Year: 2010
Type: other
Abstract: Li-Fraumeni Syndrome (LFS) and Von Hippel-Lindau disease (VHL) are two of these rare syndromes.The wide range of possible tumor sites and variable age of onset (from early childhood into adulthood) represent an extra source of uncertainty and distress.Predisposition to such a tumor susceptibility syndrome may lead to heightened vigilance for early signs and symptoms in those family members diagnosed with or at high risk of LFS and VHL.In order to receive adequate medical and psychosocial care, individuals with or at risk for LFS or VHL and their close relatives must often rely on the few physicians with special interest in and knowledge of these syndromes.The severity of these syndromes and the paucity of information on their psychosocial impact prompted us to initiate a nationwide study to investigate the psychosocial and behavioral impact of LFS and VHL on individuals diagnosed with or at high risk (e.g., first degree relatives of carriers) and on their partners, as well as on those who received a negative test result (i.e., proven non-carrier). BACKGROUND OF LI-FRAUMENI SYNDROME (LFS) LFS case example 12Ann is a 28 year old young woman referred to the family cancer clinic by her general practitioner because of the occurrence of multiple cancers in her family.Genetic counselling and, if possible, testing is requested to obtain more certainty about Ann's cancer risk.At the age of nine Ann lost her mother from breast cancer.Her younger brother died of a rhabdomyosarcoma at the age of three and her cousin died at the age of ten from acute leukaemia.Her grandfather died at the age of 43 from a brain tumor.Ann is currently in an important phase of her life.She is working on her career as a clinical psychologist, has a steady relationship and feels she should be planning to have children in the near future.Due to her family history, Ann is afraid that she too might develop and die of cancer at a young age or that her future children might be affected.She has decided that she wants to find out whether the cancer occurrence in her family is hereditary and, if so, what her risk and options are.After undergoing counselling and genetic testing, Ann is told that the cancer in her family is indeed hereditary.She comes from a family with Li-Fraumeni syndrome, and unfortunately has the causative p53 germline mutation.+ Leukaemia † 10 Brain 43 † 3 Rhab † Breast 36 + + Ann Male/female Affected male/female Deceased male/female Carrier/Non-carrier +/-+ Leukaemia † 10 Brain 43 † 3 Rhab † Breast 36 + + Ann Male/female Affected male/female Deceased male/female Carrier/Non-carrier +/-Chapter 1 13LFS & History Li-Fraumeni syndrome was first described by Frederic P. Li and Joseph F. Fraumeni in 1969 in a study in which they identified four families with siblings and/or cousins with childhood sarcomas.They investigated the association between childhood-onset sarcomas and early onset breast cancer 1 .However, it was not until 1982 that this new suggested cancer syndrome finally was named Li-Fraumeni Syndrome (LFS) 2 . LFS & Clinical diagnosisIn the following years, two forms of LFS were defined, namely the 'classic' Li-Fraumeni Syndrome and Li-Fraumeni Like Syndrome (LFL).The defining clinical criteria for classic LFS are: 1) a proband with a sarcoma diagnosed before the age of 45; and 2) a first degree relative with any cancer under 45 years of age; and 3) a first-or second-degree relative with any type of cancer under the age of 45 or a sarcoma at any age 3 .The clinical criteria for LFL are: 1) a proband with any childhood cancer or sarcoma, brain tumor or adrenocortical tumor under the age of 45 or a sarcoma at any age; and 2) a first-or second-degree relative with a typical LFS cancer at any age; and 3) a first-or second-degree relative in the same lineage with any cancer under the age of 60 4 . LFS & Disease characteristicsLFS is a rare hereditary cancer syndrome, which is inherited in an autosomal dominant manner.This means that the causative gene mutation need only be inherited from one parent.The risk of this occurring is 50%.LFS is characterized by a high risk of developing various types of cancer from early childhood into adulthood 1,3,5 .Classical LFS-tumors include soft-tissue sarcomas and osteosarcomas, early-onset breast cancer, acute leukemia, adrenocortical neoplasms and central nervous system tumors (e.g., brain tumors) 6 .Additionally, among those individuals with p53 mutations, gastrointestinal, pancreatic, prostate, lung, and gynecological cancers, Wilm's tumors, phyllodes tumors, lymphoma, and neuroblastoma have been observed [7][8][9][10] .Approximately 20% of the proven carries develop cancer before the age of 20 11 .Multiple primary tumors are common, especially if the first cancer has occurred in childhood 12 . LFS & GeneticsGenetic testing for LFS has been available since 1990 (in the Netherlands, since 1995).The underlying genetic defect in many Li-Fraumeni families is a germline mutation in the p53 gene 13 .Depending on the criteria used for p53 germline mutation genetic testing, a p53 gene mutation is found in 20% to 75% of the suspected families 3,4,14,15 .Carriers of a p53 mutation have a lifetime risk of developing cancer of, on average, 90% (73% in males and nearly 100% in females; the difference almost entirely explained by breast cancer) 16 .Male/female Affected male/female Deceased male/female Carrier/Non-carrier +/-+ † CHAB 43 + -Ben † RCC 42 Male/female Affected male/female Deceased male/female Carrier/Non-carrier +/-+
Author: Chantal R.M. Lammens
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: Cancer Center Amsterdam
OpenAlex ID: W1921657524