network
• NHS England: National Genomic Test Directory
• U.S. National Library of Medicine: ClinicalTrials.gov (database)
• UK Cancer Genetics Group: UKCGG leaflets and guidelines (See ‘PTEN’)

References:

• Macken WL, Tischkowitz M and Lachlan KL. ‘PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature‘. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2019: volume 181, issue 4, pages 591–610. DOI: 10.1002/ajmg.c.31743

For patients

• Boston Children’s Hospital: PTEN hamartoma tumor syndrome (PHTS)
• PTEN UK and Ireland Patient Group
• The PTEN Foundation