Li-Fraumeni Syndrome – Definition
Li-Fraumeni syndrome (LFS; OMIM #151623) is a highly aggressive cancer predisposition syndrome that often leads to malignancies in childhood. It predisposes to bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer, adrenocortical carcinoma (ACC), leukemia and other neoplasias.
Synonyms:
Sarcoma Breast Leukemia, Adrenal Gland Cancer Syndrome
Gene:
TP53 (tumor protein 53, tumor suppressor gene)
Gene product:
p53
Function:
Transcription factor that is activated by cellular stress (e.g. DNA damage) and regulates multiple anti-tumor signalling pathways
Pattern of inheritance:
Autosomal dominant, de novo mutations (~7-25%)
Prevalence:
~ 1:5,000, in Brazil sometimes much more often
Genotype-phenotype correlation:
It is not yet fully understood. There is evidence that dominant negative mutations in the DNA-binding domain are associated with the highest risk of cancer. However, no predictions can be made for the individual patient based on the genotype. There are also many modifying factors.
Penetrance:
Almost 100% cumulative tumor incidence up to the age of 70 (50% for women up to age 31. LJ; 50% for men up to 46. LJ)
– 4% in the first year of life
– 22% until the age of 5
– 41% until the age of 18
Li-Fraumeni Syndrome – Diagnosis
Classic Diagnostic Criteria
- A patient with a diagnosis of sarcoma aged ≤ 45 years
AND - A first-degree relative with cancer aged ≤ 45 years
AND - A first- or second-degree relative with cancer aged ≤45 years or sarcoma, regardless of age of onset
Increasingly, LFS is equated with positive evidence of a TP53 germline mutation.
Chompret Criteria
The so-called “Chompret” criteria were last revised in 2015 to define four different clinical constellations for which TP53 mutational analysis should be offered:
- Familial presentation: Proband with a tumor of the LFS Tumor spectrum (premenopausal breast cancer, soft tissue sarcoma, brain tumor, ACC) before 46 years of age AND at least one first- or second-degree relative with an LFS tumor (except breast cancer, if the patient has breast cancer himself/herself) before 56 years of age or with multiple tumors
- Multiple tumors: Subject with multiple tumors (excluding multiple breast cancers), two of which are in the LFS spectrum, before age 46
- Rare tumors: patients with ACC, choroid plexus carcinoma, embryonal anaplastic subtype rhabdomyosarcoma, regardless of family history
- Breast cancer before the age of 31
Further Suspicions
In addition to the Chompret criteria, there is a suspicion of the existence of an LFS in:
- Children with low hypodiploid ALL
- Children with medulloblastoma of the Sonic Hedgehog subtype
- Patients with osteosarcoma (recent studies indicate that constitutional TP53 changes can be detected in about 10% of those affected)
- Children with ALL recurrence with TP53 mutation in the leukemic cells
A characteristic somatic mutation spectrum can often be detected in tumors of patients with LFS. Therefore, such signatures should lead to TP53 germ line analysis or genetic counseling. An example is the phenomenon of chromothripsis in LFS-associated medulloblastomas.
Differential Diagnoses
- Hereditary Breast-Ovarian Cancer Syndrome (BRCA1 and BRCA2 mutation)
- Constitutional Mismatch Repair Deficiency (CMMRD)
Clinical Presentation
The most common LFS-associated neoplasms are referred to as “core cancers,” including soft tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumors (choroid plexus tumors, sonic hedgehog medulloblastomas, gliomas), and adrenocortical carcinoma.
Typical Presentation in Childhood
- Sarcomas (osteosarcomas, soft tissue sarcomas)
- ACC
- CNS tumors (choroid plexus tumors, SHH medulloblastoma)
- ALL (especially hypodiploid), AML, MDS
- ALL-relapses
Typical Presentation in Adulthood
- Breast cancer, especially young women
- Soft tissue sarcomas
Other Common Tumors
- Melanomas
- Lung carcinomas
- Tumors of the gastrointestinal tract
- Neuroblastomas
- Lymphomas
- Nephroblastomas
- Thyroid carcinomas
Special Features of Treatment
So far, no detailed recommendations are available for the treatment of individuals with LFS and cancer. It is treated according to the treatment protocols for the respective tumor diagnosis. There are a few exceptions: For example, in LFS-associated breast cancer, mastectomy is preferred to lumpectomy to reduce the risk of a second primary breast tumor and avoid radiotherapy.
A new therapy concept adapted to LFS will be offered for patients with medulloblastoma and LFS. Please get in touch with the HIT Study Center for more information.
If a curative therapy approach is possible, radiotherapy should be avoided. Alkylating substances and other genotoxic substances should also be avoided where acceptable. The primary treatment success remains superior to the secondary consequences.
