Li-Fraumeni syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.

The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.

A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Li-Fraumeni syndrome is associated with mutations in the TP53 gene. Nearly three-quarters of families with Li-Fraumeni syndrome and about one-quarter with Li-Fraumeni-like syndrome have germline mutations in the TP53 gene. Germline mutations are typically inherited and are present in essentially every cell in the body. TP53 is a tumor suppressor gene, which means that it normally helps control the growth and division of cells. Mutations in this gene can allow cells to divide in an uncontrolled way and form tumors. Other genetic and environmental factors are also likely to affect the risk of cancer in people with TP53 mutations.

A few families with cancers characteristic of Li-Fraumeni syndrome and Li-Fraumeni-like syndrome do not have TP53 mutations. The genetic factors involved in these cases are unclear.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Li-Fraumeni syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing cancer. Most people with Li-Fraumeni syndrome inherit an altered copy of the gene from an affected parent. In 7 to 20 percent of cases, however, the altered gene is the result of a new (de novo) mutation in the gene that occurred during the formation of reproductive cells (eggs or sperm) or very early in development.

For a cancer to develop in Li-Fraumeni syndrome, a mutation involving the other copy of the TP53 gene must occur in the body's cells during a person's lifetime. Cells with two altered copies of this gene do not make functional TP53 protein, which allows tumors to develop. Almost everyone who inherits one TP53 gene mutation will eventually acquire a mutation in the second copy of the gene in some cells. The second mutation often occurs in cells within the breast, bone, or muscle tissue, typically leading to the tumors common in Li-Fraumeni syndrome.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Li-Fraumeni syndrome is thought to occur in 1 in 5,000 to 1 in 20,000 people worldwide.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Neoplasm · Very frequent (99-80%)

An organ or organ-system abnormality that consists of uncontrolled autonomous cell-proliferation which can occur in any part of the body as a benign or malignant neoplasm (tumor).

Breast carcinoma · Frequent (79-30%)

The presence of a carcinoma of the breast.

Adrenocortical carcinoma · Occasional (29-5%)

A malignant neoplasm of the adrenal cortex that may produce hormones such as cortisol, aldosterone, estrogen, or testosterone.

Astrocytoma · Occasional (29-5%)

Astrocytoma is a neoplasm of the central nervous system derived from astrocytes. Astrocytes are a type of glial cell, and thus astrocytoma is a subtype of glioma.

Central primitive neuroectodermal tumor · Occasional (29-5%)

A primitive neuroectodermal neoplasm that occurs in the central nervous system.

Choroid plexus carcinoma · Occasional (29-5%)

Intraventricular papillary neoplasm derived from choroid plexus epithelium. Plexus tumors are most common in the lateral and fourth ventricles; while 80% of lateral ventricle tumors present in children, fourth ventricle tumors are evenly distributed in all age groups. Clinically, choroid plexus tumors tend to cause hydrocephalus and increased intracranial pressure. Histologically, choroid plexus papillomas correspond to WHO grade I, choroid plexus carcinomas to WHO grade III.

Colorectal polyposis · Occasional (29-5%)

Multiple abnormal growths that arise from the lining of the large intestine (colon or rectum) and protrude into the intestinal lumen.

Ependymoma · Occasional (29-5%)

The presence of an ependymoma of the central nervous system.

Other findings in the same source

From: Orphanet

Additional reported features include Glioblastoma multiforme (Occasional (29-5%)); Leukemia (Occasional (29-5%)); Lymphoma (Occasional (29-5%)); Neoplasm of the central nervous system (Occasional (29-5%)); Neoplasm of the gastrointestinal tract (Occasional (29-5%)); Osteosarcoma (Occasional (29-5%)); Stomach cancer (Occasional (29-5%)); Rhabdomyosarcoma (Occasional (29-5%)); Acute lymphoblastic leukemia (Very rare (<4-1%)); Acute myeloid leukemia (Very rare (<4-1%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Li-Fraumeni syndrome is Oncology, with a oncologist and relevant organ specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics; Relevant organ specialist / Surgical Oncology as indicated.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Has the exact tumour type been confirmed, and is staging relevant?
• What is the goal of each proposed treatment option?
• How will side effects, daily function and supportive care be addressed?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Li-Fraumeni syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.