Li-Fraumeni syndrome

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Li-Fraumeni syndrome
ICD-9 758.3
OMIM 151623
DiseasesDB 7450
eMedicine ped/1305 
MeSH D016864

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Li-Fraumeni syndrome is a rare autosomal dominant hereditary disorder. It is named after Frederick Pei Li and Joseph F. Fraumeni, American physicians who originally described the syndrome. It increases greatly the susceptibility to cancer. The syndrome is a mutation in the p53 tumor suppressor gene, which normally helps control cell growth.

Tumor types

The classic tumors that have been seen in Li-Fraumeni syndrome are:

Other malignancies that have been associated with the syndrome include:


What makes Li-Fraumeni Syndrome unusual is that

  • several kinds of cancer are involved,
  • cancer often strikes at a young age, and
  • cancer often strikes several times throughout the life of an affected person.

DIfferentiating Li-Fraumeni syndrome from other diseases

Disease Gene Chromosome Differentiating Features Components of MEN Diagnosis
Parathyroid Pitutary Pancreas
von Hippel-Lindau syndrome Von Hippel–Lindau tumor suppressor 3p25.3
  • Angiomatosis, 
  • Hemangioblastomas,
  • Pheochromocytoma, 
  • Renal cell carcinoma,
  • Pancreatic cysts (pancreatic serous cystadenoma)
  • Endolymphatic sac tumor,
  • Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)
- - +
  • Clinical diagnosis
  • In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex  PRKAR1A 17q23-q24
  • Myxomas of the heart
  • Hyperpigmentation of the skin (lentiginosis)
  • Endocrine (ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease)
- - -
  • Clinical diagnosis
Neurofibromatosis type 1 RAS 17 - - - Prenatal
  • Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.

Postnatal Cardinal Clinical Features" are required for positive diagnosis.

  • Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.
  • Two or more neurofibromas of any type or 1 plexiform neurofibroma
  • Freckling in the axillary (Crowe sign) or inguinal regions
  • Optic glioma
  • Two or more Lisch nodules (pigmented iris hamartomas)
  • A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome TP53 17 Early onset of diverse amount of cancers such as - - -


  • Sarcoma at a young age (below 45)
  • A first-degree relative diagnosed with any cancer at a young age (below 45)
  • A first or second degree relative with any cancer diagnosed before age 60.
Gardner's syndrome APC  5q21
  • Multiple polyps in the colon 
  • Osteomas of the skull
  • Thyroid cancer,
  • Epidermoid cysts,
  • Fibromas
  • Desmoid tumors
- - -
  • Clinical diagnosis
  • Colonoscopy
Multiple endocrine neoplasia type 2 RET - + - -

Criteria Two or more specific endocrine tumors

Cowden syndrome PTEN -  Hamartomas - - -
  • PTEN mutation probability risk calculator
Acromegaly/gigantism - - - + -
Pituitary adenoma - - - + -
Hyperparathyroidism - - - + - -
  • An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism.
  • Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium.
  • An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.


- Characterized by - - -
  • Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma
  • p53
  • Retinoblastoma h19
  • Insulin-like growth factor II (IGF-II)
  • p57kip2
17p, 13q  - - -
  • Increased serum glucose
  • Increased urine cortisol
  • Serum androstenedione and dehydroepiandrosterone
  • Low serum potassium
  • Low plasma renin activity
  • High serum aldosterone.
  • Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[1]

Diagnosis and treatment

Li-Fraumeni Syndrome is diagnosed if the following three criteria are met:

  1. the patient has been diagnosed with a sarcoma at a young age (below 45),
  2. a first-degree relative has been diagnosed with any cancer at a young age (below 45),
  3. and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.

Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her. If caught early the cancers can often be successfully treated. Unfortunately, people with Li-Fraumeni are likely to develop another primary malignancy at a future time.

Genetic etiology

Li-Fraumeni Syndrome is inherited in an autosomal dominant fashion.

Li-Fraumeni Syndrome is caused by mutations in p53, a tumor suppressor gene. Sufferers inherit one defective copy of the p53 gene retaining one normal copy. This significantly increases the chance that a carrier of a defective gene will develop cancer. This tendency is described in Knudson's two-hit hypothesis, originally devised to explain the incidence of tumours in retinoblastoma patients. In this model, usually in a healthy individual, two spontaneous mutation events must occur in the same gene (such as p53), in the same cell, for cancer to develop. If, however, one defective copy is inherited, only one further mutational event is required to 'knock out' normal p53 function. It is this feature that results in the early age of tumour development and the persistent recurrence of further tumours that are not produced through metastasis, this being a common feature of all the cancer syndromes. Loss of function mutations in a tumor suppressor gene act in a recessive manner, meaning that a mutation for each allele must occur so that the function of that gene is eliminated. For tumor suppressors related cancers, individuals unusually inherit one mutant copy of the p53 tumor suppressor gene and the second mutation occurs sometime during life in a target cell. A clone of cells derived from the target cell can lead to tumor formation. The likelihood that the second mutation will occur is very high, so, as indicated by many pedigree analyses of families with Li-Fraumeni syndrome, there appears to be an autosomal dominant inheritance pattern.

p53 is a transcription factor that tetramerizes before binding to DNA to transactivate genes involved in inducing, cell cycle arrest, and apoptosis. In most cases, individuals with Li-Fraumeni Syndrome have p53 mutations within the DNA-binding domain. p53 is activated by ATM and ATR.


  • Li FP, Fraumeni Jr JF. Soft-tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann Intern Med 1969;71:747-52. PMID 5360287.

External links

de:Li-Fraumeni-Syndrom et:Li-Fraumeni sündroom

Template:WikiDoc Sources Template:Jb1

  1. Toledo SP, Lourenço DM, Toledo RA (2013). "A differential diagnosis of inherited endocrine tumors and their tumor counterparts". Clinics (Sao Paulo). 68 (7): 1039–56. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.