PTEN-Related Disorders

  • Use to confirm clinical diagnosis of PHTS.
  • Use to determine if at-risk family members have a PTEN variant when a familial variant is unknown and affected relatives are unavailable for testing.

PTEN hamartoma tumor syndromes (PHTS) are a group of disorders caused by pathogenic variants in the PTEN gene and characterized by hamartomatous tumors. These disorders include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome (PLS). Clinical presentation varies widely among the disorders, but the most serious clinical concerns for individuals with PHTS are malignancy (generally organ specific) and developmental disorders (including autism spectrum disorder [ASD]).  PHTS may be diagnosed with clinical diagnostic criteria or by identification of a pathogenic variant in PTEN.

Disease Overview


CS: ~1/200,000

Clinical Presentation

Clinical Presentation of PTEN-Related Disorders
Syndrome Typical Age of Onset Common Features Tumor Risks


By late 20s

  • Macrocephaly
  • ASD or intellectual disability
  • Lipomas
  • Fibromas
  • Mucocutaneous lesions
    • Facial trichilemmomas
    • Palmoplantar keratoses
    • Oral mucosal papillomatosis
  • Gastrointestinal polyps with hamartomatous and mixed pathology
  • Fibrocystic disease of the breast

CS carries the following lifetime cancer risks :

  • Breast: 85%
  • Nonmedullary thyroid: ~35%
  • Endometrial: ~28%
  • Colorectal: ~9%
  • Renal cell carcinoma: ~35%
  • Melanoma: up to 6%
  • Brain tumors: occasional


Birth to early childhood

  • Macrocephaly
  • Gastrointestinal hamartomatous polyps
  • Lipomas
  • Hemangiomas
  • Pigmented macules of the glans penis
  • Developmental delay/intellectual disability
  • Joint hyperextensibility
  • Pectus excavatum
  • Scoliosis
  • Proximal myopathy

If a germline PTEN variant is present, cancer risks are the same as in CS

PS and PLS

Early childhood

  • Mosaic distribution of tissue overgrowth (most commonly affecting skeleton, skin, adipose tissue, and central nervous system)
  • Vascular malformations

Tumors and malignancies are not common, although central nervous system tumors, cystadenoma of the ovary, parotid monomorphic adenomas, and testicular tumors have been reported

Yehia, 2021 ; Yehia, 2020 





Inheritance is autosomal dominant, although de novo variants cause all cases of PS and 50-90% of CS cases.


The penetrance for Cowden syndrome is 99% by age 30.

Test Interpretation


Clinical Sensitivity

  • CS (based on strict diagnostic criteria): 25-85%   
  • BRRS: 60%   
  • PS: 20% 
  • PSL: 50% 
  • ASD with significant macrocephaly: up to 20%  

Analytical Sensitivity/Specificity

  • Sequencing: 99%
  • Multiplex ligation-dependent probe amplification (MLPA): 90% and 98% respectively


Result Variant(s) Detected Clinical Significance


Pathogenic variant in PTEN detected

Confirms diagnosis of  PHTS


No variant detected

Decreases, but does not exclude, the probability of a PTEN-related disorder


Sequence variant of unknown clinical significance detected



  • Diagnostic errors can occur due to rare sequence variations.
  • Some regulatory region mutations, deep intronic mutations, and large deletions of exon 3 may not be detected.
  • Breakpoints for large deletions/duplications will not be determined.
  • This assay is not designed to detect somatic variants associated with malignancy.
  • Interpretation of this test result may be impacted if the patient has had an allogeneic stem cell transplantation.