Case Report
LI-FRAUMENI SYNDROME IN A TURKISH FAMILY
Zeynep Karakas, Deniz Tugcu, Aysegul Unuvar, Didem Atay, Arzu Akcay, and Hakan Gedik ✷ ☐ Department of Pediatrics, Division of Haematology/Oncology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
Hulya Kayserili ☐ Department of Pediatrics, Division of Medical Genetics, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
Oner Dogan ☐ Department of Pathology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
Sema Anak and Omer Devecioglu ☐ Department of Pediatrics, Division of Haematology/Oncology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey
✷ ☐ Li-Fraumeni syndrome (LFS) is one of the familial cancers characterized by different tumors and hereditary TP53 mutations. The adrenocortical carcinoma (ACC) association with acute leukemia is unusual in childhood, even in LFS. The authors here present a family with pR337P muta- tion in TP53 gene who had a child with acute lymphoblastic leukemia (ALL) and associated adrenocortical carcinoma as a case 1 and his cousin with brain tumor as a case 2. A hereditary TP53 mutation supported the diagnosis of LFS in this family. The patients had many difficulties in treatment strategies and succumbed to death. The availability of a reliable molecular marker to detect the R337P TP53 mutation allows the rapid identification of carriers in families that have a child with ACC. Once identified, carriers could be screened for early detection of ACC by imaging and endocrine studies and should be given psychological support to prevent anxiety for death. Whether early detection of ACC will reduce the mortality in these patients remains to be determined.
Keywords acute lymphoblastic leukemia, adrenocortical cancer, Li-Fraumeni syndrome
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Received 27 December 2008; Accepted 27 January 2010.
Address correspondence to Dr. Zeynep Karakas, Department of Pediatrics, Division of Haema- tology/Oncology, Istanbul University, Istanbul Medical Faculty, Istanbul, 34104 Turkey. E-mail: zkarakas@ist.edu.tr
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Li-Fraumeni syndrome (LFS) is one of the familial cancer syndromes that is associated with TP53 tumor suppressor gene mutations inherited in an autosomal dominant manner. The carriers for TP53 gene mutation have an increased risk for breast carcinoma, soft tissue sarcoma, brain tumor, osteosarcoma, leukemia, and adrenocortical carcinoma (ACC). These tu- mors develop in family members at unusually early ages and multiple primary tumors are frequent [1-4]. Although ACC is the primary tumor in less than 5% of cases and occurs in young patients, its association with acute leukemia is unusual and predisposes to many difficulties for treatment strategies and genetic counseling [5].
CASE REPORTS
Case 1
A boy 5 years and 10 months of age was admitted due to fever, fatigue, ab- dominal pain, and predominant joint and muscle pain. Anemia and throm- bocytopenia were determined at blood count and bone marrow aspiration revealed the diagnosis of acute lymphoblastic leukemia (ALL). Modified ALL chemotherapy protocol of Children Cancer Study Group (CCG-106) was initiated for standard risk ALL according to age, initial leukocyte count, and negative chromosomal translocations. Although abdominal pain per- sisted, fever and joint and muscle pain improved dramatically. An abdominal ultrasound showed a surrenal hyperechoic lesion at first-month follow-up, although it was not shown initially due to gas distention. Further abdominal imaging studies demonstrated that there was a 5 x 5-cm mass in the left surrenal region. No accompanying hormonal abnormality was found; tumor was totally excised and microscopic metastases were shown. There wasn’t any mass in the surrenal cortex after operation in abdominal magnetic resonance imaging (MRI) study. In histological studies the specimen was considered as pleomorphic large cell surrrenal cortex carcinoma (Figure 1).
The chemotherapy protocol was changed to augmented Berlin- Frankfurt-Munster therapy (BFM) for high-risk patients and Mitotan was started for ACC. The patient developed anaphylaxis against l-asparaginase and polyethylene glycol (PEG) l-asparaginase was used for the treatment of leukemia. When the patient completed the intensive chemotherapy except l-asparaginase and achieved remission, surrenal mass reappeared. Chemotherapy was stopped and total tumor resection was carried out, but ALL relapsed before wound healing. The patient received BFM residue protocol for the first ALL relapse and IDA-FLAG (fludarabine, Ara-C, idaru- bicin) for the second one but he had no response and succumbed to death due to central nervous system involvement at thirteenth month after initial diagnosis.
The family history revealed several cases of deaths due to leukemia, brain tumors, and lymphoma. The mother and father were not consanguineous. The paternal grandfather and the grandchild of his paternal great-uncle had died of gastric carcinoma and leukemia, respectively, and his uncle had died of lymphoma. One of his great-great-uncles had died of prostate carcinoma. Two of his paternal cousins had died of brain cancer (case 2 and her brother). One of the father’s uncles had died of lymphoma. One of his aunts had treated for breast carcinoma and his grandfather’s nephew had treated for retro-orbital tumor (Figure 2).
