There are more rare genetic cancer predisposition syndromes that can have other clinical manifestations. The National Comprehensive Cancer Network (NCCN v 1.2018) recommends further evaluation for the following:


Any individual with a personal or family history of any of the following should be offered further evaluation for Peutz-Jeghers syndrome:

  • dermatologic manifestations (trichilemmomas, palmoplantar keratoses, oral mucosal papillomatosis, cutaneous facial papules)
  • macrocephaly
  • hamartomatous polyps of the GI tract



Any individual with a personal or family history of any of the following should be offered further evaluation for Li Frameni syndrome:

  • From a family with a known TP53 gene mutation
  • Meeting Classic Li-Fraumeni syndrome criteria:
    • Any individual diagnosed with a sarcoma before age 45, AND
    • A first-degree relative diagnosed with cancer before age 45, AND
    • An additional first- or second-degree relative in the same lineage with cancer diagnosed before age 45, or diagnosed with sarcoma at any age
  • Meeting Chompret criteria:
    • Any individual with a tumor from LFS tumor (soft tissue sarcoma, osteosarcoma, CNS tumor, breast cancer, adrenocortical carcinoma) before age 46 AND at least one first- or second-degree relative with a LFS tumor before the age of 56 (both cannot be breast cancer), or with multiple primaries at any age
    • Any individual with multiple tumors (except multiple breast tumors), two of which are LFS tumors, with the initial cancer being diagnosed before the age of 46
    • Any individual with adrenocortical carcinoma, or choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype at any age of onset regardless of family history
    • Breast cancer diagnosed before age 31



In order to more clearly understand the criteria for referral, it is helpful to be familiar with the ‘Major’ and ‘Minor’ criteria for Cowden syndrome:

    • Breast cancer
    • Endometrial cancer
    • Follicular thyroid cancer
    • Multiple GI hamartomas or ganglioneuromas
    • Macrocephaly/Megalocephaly (above the 97th percentile; 58cm in women and 60cm in men)
    • Macular pigmentation of the glans penis
    • Mucocutaneous lesions
      • One biopsy-proven trichilemmoma
      • Multiple palmoplantar keratoses
      • Multifocal or extensive oral mucosal papillomatosis
      • Multiple cutaneous facial papules
    • Autism spectrum disorder
    • Colon cancer
    • Three or more esophageal glycogenic acanthoses
    • Lipomas
    • Intellectual disability (IQ of 75 or less)
    • Papillary or follicular variant of papillary thyroid cancer
    • Thyroid structural lesions (adenoma, nodules, goiter, etc)
    • Renal cell carcinoma
    • Single GI hamartoma or ganglioneuroma
    • Testicular lipomatosis
    • Vascular anomalies (including multiple intracranial developmental venous anomalies)


Any individual with any of the following should be offered further evaluation for Cowden syndrome/PTEN hamartoma tumor syndrome:

  • From a family with a known PTEN gene mutation
  • Personal history of Bannayan-Riley-Ruvalcaba syndrome
  • Meeting clinical diagnostic criteria
    • Three or more major criteria (one must include macrocephaly, Lhermitte-Duclos disease, or GI hamartomas), OR
    • Two major and three minor criteria
  • NOT meeting clinical diagnostic criteria, but with a personal history of:
    • Adult Lhermitte-Duclos disease (cerebellar tumors), OR
    • Autism spectrum disorder and macrocephaly, OR
    • Two or more biopsy-proven trichilemmomas, OR
    • Two or more major criteria (one must be macrocephaly), OR
    • Three major criteria (without macrocephaly), OR
    • One major and three or more minor criteria
    • Four or more minor criteria
  • From a family with a relative who has a clinical diagnosis of Cowden syndrome (but genetic testing has not been done), and the individual has any one major or two minor criterion