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 mutations2.  

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). 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. However, based on the estimate that up to 2% of individuals with ASD have a PTEN mutation, the prevalence of PHTS may be higher6. For more details about the prevalence of PHTS and orphan drug designation criteria see here


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 indicated7. 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 average lifetime risk of cancer in individuals with PHTS are significantly increased compared with the background population. 

The risks for individual cancer types reported in a recently published prospective longitudinal study of over 700 patients are shown in Box 28. Several other estimates of the lifetime risk of cancer for individuals with PHTS have been published on the basis of analyses varying in study design, sample size and methodology. However, in general, all published studies point to a increased lifetime risk for multiple cancer types 9-16.

Box 2: Lifetime cancer risk estimates for PHTS patients

Cancer type Lifetime risk estimate (PHTS)8 Lifetime risk estimate (general population)17

Female breast cancer

Up to 91%


Thyroid cancer

Up to 33%


Endometrial cancer

Up to 48%


Renal cancer

Up to 30%


Colorectal cancer

Up to 17%



Up to 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 treatments9,18.  The value of cancer surveillance in PHTS has been demonstrated19-21

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 and its downstream effectors such as mTOR, 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 is large (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. Genetics in Medicine. 2012;14(9):819-822. doi:10.1038/gim.2012.51
  2. Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019;129(2):452-464. doi: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 C Semin Med Genet. 2019;181(4):591-610. doi:10.1002/ajmg.c.31743
  4. Yehia L, Eng C. PTEN Hamartoma Tumor Syndrome. Gene Reviews NCBI Bookshelf. Published online February 11, 2021. Accessed June 24, 2022.
  5. Nelen MR, Kremer H, Konings IB, et al. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999;7(3):267-273. doi:10.1038/sj.ejhg.5200289
  6. Frazier TW. Autism Spectrum Disorder Associated with Germline Heterozygous PTEN Mutations. Cold Spring Harb Perspect Med. 2019;9(10):a037002. doi:10.1101/cshperspect.a037002
  7. Tan MH, Mester J, Peterson C, et al. A clinical scoring system for selection of patients for pten mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88(1):42-56. doi:10.1016/j.ajhg.2010.11.013
  8. Yehia L, Plitt G, Tushar AM, et al. Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants. JAMA Netw Open. 2023;6(4):e239705. doi:10.1001/jamanetworkopen.2023.9705
  9. Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N, PHTS Guideline Development Group, The European Reference Network GENTURIS. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. European Journal of Human Genetics. 2020;28:1387-1393. doi:10.1038/s41431-020-0651-7
  10. Hendricks LAJ, Hoogerbrugge N, Schuurs-Hoeijmakers JHM, Vos JR. A review on age-related cancer risks in PTEN hamartoma tumor syndrome. Clin Genet. 2021;99(2):219-225. doi:10.1111/cge.13875
  11. Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. J Natl Cancer Inst. 2023;115(1):93-103. doi:10.1093/jnci/djac188
  12. Riegert-Johnson DL, Gleeson FC, Roberts M, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010;8(1):6. doi:10.1186/1897-4287-8-6
  13. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer. 2014;13(1):57-63. doi:10.1007/s10689-013-9674-3
  14. Starink TM, van der Veen JP, Arwert F, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986;29(3):222-233. doi:10.1111/j.1399-0004.1986.tb00816.x
  15. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013;50(4):255-263. doi:10.1136/jmedgenet-2012-101339
  16. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407. doi:10.1158/1078-0432.CCR-11-2283
  17. Yehia L, Eng C. 65 YEARS OF THE DOUBLE HELIX: One gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat Cancer. 2018;25(8):T121-T140. doi:10.1530/ERC-18-0162
  18. Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(1):77-102. doi:10.6004/jnccn.2021.0001
  19. Hoxhaj A, Drissen MMCM, Vos JR, Bult P, Mann RM, Hoogerbrugge N. The yield and effectiveness of breast cancer surveillance in women with PTEN Hamartoma Tumor Syndrome. Cancer. 2022;128(15):2883-2891. doi:10.1002/cncr.34326
  20. Kwinten KJJ, Drissen MMCM, de Hullu JA, Vos JR, Hoogerbrugge N, van Altena AM. Yield of annual endometrial cancer surveillance in women with PTEN Hamartoma Tumor Syndrome. Eur J Med Genet. 2023;66(7). doi:10.1016/j.ejmg.2023.104785
  21. Drissen MMCM, Vos JR, van der Biessen-van Beek DTJ, et al. Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome. Cancers (Basel). 2022;14(16):4005. doi:10.3390/cancers14164005