Confirming a diagnosis of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, or Proteus-like syndrome
Identifying mutations in the PTEN gene
Germline mutations in the PTEN gene are associated with a rare collection of clinical syndromes referred to as PTEN hamartoma tumor syndrome (PHTS). This includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS) and Proteus-like syndrome (PLS). Although each of these syndromes has its own unique features, all 4 appear to be associated with multiple hamartomatous lesions, vascular lesions, and macrocephaly. Affected individuals have an increased risk of cancer, including cancers of the breast, endometrium, thyroid, colon, and kidney. PHTS is an autosomal dominant disorder and penetrance is believed to be quite high.
CS is a multiple hamartoma syndrome associated with trichilemmomas, mucocutaneous papillomatous papules, and macrocephaly. Affected individuals are at an increased risk for breast, thyroid, and endometrial carcinoma.
BRRS is characterized by macrocephaly, intestinal hamartomas, lipomatosis, hemangiomatosis, and pigmented macules on the glans penis.
PS is associated with congenital malformations, overgrowth, macrocephaly, hyperostosis, connective tissue nevi, and epidermal nevi.
PLS refers to individuals who have features of PS, but do not meet diagnostic criteria.
All detected alterations are evaluated according to American College of Medical Genetics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
A small percentage of individuals who have a diagnosis of PTEN hamartoma tumor syndrome (PHTS) may have a mutation that is not identified by this method (eg, promoter mutations, deep intronic alterations). The absence of a mutation, therefore, does not eliminate the possibility of the diagnosis of PHTS. For testing asymptomatic individuals it is important to first document the presence of a PTEN gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424
2. Eng C: PTEN Hamartoma Tumor Syndrome (PHTS). In GeneReviews (Internet). Edited by RA Pagon, TD Bird, CR Dolan, et al. University of Washington, Seattle, Updated 2011 Jul 21
3. Pilarski R, Stephens JA, Noss R, et al: Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet 2011 Aug;48(8):505-512
4. Zhou XP, Waite KA, Pilarski R, et al: Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 2003 Aug;73(2):404-411
5. 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 Jan;88:42-56