Case 2: Case 1 Patient’s Cousin
A girl 2 years and 6 months of age (the aunt’s daughter of the first case) was admitted at another center with fatigue, stomachache, and not being able to extend the leg while sitting. When proptosis and internal deviation of left eye developed after 20 days, she was referred to our center.
Neurodevelopmental growth was normal. In family history, there were some deaths at young age from leukemia and other cancers (Figure 2). Her brother had died with medulloblastoma, father of his mother had died of gastric carcinoma, and her mother had been treated for breast carci- noma. She was the product of a second-generation consanguinity marriage. At physical examination the abdomen was tender, but no rebound tender- ness or defence was present. There was no hepatomegaly or splenomegaly. She had restricted up-outward gaze and bilateral papilla stasis. Mild
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case 2
8 patients genetic screening was performed
uterin cancer
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prostate cancer
gastric cancer
lymphoma
breast cancer
brain tumor
leukemia+adrenocortical cancer
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retroorbital tumor
thrombocytosis and anemia were detected in whole blood count. The other blood tests were normal. The cranial MRI showed a 6 x 5-cm mass that covered almost all of the left parietal hemisphere with solid and cystic com- ponents. The mass had caused edema effect and had shifted the midline by 9 to 10 mm. The spinal MRI showed dilatation of the central canal of medulla spinalis. There were some nonspecific areas with contrast enhancement at medulla spinalis.
The mass had been resected totally by left parietal craniotomy. Histopathologic examination was compatible with anaplastic ependymoma. During the recovery period, her legs became relaxed and her restricted eye movements were improved. The convenient radiotherapy and chemother- apy protocols were applied. But unfortunately she succumbed to death due to recurrence of ependymoma after 14 months from initial diagnosis.
Genetics
After genetic counseling, DNA analysis was perfomed for case 1, his fa- ther, mother, 2 brothers, and an uncle. A R337Pmutation, a novel mutation, was detected in the TP53 gene in case 1. This result confirmed the carrier status of the patient. R337P mutation was also found in his father, brother, and uncle. Patient 1 was shown to be also homozygous for R72 polymorphism and heterozygous for an additional mutation, E9+12 T-C, of the p63 gene, explaining the affected status for LFS.
R337P mutation wasn’t investigated in case 2. She was diagnosed in our center 2 years before the diagnosis of case 1. This mutation was performed to her 2 uncles, one of them was case 1’s father and the other was case 1’s uncle.
DISCUSSION
Familial cancer syndromes are characterized with the increased inci- dence of several kinds of tumors in a family. LFS is a rare autosomal dominant syndrome characterized by multiple cases of early-onset primary tumors that include bone and soft tissue sarcomas, breast cancer, brain cancer, leukemia, and childhood adrenocortical tumors. Individuals with LFS are at increased risk for developing multiple primary cancers [1-4].
Two forms of LFS are recognized: classic LFS and Li-Fraumeni-like syn- drome (LFL). Classic LFS is defined with a sarcoma diagnosed before 45 years of age and a first-degree relative with any cancer under 45 years of age and a first- or second-degree relative with any cancer under 45 years of age or a sarcoma at any age [5]. LFL shares some, but not all, of the features listed for LFS. Birch’s definition of LFL is a proband with any childhood can- cer or sarcoma, brain tumor, or adrenal cortical tumor diagnosed before 45 years of age and a first- or second-degree relative with a typical LFS cancer (sarcoma, breast cancer, brain tumor, adrenal cortical tumor, or leukemia) at any age and a first- or second-degree relative with any cancer under the age of 60 years [6]. Eeles defined LFL as 2 first- or second-degree relatives with LFS-related malignancies at any age [5, 7].
Germline mutations in the TP53 tumor suppressor gene can be detected for the majority (80%) of LFS cases. The TP53 gene encodes a transcription factor that has critical roles in cell cycle checkpoint control and apoptosis in response to genotoxic stress. Loss of TP53 function is thought to suppress a protective mechanism against accumulation of genetic alterations. Substan- tial evidence demonstrates that the obliteration of the normal TP53 pathway is a critical step in the initiation and progression of tumors. In addition to its role in the surveillance mechanisms that arrest cell cycle progression, TP53 can also trigger apoptosis in response to DNA damage. Germline mu- tations of the TP53 gene confer a high risk of diverse malignancies, wherein
mutation carriers have a lifetime risk of cancer that approaches 90%. The majority of mutations described to date are in exons 5 to 8, which encode a DNA-binding domain critical for TP53 function. Mutations that affect splic- ing have also been reported. DNA testing for TP53 gene mutations enables an accurate and routine determination of the TP53 status of patients with cancer and may be applied in clinical oncology to cancer diagnosis, predic- tion of prognosis, and response to treatment [8-11].
