PTEN Gene Mutation Analysis
PTEN hamartoma tumor syndrome (PHTS)
The germline mutations in the PTEN gene are associated with a collection of phenotypically distinct hamartomatous overgrowth syndromes including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome1,2. The PTEN is a tumor suppressor gene located at 10q23.3 and encodes a lipid phosphatase which signals down the phosphoinositol-3-kinase/Akt pathway and leads to G1 cell cycle arrest and apoptosis 3,4. The germline mutations in PTEN gene are associated with about 85% of Cowden syndrome (CS), 65% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), up to 20% of Proteus syndrome (PS), and approximately 50% of a Proteus-like syndrome (PSL) cases 4,5,6. PTEN mutations can also be associated with Autism Spectrum Disorders (ASD) 9. The mutations for PTEN hamartoma tumor syndrome are inherited in an autosomal dominant manner 2.
Cowden syndrome (CS)
The Cowden Syndrome is a multiple hamartoma cancer predisposition syndrome associated with an increased risk of malignant and benign tumors of breast, thyroid, and endometrial cancers. It also characterized by hamartomas, mucocutaneous lesions (facial trichilemmomas, papillomatous papules, acral and plantar keratosis), adult Lhermitte-Duclos disease (LDD), autism, mental retardation (12%) and macrocephaly as well as benign manifestations 3,8. The estimated prevalence of CS is 1 in 200,000 individuals, though that is believed to be an under estimation4. Almost 40-60% PTEN mutations are inherited in CS and others are denovo 4. The lifetime risk for individuals with CS is estimated to be 25-50% for breast cancer (for women), about 10% for thyroid cancer (for both sexes) and 5-10% for endometrial cancer (for women) 7.
Bannayan-Riley-Ruvalcaba syndrome (BRRS)
It is a congenital disorder that is characterized by macrocephaly, lipomatosis, hemangiomas, intestinal polyposis, pigmented macules of the penis, macrosomia, proximal muscle myopathy , joint hyperextensibility, pectus excavatum, scoliosis , developmental delay or mental retardation1.
Proteus syndrome (PS)
It is an extremely rare and variable disorder characterized by progressive, asymmetric, and disproportionate overgrowth. Some of the key features are malformations and hamartomatous overgrowths of tissues, connective tissue nevi, epidermal nevi, parotid adenomas, vascular malformations, hyperostosis, lung cysts, facial abnormalities, hamartomatous tissue overgrowth, hyperostoses, connective tissue and epidermal nevi, dysregulated adipose tissue, vascular malformations and other congenital malformations1.
Proteus-like syndrome (PSL)
The individuals with some of the characteristics of Proteus syndrome but who do not meet clinical diagnostic criteria for it are diagnosed with Proteus-like syndrome 1.
Autism Spectrum Disorders (ASD)
Autism spectrum disorders are characterized by impaired social relationships, impaired language and communication, and a narrow range of interests or repetitive behavior 10. PTEN gene plays an important role in brain development and plasticity. Although the exact frequency of PTEN mutations in patients with ASD is uncertain, they may be found in up to 17 % patient s with autism and macrocephaly 9.
- Blumenthal, G.B. and Dennis, P.A. (1998). European Journal of Human Genetics 16, 1289–1300
- Orloff, M.S. and Eng, C. (2008). Oncogene 27:5387–5397.
- Eng, C. (2003). Human Mutation 22:183-198.
- Zhou, X.P. et al. (2003). Am. J. Hum. Genet. 73:404–411.
- Maehama, T. et. al. (2004). Biochemical Society Transactions 32;343-347.
- Teresi, R.E. et al. (2007). Am. J. Hum. Genet.81:756–767.
- Zbuk, K.M. and Eng, C. (2007). Gastroenterology and Hepatology 4:492-502.
- Hanssen A.M.N. and Fryns, J.P. (1995). J Med Genet. 32:117–119.
- Butler M.G., et.al. (2005). J Med Genet. 42:318–21
- Pardo, C.A. and Eberhart, C.G. 2007 Brain Pathol. 17:434–447.