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%.
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.
- Cowden syndrome 1,
- 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
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
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
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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