Disease  

PTEN hamartoma tumor syndrome (PHTS)

Description  

PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant condition caused by germline mutations in PTEN. PHTS is associated with predisposition for benign and malignant hamartoma tumors and includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome, and Proteus-like syndrome. The majority of individuals with a PTEN mutation will show some signs of the disease, although there is a wide range of variability among affected individuals. The penetrance of PHTS is predicted to be approximately 80%.

Individuals with Cowden syndrome (CS) have an increased risk for tumors of the thyroid, breast, and endometrium.  CS is also characterized by macrocephaly, hamartomatous intestinal polyps, and skin findings such as trichilemmomas and papillomatous papules that often occur on the face and oral mucosa.  Bannayan-Riley-Ruvalcaba (BRRS) is characterized by developmental delay, macrocephaly, hamartomatous intestinal polyps, lipomas, and pigmented macules on the glans penis. Proteus syndrome (PS) is characterized by hemihypertrophy and subcutaneous tumors with Proteus-like syndrome referring to individuals with clinical features of PS that do not meet diagnostic criteria.  

Indications  

  • Bannayan-Riley-Ruvalcaba syndrome
  • Cowden syndrome 1, Lhermitte-Duclos syndrome
  • Proteus syndrome
  • Proteus-like syndrome

Testing Methodology  

Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the PTEN gene

Test Sensitivity  

Clinical Sensitivity  

Approximately 80% of patients with CS, 60% patients with BRRS, 20% of patients with PS/PSL syndrome will have a PTEN mutation identifiable by sequencing.

Additional genetic testing may be recommended for patients with normal sequencing results in order to identify deletions, duplication, and promoter mutations that have been reported in PTEN.

Analytical Sensitivity  

Up to 85% of reported mutations in association with PTEN-related hamartoma tumor syndromes are detectable by this test. The sensitivity of DNA sequencing is over 99% for the detection of nucleotide changes, small deletions and insertions in the regions analyzed.

Mutations in regulatory regions or other untranslated regions are not detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events have been reported in PTEN and will not be identified using this test methodology. Rare primer site variants may lead to erroneous results.

Deletion/duplication analysis of PTEN will detect a mutation in about 10% of individuals with Bannayan-Riley-Ruvalcaba syndrome. Promoter analysis of PTEN will identify mutations in about 10% of patients with Cowden syndrome.

Turnaround Time  

28 days

References  

Blumenthal, G.M. and P.A. Dennis (2008) "PTEN Hamartoma Tumor Syndromes." Eur J Hum Genet 16(11): 1289–300.

Busa, T., M. Milh, et al. (2015) "Clinical Presentation of PTEN Mutations in Childhood in the Absence of Family History of Cowden Syndrome." European Journal of Paediatric Neurology: EJPN: Official Journal of the European Paediatric Neurology Society 19(2): 188-92.

Jelsiq, A.M. and N. Qvist (2014) “Hamartomatous polyposis syndromes: A Review.” J Rare Dis 9 (101): 1-10.

Orloff, M.S. and C. Eng (2008) "Genetic and Phenotypic Heterogeneity in the PTEN Hamartoma Tumour Syndrome." Oncogene 27(41): 5387–97.

Tan, M.H., J. Mester, et al. (2011) "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 88(1): 42–56.