PTEN hamartoma tumor syndrome (PHTS)
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.
- Bannayan-Riley-Ruvalcaba syndrome
- Cowden syndrome 1, Lhermitte-Duclos syndrome
- Proteus syndrome
- Proteus-like syndrome
Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the PTEN gene
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.
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.
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