PTEN hamartoma tumour syndrome (PHTS)

Phenotypically, PTEN hamartoma tumour syndrome (PHTS) can be divided into Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS) and Proteus-like syndrome depending on the clinical manifestation.

Bannayan-Riley-Ruvalcaba syndrome is characterized by macrocephaly, intestinal hamartomatous polyps, lipomas, and genital macules. The prevalence of BRRS is unknown. The most common manifestations of Proteus syndrome are macrodactyly and hemihyperplasia.

Cowden syndrome (CS) is an autosomal dominant inherited disease with a prevalence of 1:200,000 that is characterized by the presence of gastrointestinal hamartoma, breast cancer, endometrial carcinoma, follicular thyroid carcinoma, mucocutaneous lesions and macrocephaly (major criteria). In addition, colorectal cancer, lipomas, intellectual disability, renal cell carcinoma and/or vascular abnormalities (secondary criteria) may occur.

In approximately 60–80% of patients, PTEN hamartoma tumour syndrome is caused by pathogenic germline variants in the PTEN tumour suppressor gene. The phosphatase PTEN is mainly involved in the regulation of the AKT/PKB signalling pathway and inhibits cell proliferation. Pathogenic variants in PTEN can lead to dysregulation of the cell cycle and to the uncontrolled division of the affected cell. In about 30% of the patients with Cowden-like symptoms and without evidence of a pathogenic PTEN variant, hypermethylation of the KLLN gene can be detected. Pathogenic germline variants in the SDHB, SDHC, SDHD, AKT1 and PIK3CA genes are detected less frequently.

According to the 2018 diagnostic recommendations of the National Comprehensive Cancer Network, genetic testing is indicated if a patient:

• Meets three or more major criteria, with either macrocephaly, Lhermitte-Duclos disease or gastrointestinal hamartomas detected or
• Meets two main criteria and three secondary criteria.

Differential diagnosis should also exclude suspicion of (PJS), (BHD) and (NF1).

If a pathogenic PTEN variant is detected, patients should undergo enhanced preventive screening examinations, such as thyroid ultrasound and colonoscopy. Female carriers should be offered
enhanced screening for breast and endometrial carcinomas. Furthermore, a prophylactic hysterectomy can be considered from the age of 40 (or 5 years before the earliest age of illness in the family).

• Valle et al. 2019, J Pathol 247:574
• Pilarski et al. 2019, Cancers 11:844
• Leitlinienprogramm Onkologie: Diagnostik, Therapie und Nachsorge der Patientinnen mit Endometriumkarzinom, Langversion 1.0, 2018
• Lorans et al. 2018, Clin Colorectal Cancer 17:e293
• Syngal et al. 2015, Am J Gastroenterol 110: 223
• Eng et al. 2016, PTEN Hamartoma Tumor Syndrome, GeneReviews®,
• Jelsing et al. 2014, Orphanet Journal of Rare Disease 9:101