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PHTS and the PTEN gene

What is PHTS?

PTEN hamartoma tumour syndrome (PHTS) is a rare syndrome caused by a constitutional heterozygous pathogenic variant in the Phosphatase and Tensin Homolog (PTEN) tumour suppressor gene. Whilst PHTS is a hereditary condition following an autosomal dominant pattern, 10-45% of cases are due to new (de novo) variants1.

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 variant 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 pathogenic PTEN constitutional variants2.

There are currently limited clear data supporting a genotype-phenotype correlation in PHTS. Further, cases of both BRRS and CS have been reported within families where individuals have the same PTEN variant3. Age and gender also influence clinical presentation.

As such, all people with a constitutional pathogenic/likely pathogenic PTEN variant 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 (ASD) and cognitive impairment
  • Vascular anomalies
  • GI polyposis

Prevalence

The true prevalence of PHTS remains uncertain. However, recent large-scale genomic data provide more robust estimates. Analysis of whole-genome sequencing data from over 700,000 individuals suggests that the prevalence of constitutional PTEN pathogenic or likely pathogenic variants, and by extension PHTS, ranges from approximately 1 in 9,000 to 1 in 13,000 in the general population 5. This is 10- to 20-fold higher than previous estimates cited in the literature6.

For more details about the prevalence of PHTS and orphan drug designation criteria see here.

Diagnosis

A diagnosis of PHTS may be suspected based on 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, and can be used with both adult and paediatric patients to estimate the likelihood of an underlying pathogenic PTEN variant and thus inform when genetic testing may be indicated7. Depending on medical history and presentation, either single gene testing for a PTEN variant, or a multi-gene panel including PTEN and other genes of interest may be appropriate4.

Prognosis and management

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

The risks for individual cancer types reported in a recently published prospective longitudinal study of over 700 PHTS 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 an 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%

12%

Thyroid cancer

Up to 33%

1%

Endometrial cancer

Up to 48%

2.6%

Renal cancer

Up to 30%

1.6%

Colorectal cancer

Up to 17%

5.5%

Melanoma

Up to 5%

2%

Current published management guidelines for PHTS focus on malignancy, recommending a comprehensive program of age-appropriate cancer surveillance for patients to support early identification of disease and enable intervention with tumour-specific treatments9,18. Recently, a group of PHTS expert physicians, with input from patient advocacy groups, have published international consensus guidelines for the surveillance and management of cancer and overgrowth in PHTS, aiming at improving care for affected individuals and families19.  The value of cancer surveillance in PHTS has been demonstrated20-24. 

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 that downregulates the activity of 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, PTEN 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. 

However, research has demonstrated that the role of PTEN extends beyond the control of PI3K, with PTEN implicated in the regulation of processes such as DNA replication, DNA repair, and the maintenance of chromosomal integrity. These so-called non-canonical functions of PTEN have been less extensively characterised.

The spectrum of pathogenic PTEN constitutional variants identified in individuals with PHTS is large and includes point mutations and deletions, frameshifts, and mutations in intronic and promoter regions. Interestingly, these variants 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.

Studies using pre-clinical 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.

Useful Links

Overview of PHTS: Gene Reviews

Cleveland Clinic PTEN Risk Calculator

GENTURIS PHTS Cancer Surveillance Guideline

NCCN Cancer Surveillance guideline

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes

References

  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. https://www.ncbi.nlm.nih.gov/books/NBK1488/
  5. White SL, Jamil T, Bell C, et al. Population Prevalence of the Major Thyroid Cancer–Associated Syndromes. J Clin Endocrinol Metab. Published online April 15, 2025. doi:10.1210/clinem/dgaf236
  6. 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
  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. Dhawan A, Baitamouni S, Liu D, et al. Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clinical Cancer Research. 2025;31(9):1754-1765. doi:10.1158/1078-0432.CCR-24-3819

  20. 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
  21. 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
  22. 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

  23. Drissen MMCM, Vos JR, Netea-Maier RT, Gotthardt M, Hoogerbrugge N. Detection and yield of thyroid cancer surveillance in adults with PTEN Hamartoma Tumour Syndrome. Endocr Relat Cancer. 2023;30(10):e230009. doi:10.1530/ERC-23-0009

  24. Bormans EMG, Schuurs-Hoeijmakers JHM, van Setten P, et al. Experience in a PHTS Expertise Centre: Yield of Thyroid Ultrasound Surveillance in Children with PTEN Hamartoma Tumor Syndrome. J Clin Res Pediatr Endocrinol. 2025;17(1):45-57. doi:10.4274/jcrpe.galenos.2024.2024-3-14

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