PTEN-RELATED DISORDERS
Comprehensive Test - Test 1
DESCRIPTION
Mendelian Inheritance in Man number: *601728 (PTEN gene); 158350 (Cowden syndrome, CS); 153480(Bannayan-Riley-Ruvalcaba syndrome, BRRS); 176920 (Proteus syndrome, PS); 605309 (Macrocephaly/Autism syndrome)
Click here forGene Reviews Clinical Summary.
PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This group of disorders shares significant clinical overlap [Eng, 2003]. Each of these disorders is inherited in an autosomal dominant manner, and de novo mutations are common.
1. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid (10%), breast (25-50%), and endometrium (10%). Most patients usually have macrocephaly and pathognomonic mucocutaneous lesions, including trichilemmomas, papillomatous papules, and acaral and plantar keratoses. Other tumors include harmartomatous polyps of the GI tract, fibrocystic disease of the breast, fibromas, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), skin cancers, renal cell carcinomas, uterine leiomyoma, and brain tumors as well as vascular malformations affecting any organ.
2. BRRS is characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. Other common features include developmental delay, mental retardation, hamartomatous polyps of the GI tract, a myopathic process in proximal muscles, joint hyperextensibility, pectus excavatum, and scoliosis. Individuals with BRRS who have PTEN gene mutations are thought to have the same cancer risks as individuals with CS.
3. PS is a complex, highly variable disorder consisting variably of disproportionate, asymmetric overgrowth of body parts; cerebriform connective tissue nevi; epidermal nevi; vascular malformations of the capillary, venous, and lymphatic types; dysregulated adipose tissue; and hyperostoses[Cohen, 2005]. Unusual tumor types have been observed, such as cystadenoma of the ovary, various types of testicular tumors, central nervous system tumors, and parotid monomporphoic adenomas. Somatic mosaicism, lethal in the nonmosaic state, is the present hypothesis for PS.
4. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.
5. Macrocephaly/Autism Syndrome is one of PTEN-related disorders. Autism is associated with macrocephaly in approximately 20% of cases. Several studies have shown that PTEN mutations can be found in a subset of individuals who present with autism and macrocephaly, with or without the presence of other features of PTEN-related tumor syndrome [Butler et al. 2005, Buxbaum et al. 2007, Goffin et al. 2001, Herman et al. 2007]. Therefore, PTEN sequence analysis may be considered as additional testing when other genetic causes of autism have been ruled out through the autism panel.
INDICATIONS FOR DIRECT TESTING
- Individuals suspected to have PTEN-related disorders
- Individuals who seek confirmation of a clinical diagnosis
TESTING METHODOLOGY
From a fresh EDTA blood sample, DNA is extracted and used as the starting material for direct sequencing of the entire coding region.MLPA analysis to detect copy number changes is performed. Mutations screened for include truncating mutations (nonsense, frameshift, splicing mutations), missense mutations, multi-exon deletions and total gene deletions.
Test sensitivity varies depending on the clinical diagnosis. The sequencing approach used by MGL will identify >99% of intragenic minor lesion mutations in the PTEN gene. Partial or whole gene deletions/duplications can be detected by MLPA copy number analysis.
SPECIMEN REQUIREMENTS
We require 10 milliliters of whole blood. Blood samples must be collected in EDTA (purple topped) tubes. For pediatric patients or those for whom venipuncture is very difficult, please send a minimum of 3 ml in EDTA. Please note that if you order PTEN gene testing in addition to Fragile X testing for pediatric patients, we require a minimum of 5 milliliters of whole blood.
TRANSPORT
If specimen is from clinics within UAB or Kirklin Clinic, please call 934-5562 for pick-up. If specimens are being sent from some other location, please ship via UPS or Federal Express.
IMPORTANT!
Blood specimens must be kept at room temperature and received within 60 hours of collection.
1. DO NOT SHIP ON ICE.
2. Be sure that the shipping air bill is marked “Priority”, either Domestic or International.
3. Specimens must be packaged to prevent breakage and absorbent material must be included in the package to absorb liquids in the event that breakage occurs. Also, the package must be shipped in double watertight containers (e.g. a specimen pouch + the shipping companies Diagnostic Envelope). You can use our collection kits, which we will send to physicians directly upon request.
4. Please contact us (Emailmedgenomics@uabmc.edu, Phone – 205-934-5562) prior to sample shipment and provide us with the date of shipment and the tracking number of the package, so that we can better ensure receipt of the samples within the 60-hour window. Please include the form for customs. This is especially important for samples sent from outside the US.
TURN AROUND TIME
25 working days
REQUIRED FORMS
PTEN Test Requisition including the phenotypic data form.
Form for customs (International shipment)
Note: Requests for Molecular Genetic testing for PTEN will not be accepted for the following reasons:
No label (patient’s full name and date of collection) on the specimens
- No billing information
For more information, test requisition forms, or sample collection and mailing kits, please call: 205-934-5562.
REFERENCES
Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J (2001) PTEN mutations are uncommon in Proteus syndrome J Med Genet. 38: 480-1 (PubMed)
Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reiehert J, et al. (2007) Mutation Screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet. 144B:484-91. (PubMed)
Butler MG, Dasouki MJ, Zhou XP, Talebizadeh X, Brown M, Takahashi TN, et al. (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumor suppressor gene mutations. J Med Genet. 42:318-21. (PubMed)
Cohen MM Jr. (2005) Proteus syndrome: An update. Am J Med Genet. 137C:38-52. (PubMed)
Eng C. (2003) PTEN: one gene, many syndromes. Hum Mutat. 22(3):183-98. (PubMed)
Eng C, Thiele H, Zhou XP, Gorlin RJ, Hennekam RC, Winter RM (2001) PTEN mutations and proteus syndrome. Lancet. 358: 210-1 (PubMed)
Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP. (2001) PTEN Mutation in a Family With Cowden Syndrome and Autism. Am J Med Genet 105(6):521-24. (PubMed)
Herman GE, Butter E, Enrile B, Matthew P, Prior TW, Sommer A. (2007) Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genet. 143A:589-93. (PubMed)
Pezzolesi MG, Zbuk KM, Waite KA, Eng C (2007) Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome Hum Mol Genet. 16: 1058-71 (PubMed)
Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ (2002) Germline mutation of the tumour suppressor PTEN in Proteus syndrome J Med Genet. 39: 937-40 (PubMed)
Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C (2003) 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. 73: 404-11 (PubMed)
Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C (2000) Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis Hum Mol Genet. 9: 765-8 (PubMed)