Li-Fraumeni syndrome

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:

• Breast cancer
• osteosarcoma
• Soft tissue sarcoma
• Adrenal cortical tumors
• Leukemia
• Astrocytoma
• Meningioma

Other malignancies that have been associated with the syndrome include:

• Gastric cancer
• Pharyngeal cancer
• Choroid plexus carcinoma
• Pancreatic Cancer
• Melanoma
• Germ cell tumors
• Wilm's tumor
• Colorectal Cancer
• Phyllodes tumor
• Ovarian Cancer
• Thyroid Cancer
• Endometrial cancer
• Prostate cancer
• Cervical cancer

Characteristics

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	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	-	-	-	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 Cancers of Breast Brain Adrenal glands	-	-	-	Criteria 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	-	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	-	-	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	-	Hamartomas	-	-	-	PTEN mutation probability risk calculator
Acromegaly/gigantism	-	-	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	-	+	-	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	-	-	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	-	+	-	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	-	-	- Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	-	-	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.
Pheochromocytoma/paraganglioma	VHL RET NF1   SDHB  SDHD	-	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	-	-	-	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	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	-	-	-	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

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.

Reference

• 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

• li-fraumeni at NIH/UW GeneTests

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