Penetrance

Penetrance in LFS is variable and is partially due to the type of pathogenic variant . For classic LFS, there is an 80% risk of cancer by age 70, with 22% of the cancers occurring between ages 0 and 15 years, 51% between ages 16 and 50 years, and 27% between ages 51 and 80 years . However, low-penetrance TP53 pathogenic variants have been identified . Some TP53 variants that are suspected to be associated with low penetrance may have discordant variant classifications among different laboratories . A study of 140 families with LFS found that affected individuals from 11% of families had a TP53 variant with clinically significant discordant classifications (e.g., variant of uncertain significance vs likely pathogenic variant) .

Source: GeneReviews — "Li-Fraumeni Syndrome"

Diagnostic Criteria

Consensus clinical diagnostic criteria for Li-Fraumeni syndrome (LFS) have been published .

Suggestive Findings

LFS should be suspected in probands who meet modified Chompret criteria or have any additional suggestive findings. Modified Chompret criteria

Source: GeneReviews — "Li-Fraumeni Syndrome"

Differential Diagnosis

Table 2. Other Genes of Interest in the Differential Diagnosis of Li-Fraumeni Syndrome

Management Guidelines

Clinical practice guidelines for Li-Fraumeni syndrome (LFS) have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LFS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Li-Fraumeni Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment1

All cancers

| • Complete physical exam w/high index of suspicion for cancer (incl blood pressure, full neurologic exam, assessment of growth, sudden weight gain or loss, cushingoid appearance, or signs of virilization in a child)2

• Whole-body MRI w/o contrast3

| At diagnosis (all ages)

Breast cancer

| • Clinical breast exam

• Breast MRI w/ w/o contrast

| Beginning at age 20 yrs

CNS tumors

| • Neurologic exam

• Brain MRI w/contrast

Clinical Guidance

Individuals with LFS are encouraged to avoid or minimize exposures to known or suspected carcinogens, including ionizing radiation, unprotected sun exposure, tobacco use, occupational exposures, and excessive alcohol use, because the effects of carcinogenic exposures and germline TP53 pathogenic variants may be cumulative.

Source: GeneReviews — "Li-Fraumeni Syndrome"

Surveillance Guidelines

Surveillance guidelines for adults and children with LFS have been developed and modified from the Toronto protocol . Other published guidelines (e.g., American Association for Cancer Research and National Institute for Health and Care Excellence guidelines) may differ slightly from the recommendations in due to the lack of definitive data on the efficacy of these strategies. Table 4. Li-Fraumeni Syndrome: Recommended Surveillance

Source: GeneReviews — "Li-Fraumeni Syndrome"