Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome

Eur J Med Genet. 2021 Dec;64(12):104364. doi: 10.1016/j.ejmg.2021.104364. Epub 2021 Oct 9.


Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics' prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94-100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.

Keywords: Early diagnosis; Hamartoma syndrome; Hereditary; Multiple; Neoplastic syndromes; PTEN Phosphohydrolase; Phenotype.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Hamartoma Syndrome, Multiple / diagnosis*
  • Hamartoma Syndrome, Multiple / metabolism*
  • Humans
  • Male
  • Megalencephaly / diagnosis
  • Megalencephaly / metabolism
  • Middle Aged
  • PTEN Phosphohydrolase / metabolism*
  • Young Adult


  • PTEN Phosphohydrolase
  • PTEN protein, human