PHTS and the PTEN Gene

What is PHTS?

PHTS is a rare syndrome caused by a germline heterozygous pathogenic mutation in the Phosphatase and Tensin Homolog (PTEN) tumour suppressor gene. Most PTEN mutations are inherited in a family for generations, following an autosomal dominant pattern, but 10-45% of cases are due to new (de novo) mutations1.

Before the identification of the PTEN gene and routine genetic testing of patients with rare congenital conditions, several syndromes were described based on clinical features which have subsequently been found to be causally related to a PTEN gene mutation in most cases. These include Cowden syndrome (CS), and Bannayan-Riley-Ruvalcaba syndrome (BRRS), with studies indicating that 25-85% and 60% of cases respectively have PTEN germline mutations.2.  

There are currently limited clear data supporting a genotype-phenotype correlation. Further, cases of  both BRRS and CS have been reported within families where individuals have the same PTEN mutation3. Age and gender also influence clinical presentation.

As such, all people with a PTEN mutation should be considered as having a PHTS diagnosis regardless of earlier syndrome-based diagnoses.  

Clinical manifestations

PHTS has a range of clinical manifestations (see Box 1), with the most common being macrocephaly (>90% patients) and increased lifetime risk of cancer (>85% of patients). Clinical symptoms and signs of PHTS vary in incidence and severity. Patients may present in infancy or adulthood, and there is age-related penetrance with new medical issues, such as malignancy, emerging throughout life3,4.   

Box 1: Clinical manifestations of PHTS

  • Increased risk of malignancy – particularly breast, thyroid, renal and endometrial cancer
  • Benign hamartomas
  • Macrocephaly
  • Neurobehavioural deficits (including autism spectrum disorder, cognitive impairment)
  • Vascular anomalies
  • GI polyposis


Estimating the prevalence of PHTS is complex due to the varied presentations and historical diagnoses, and because some features, such as benign breast lesions, also commonly occur in the general population. However, it is estimated that approximately 1 in 200,000 individuals could have PHTS. This corresponds to around 2000 individuals in the US population, and around 47,000 individuals worldwide5.


A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation revealing the presence of characteristic findings described above, and a detailed patient and family history.  The Cleveland Clinic Score is available online, for use with both adult and paediatric patients, to estimate the likelihood of an underlying PTEN variant and thus inform when genetic testing may be indicated6. Depending on history and presentation, either single gene testing for a PTEN mutation, or a multi-gene panel which includes PTEN and other genes of interest may be appropriate4.

Prognosis and management

The reported average lifetime risk of cancer in PHTS patients is approximately 85% for any cancer, with most diagnosed after the age of 30 years7. An exception is thyroid cancer which has been diagnosed in children as young as 7 years3. The risks for individual cancer types are shown in Box 27.  These estimates are likely to be at the upper end of the true range due to the retrospective methodology of the source studies. More accurate estimates will come from future longitudinal studies.

Box 2: Lifetime cancer risk estimates for PHTS patients

Cancer type Lifetime risk estimate

Female breast cancer

Up to 85%

Thyroid cancer

Up to 38%

Endometrial cancer

Up to 28%

Renal cancer

Up to 34%

Colorectal cancer

Up to 16%


Approximately 5%

Published management guidelines for PHTS focus on malignancy, recommending a comprehensive program of cancer surveillance for adult patients to support early identification and intervention with tumour-specific treatments7,8

Other management is essentially supportive for individual symptoms. For paediatric patients, a recent review includes useful management recommendations for common clinical features in this population3.

PTEN and the pathogenesis of PHTS

PTEN is a phosphatase involved in downregulating the PI3K/AKT/mTOR signalling pathway. This signal transduction pathway plays an important role in the regulation of multiple biological processes, such as cell proliferation, apoptosis, metabolism, and angiogenesis. When dysfunctional or absent, the PTEN enzyme fails to dephosphorylate PIP3 (phosphatidylinositol-3,4,5-trisphosphate), produced by PI3K, to PIP2 (phosphatidylinositol-4,5-diphosphate) and hence fails to inhibit AKT, resulting in decreased apoptosis and increased cell growth1. In addition to its role in PHTS, the PTEN gene is one of the most frequently somatically mutated genes in cancer2.

The spectrum of pathogenic PTEN germline mutations identified in individuals with PHTS are varied (including point mutations and deletions, frameshifts and mutations in intronic and promoter regions). Interestingly these mutations are enriched in the catalytic domain that is responsible for PTEN’s phosphatase activity, pointing to a key role for the deregulation of the PI3K pathway in the pathogenesis of PHTS.

Furthermore, studies using in-vivo models have demonstrated that loss of PTEN function results in PHTS-like symptoms, some of which can be ameliorated by administering inhibitors of the PI3K/AKT/mTOR signalling pathway. This has prompted interest in evaluating inhibitors of this signalling pathway as possible therapeutics for PHTS, which are the subject of ongoing clinical and pre-clinical studies2.


  1. Mester J, Eng C. Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome. Genet Med 2012 Sep;14(9):819-22. doi: 10.1038/gim.2012.51
  2. Yehia L, Ngeow L, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019 Feb 1; 129(2): 452–464.: 10.1172/JCI121277. 
  3. Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature. Am J Med Genet 2019:181C:591-610. (LINK) 
  4. Yehia L, Eng C. PTEN Hamartoma Tumor Syndrome. Gene Reviews 2021 NCBI Bookshelf.
  5. Nelen M, Kremer J, Konings I, Schoute F et al: Novel PTEN mutations in patients with Cowden disease: absence of clear genotype–phenotype correlations. European Journal of Human Genetics (1999) 7, 267–273
  6. Tan, M. H., Mester, J., Peterson, C., Yang, Y., Chen, J. L., Rybicki, L. A., Eng, C. (2011). A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. American Journal of Human Genetics, 88(1), 42–56. (LINK) 
  7. Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N, for the PHTS Guideline Development Group; European Reference Network GENTURIS. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. Eur J Hum Genet 2020;10.
  8. Daly MB, Pilarski R, Berry M et al. NCCN Clinical Practice Guidelines in Oncology: Genetic/familial high-risk assessment: breast and ovarian. Version 1.2020. (LINK)