Individuals with early-onset primary tumors, including bone and soft tis- sue sarcomas, breast cancer, brain cancer, leukemia, and childhood adreno- cortical tumors (ACTs) and the individuals carrying other criterias of LFS should be evaluated for the TP53 gene mutations.
ACTs are rare in children and adolescents. ACTs represent 1.3% of all carcinomas in this age group. Because of the rarity of pediatric ACTs, no single pediatric oncology center has acquired extensive experience with this tumor. Most reported series describe only a few patients observed over a period of several years. Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is re- quired for cure. Residual or metastatic disease carries a poor prognosis [12,13].
Pediatric patients are rarely screened for malignancies. In selected in- stances of inherited cancer susceptibility, however, screening is warranted. For example, the early detection and treatment of familial retinoblastoma cures nearly 100% of patients while preserving vision in the affected eye [14]. Similarly, when detected at an early stage, ACT is almost always curable, whereas large or metastatic ACT carries a dismal prognosis. The availability of a reliable molecular marker to detect the predisposed high-risk persons in a family is very important. The R337P TP53 mutation that was detected in the family allows the rapid identification of carriers in families that have a child with ACT. Once individuals are identified as carriers, they could be screened for early detection of ACT by imaging and endocrine studies. Whether early detection of ACT will reduce the mortality in these patients remains to be determined [13].
The finding of germline mutations in the TP53 gene in LFS families raises the issue of predictive testing in asymptomatic members of these families. However, such testing presents a number of ethical, technical, and clinical difficulties that need to be addressed. Present data suggest that the prevalence of birth incidence of TP53 mutations is about 1 in 5000 [15]. In common with current practice for other cancer-associated genes, predictive presymptomatic testing should be offered only to individuals judged to be at risk in families where a germline TP53 mutation has already been identified. Counseling families on cancer risks associated with germline TP53 muta- tions is difficult because the morphology and site-, age-, and sex-specific incidence of cancer carriers of such mutations are uncertain. Furthermore, it is possible that there may be mutation-specific variations in cancer risks
[5, 16]. Currently, the best available risk estimates in carriers provide figures for cancers in general; few risk estimates are available for specific cancers [17]. The main spectrum of cancers and their frequencies in specific age groups relative to the expected population frequencies has been defined [18] and this provides some basis for counseling individual carriers about possible site-specific risks. However, the occurrence of cancers other than those for which a clear association has been demonstrated cannot be ruled out. Childhood cancers are a common feature in LFS families, and a further difficulty therefore arises as to whether it would be ethical to test healthy children for the presence of a germline TP53 mutation. This could only be justified if it could be demonstrated that screening for early detection of can- cers in such children conferred a survival benefit or reduction in morbidity. At present there is only weak evidence to suggest that this is the case; but each case should be treated on its own merits, and it may be appropriate in rare cases [19]. LFS poses similar quandaries to Huntington disease. LFS causes malignancies, which may appear in childhood or more commonly in adult life. The range and number of tumors and sites make screening or removal of all at-risk tissues impossible. Although early diagnosis may allow cure of a particular primary cancer, many go on to develop further primaries and 90% will have developed a malignancy by 50 years of age [19]. Testing young children affects their autonomy, and prevents them being able to decide whether or not to have tests as adults [20]. For many cancer-predisposing syndromes, such as in familial adenomatous polyposis, neurofibromatosis type 2, von Hippel-Lindau disease, and multiple endocrine neoplasia, there are clear indications for childhood testing, particularly because of the avail- ability of early screening and treatment options. Also, in these conditions adult uptake of predictive testing is high [21], suggesting most adults would take the test themselves. On the other hand, uptake of predictive testing for LFS by at-risk adults is low, with only 25% of adults going ahead with testing [21, 22].
CONCLUSIONS
The occurrence of unaffected carriers in this family raises questions about appropriate methods of cancer surveillance and counseling for these people. Perhaps most importantly, individuals at risk and their physicians are urged to pay greater attention to lingering symptoms and illnesses, par- ticularly headaches, bone pain, or abdominal discomfort, and to schedule diagnostic tests promptly [23, 24]. Psychological support is also important to prevent anxiety and fear for death in parents, especially in those who have a child with familial cancer, as in our case. Further discussions are needed for the indications of presymptomatic screening, whether prenatal diagno- sis should be offered in cancer families or not, and available reproductive
options may be discussed with the family in an appropriate ethical setting. We have already discussed all of these issues with the patient’s family and made a decision to provide a psychological support in a routine basis at predetermined intervals.
ACKNOWLEDGMENT
The authors acknowledge the support of the Georgetown University Medical Center, Institute for Molecular Genetics and Human Genetics, Molecular Diagnostic Laboratory, and Director of this laboratory, Lee-Jun Wong, for mutational analysis of TP53 gene.
Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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