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:

PEUTZ-JEGHERS

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

 

LI FRAUMENI

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
                OR
    • 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
                OR
    • Any individual with adrenocortical carcinoma, or choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype at any age of onset regardless of family history
                OR
    • Breast cancer diagnosed before age 31

 

COWDEN SYNDROME/PTEN HAMARTOMA TUMOR SYNDROME

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:

  • MAJOR CRITERIA
    • 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
  • MINOR CRITERIA
    • 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