Abstract
Improvements in our understanding of the genetic basis of human disease and increased utilization of genetic testing have identified a variety of heritable disorders associated with the onset of benign or malignant neoplasms during childhood. In many cases, the optimal management of affected children is dependent upon the early detection and treatment of tumors. Surveillance strategies based on the natural history of these lesions are often complex, requiring clinical examinations and radiologic and laboratory studies that evolve over a patient’s lifetime. A general pediatrician may be the first to suspect one of these disorders in a patient, or may be faced with questions regarding genetic testing, cancer risk, and cancer screening. The pediatrician may also coordinate and interpret the results of specific surveillance studies. In this review, we present the genetic etiology, presentation, natural history, and surveillance recommendations for four disparate hereditary tumor predisposing syndromes, including Beckwith–Wiedemann syndrome/idiopathic hemihyperplasia, von Hippel–Lindau disease, Li–Fraumeni syndrome, and rhabdoid tumor/schwannomatosis. These examples are meant to offer the clinician practical recommendations as well as a framework upon which to base the understanding and management of other conditions associated with an increased risk to develop tumors in childhood.
Similar content being viewed by others
References
Baghai M, Thompson GB, Young WF Jr et al (2002) Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: a role for laparoscopic and cortical-sparing surgery. Arch Surg 137:682–688
Baldisserotto M, Peletti AB, Angelo de Araújo M et al (2005) Beckwith-Wiedemann syndrome and bilateral adrenal pheochromocytoma: sonography and MRI findings. Pediatr Radiol 35:1132–1134
Barlaskar FM, Hammer GD (2007) The molecular genetics of adrenocortical carcinoma. Rev Endocr Metab Disord 8:343–348
Beckwith JB (1998) Children at increased risk for Wilms tumor: monitoring issues. J Pediatr 132:377–379
Bémurat L, Gosse P, Ballanger P et al (2002) Successful lapaproscopic operation of bilateral pheochromocytoma in a patient with Beckwith-Wiedemann syndrome. J Hum Hypertens 16:281–284
Bliek J, Gicquel C, Maas S et al (2004) Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). J Pediatr 145:796–799
Biegel JA, Zhou J, Rorke LB et al (1999) Germ-line and acquired mutations of INI1 in atypical teratoid rhabdoid tumor. Cancer Res 59:74–79
Birch JM, Hartley AL, Tricker KJ et al (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li–Fraumeni families. Cancer Res 54:1298–1304
Birch JM, Alston RD, McNally RJ et al (2001) Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 20:4621–4628
Boyd C, Smith MJ, Kluwe L et al (2008) Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet 74:358–366
Bruggers CS, Bleyl SB, Pysher T et al (2010) Clincopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer. doi:10.1002/pbc.22757
Burgess J (2010) How should the patient with multiple endocrine neoplasia type 1 (MEN 1) be followed? Clin Endocrinol Oxf 72:13–16
Choyke PL, Siegel MJ, Craft AW et al (1999) Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 32:196–200
Clericuzio CL, Chen E, McNeil DE et al (2003) Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143:270–272
Clark PE, Cookson MS (2008) The von Hippel-Lindau gene: turning discovery into therapy. Cancer 113:1768–1778
Coleman JA (2008) Familial and hereditary renal cancer syndromes. Urol Clin North Am 35:563–572
Cooper WN, Luharia A, Evans GA et al (2005) Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet 13:1025–1032
Eaton KW, Tooke LS, Wainwright LM et al (2011) Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56(1):7–15
Engel JR, Smallwood A, Harper A et al (2000) Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. J Med Genet 37:921–926
Evans DG, Lunt P, Clancy T, Eeles R (2010) Childhood predictive genetic testing for Li–Fraumeni syndrome. Fam Cancer 9:65–69
Everman DB, Shuman C, Dzolganovski B et al (2000) Serum alpha-fetoprotein levels in Beckwith-Wiedemann syndrome. J Pediatr 137:123–127
Ferner RE (2010) The neurofibromatoses. Pract Neurol 10:82–93
Field M, Shanley S, Kirk J (2007) Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43:219–229
Hilden JM, Meerbaum S, Burger P et al (2004) Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22:2877–2884
Hisada M, Garber JE, Fung CY et al (1998) Multiple primary cancers in families with Li–Fraumeni syndrome. J Natl Cancer Inst 90:606–611
Hoyme HE, Seaver LH, Jones KL et al (1998) Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79:274–278
Hulsebos TJM, Plomp AS, Woterman RA et al (2007) Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 80:805–810
Hwang SJ, Lozano G, Amos CI, Strong LC (2003) Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 72:975–983
Jackson EM, Shaikh TH, Zhang F et al (2007) Atypical teratoid/rhabdoid tumor in a patient with Beckwith-Wiedemann syndrome. Am J Med Genet A 143A:1767–1770
Kaatsch P, Steliarova-Foucher E, Crocetti E et al (2006) Time trends of cancer incidence in European children (1978–1997): report from the automated childhood cancer information system project. Eur J Cancer 42:1961–1971
Katzenstein HM, London WB, Douglass E et al (2002) Treatment of unresectable and metastatic hepatoblastoma: a pediatric oncology group phase II study. J Clin Oncol 20:3438–3444
Kim HJ, Butman JA, Brewer C et al (2005) Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis and treatment. J Neurosurg 102:503–512
Lapunzina P (2005) Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet 137C:53–71