Diagnosis of Li-Fraumeni Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Li-Fraumeni Syndrome - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection for Children (0 to 18 Years)
In general
- Detailed physical examination every 3-4 months:
- Blood pressure measurement
- Collection of anthropometric data on the percentile curve (look for rapid increase in weight or height; percentile bend)
- Cushingoid appearance, signs of virilization (pubic hair, underarm sweating, adult body odour, androgenic aloplecia, clitoral hypertrophy or penile growth)
- Pallor, bruises/petechiae, enlarged lymph nodes, hepatosplenomegaly, fatigue, prolonged fever, night sweats, unintentional weight loss and/or bone pain
- Full neurological status, looking for frequent headaches, seizures, personality or behavioural changes, weakness, numbness or paralyses in any part of the body, weight loss, nausea, dizziness, hearing or vision loss, macrocephaly
- Examine the skin
- Immediate registration of any medical concerns with the primary physician (pediatrician)
ACC
- Abdominal and pelvic ultrasound every 3 to 4 months
If there is a time overlap with the whole-body MRI, the sonography can be omitted - In case of insufficient availability or quality of sonography → laboratory (BE¹,²) every 3-4 months: total testosterone, dehydroepiandrosterone sulfate and androstenedione
CNS Tumor
- Annual cranial MRI (first MRI with contrast agent, then without contrast agent with previous normal findings)
- If anaesthesia is required, whole-body MRI and cranial MRI can be performed at the same time
Soft Tissue Sarcoma and Osteosarcoma
- Annual whole-body MRI³
- If anesthesia is requird, whole-body MRI and cranial MRI can be performed at the same time
Melanoma
- Annual full-body skin examination for new or growing nevi with abnormal features (can be done by a paediatrician or general practitioner). Digital dermoscopy by a dermatologist for atypical, growing lesions
Leukaemia
- CBC every 3-4 months only in patients with previous exposure to leukaemia-causing agents to monitor for signs of transformation
Recommendations for Early Detection for Adults (from 18 years)
In general
- Complete physical examination every 6 months
- Heavy night sweats or fever, tiredness, unexplained bruising or bleeding, unexplained pain, unusual hardening and swelling
- Palpable tumour, increasing body size/swelling, limping/abnormal gait, persistent or worsening pain
- Abdominal mass, cushingoid appearance
- Comprehensive neurological examination, focusing on frequent headaches, seizures, personality or behavioural changes, weakness, numbness or paralyses of a body part, loss of balance, nausea, dizziness, hearing loss or visual changes
- Paleness, bruises/petechiae, enlarged lymph nodes, hepatosplenomegaly. Limping, prolonged fever, unintentional weight loss, bone pain
- Examine the skin
- Palpation of the breasts and armpits to look for lumps or other changes. Pressing on the nipple to check for discharge.
- Blood in the stools, changes in the colour or appearance of the stools, thin or stringy stools, abrupt changes in the frequency of bowel movement
- Immediate registration of any medical concerns with the primary physician (family doctor, internist)
Breast Cancer
- Risk awareness and self-examination trained by a healthcare professional from the age of 18 years
- Clinical breast examination every 6 months (from the age of 20 years)
- Annual breast MRI screening (from the age of 20 years)³
- (Annual mammography from the age of 30, could alternate with breast MRI – in consultation with the centre for familial breast and ovarian cancer)
- Consider risk-minimising bilateral mastectomy
CNS Tumor
- Annual cranial MRI³ (first MRI with contrast agent, then without contrast agent with previous normal findings)
Soft Tissue Sarcoma and Osteosarcoma
- Annual whole-body MRI³
- Abdominal and pelvic ultrasound every 6 months
If there is a time overlap with the whole-body MRI, the ultrasound can be omitted. - In case of insufficient availability or quality of ultrasound → Laboratory (BE¹,²) every 3-4 months: total testosterone, dehydroepiandrosterone sulphate and androstenedione
Gastrointestinal Tumors
- Upper endoscopy and colonoscopy every 2-5 years from the age of 25; earlier in patients who have received therapeutic whole-body or abdominal radiotherapy
Melanoma
- Annual full-body examination of the skin for new or growing nevi with conspicuous features (can be done by a general practitioner). Digital dermoscopy by a dermatologist for atypical growing lesions
Prostate
- Annual PSA in serum from the age of 35. In the event of a rapid increase, rapid clarification by a urologist should take place.
Leukaemia
- CBC evere 3-4 months only in patients with previous exposure to leukaemia-causing substances, to monitor for signs of transformation
Notes
Whole-body MRI: head to toe, including upper and lower extremities
¹ Serial blood collection drawn at the same time of day and processed in the same laboratory
² The effectiveness of biochemical monitoring for the detection of adrenocortical carcinomas has not been demonstrated.
³ Alternate breast MRI/abdominal and pelvic ultrasound with annual whole-body MRI (at least one scan every 6 months).