Lammens CRM, Aaronson NK, Wagner A et al (2010) Genetic testing in Li–Fraumeni Syndrome: uptake and psychosocial consequences. J Clin Oncol 28:3008–3014
Lammens CRM, Bleiker EMA, Aaronson NK et al (2010) Regular surveillance for Li–Fraumeni syndrome: advice, adherence and perceived benefits. Fam Cancer 9(4):647–654
Li FP, Fraumeni JF (1982) Prospective study of a family cancer syndrome. JAMA 247:2692–2694
Lonser RR, Glenn GM, Walther M et al (2003) von Hippel-Lindau disease. Lancet 361:2059–2067
MacCollin M, Chiocca EA, Evans DG et al (2005) Diagnostic criteria for schwannomatosis. Neurology 64:1838–1845
Maher ER, Yates JR, Harries R et al (1990) Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77:1151–1163
Manksi TJ, Heffner DK, Glenn GM et al (1997) Endolymphatic sac tumors: a source of morbid hearing loss in von Hippel-Lindau disease. JAMA 277:1461–1466
Masciari S, Van den Abbeele AD, Diller LR (2008) F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li–Fraumeni syndrome. JAMA 299:1315–1319
Meister M, Choyke P, Anderson C, Patel U (2009) Radiological evaluation, management and surveillance of renal masses in Von Hippel-Lindau disease. Clin Radiol 64:589–600
Moule RN, Jhavar SG, Eeles RA (2006) Genotype phenotype correlation in Li–Fraumeni syndrome kindreds and its implications for management. Fam Cancer 5:129–133
NCCN (2008) The NCCN Clinical Practice Guidelines in Oncology™ Li–Fraumeni syndrome (Version 1.2008). © 2009 National Comprehensive Cancer Network, Inc. www.nccn.org. Accessed March 15, 2009. To view the most recent and complete version of the NCCN Guidelines, login to http://www.nccn.org
Neumann HP, Bender BU, Berger DP et al (1998) Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma. J Urol 160:1248–1254
Oda Y, Tsuneyoshi M (2006) Extrarenal rhabdoid tumors of soft tissue: clinicopathological and molecular genetic review and distinction from other soft-tissue sarcomas with rhabdoid features. Pathol Int 56:287–295
Olivier M, Goldgar DE, Sodha N et al (2003) Li–Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63:6643–6650
Perilongo G, Shafford E, Maibach R (2004) Risk-adapted treatment for childhood hepatoblastoma. Final report of the second study of the International Society of Paediatric Oncology—SIOPEL 2. Eur J Cancer 40:411–421
Poulsen MLM, Budtz-Jørgensen E, Bisgaard ML (2010) Surveillance in von Hippel-Lindau disease (vHL). Clin Genet 77:49–59
Porteus MH, Narkool P, Neuberg D et al (2000) Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the national Wilms tumor study group. J Clin Oncol 18:2026–2031
Priesemann M, Davies KM, Perry LA et al (2006) Benefits of screening in von Hippel-Lindau disease—comparison of morbidity associated with initial tumours in affected parents and children. Horm Res 66:1–5
Proust F, Laquerriere A, Constantin B et al (1999) Simultaneous presentation of atypical teratoid/rhabdoid tumor in siblings. J Neuroncol 43:63–70
Rao A, Rothman J, Nichols KE (2008) Genetic testing and tumor surveillance for children with cancer predisposition syndromes. Curr Opin Pediatr 20:1–7
Reisman D, Glaros S, Thompson EA (2009) The SWI/SNF complex and cancer. Oncogene 28:1653–1668
Ries LAG, Smith MA, Gurney JG et al. editors (1999) Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. Bethesda (MD): National Cancer Institute, SEER Program NIH Pub. No. 99–4649
Rorke LB, Packer RJ, Biegel JA (1996) Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 85:56–65
Schimke RN, Collins DL, Stolle CA (2009) von Hippel-Lindau syndrome. GeneReviews. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vhl. Accessed 15 July 2010
Sévenet N, Sheridan E, Amram D et al (1999) Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancer. Am J Hum Genet 65:1342–1348
Slavin TP, Wiesner GL (2009) Developmental defects and childhood cancer. Curr Opin Pediatr 21:717–723
Strahm B, Malkin D (2006) Hereditary cancer predisposition in children: genetic basis and clinical implications. Int J Cancer 119:2001–2006
Swensen JJ, Keyser J, Coffin CM et al (2009) Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J Med Genet 46:68–72
Tabori U, Malkin D (2008) Risk stratification in cancer predisposition syndromes: lessons learned from novel molecular developments in Li–Fraumeni syndrome. Cancer Res 68:2053–2057
Tan TY, Amor DJ (2006) Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 42:486–490
Tomlinson GE, Breslow NE, Dome J et al (2005) Rhabdoid tumor of the kidney in the National Wilms' Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 23:7641–7645
Varley JM (2003) Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 21:313–320
Vousden KH, Prives C (2009) Blinded by the light: The growing complexity of p53. Cell 137:413–431
Weksberg R, Nishikawa J, Caluseriu O et al (2001) Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 10:2989–3000
Weksberg R, Shuman C, Smith A (2005) Beckwith-Wiedemann syndrome. Am J Med Genet 137C:12–23
Weksberg R, Shuman C, Beckwith JB (2010) Beckwith–Wiedemann syndrome. Eur J Hum Genet 18:8–14
Zarate YA, Mena R, Martin LJ et al (2009) Experience with hemihyperplasia and Beckwith–Wiedemann syndrome surveillance protocol. Am J Med Genet 149A:1691–1697
Acknowledgment
We gratefully acknowledge the Grundy Vision of Life Fund and the Division of Oncology at the Children's Hospital of Philadelphia, which have supported development of the Pediatric Hereditary Cancer Predisposition Program.
Conflict of Interest
The authors report no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Teplick, A., Kowalski, M., Biegel, J.A. et al. Educational paper. Eur J Pediatr 170, 285–294 (2011). https://doi.org/10.1007/s00431-010-1377-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-010-1377-2