Brain Tumors and Syndromes in Children

Abstract

(Brain) tumors are usually a disorder of aged individuals. If a brain tumor occurs in a child, there is a possible genetic susceptibility for this. Such genetic susceptibilities often show other signs and symptoms. Therefore, every child with a brain tumor should be carefully evaluated for the presence of a “tumor predisposition syndrome.” Here, we provide an overview of the various central nervous system tumors that occur in children with syndromes and of the various syndromes that occur in children with brain tumor. Our aim is to facilitate recognition of syndromes in children with a brain tumor and early diagnosis of brain tumors in children with syndromes. Diagnosing tumor predisposition syndromes in children may have important consequences for prognosis, treatment, and screening for subsequent malignancies and nontumor manifestations. We discuss pitfalls in clinical and molecular diagnoses, and the consequences of diagnosing a hereditary disorder for family members. Our improved knowledge of cancer etiology is increasingly translated into management strategies in syndromes in general and will likely lead in the near future to personalized therapeutic approaches for tumor predisposition syndromes.

Keywords

infant - child - brain tumor - gene - genetic - malformation - syndrome - surveillance

• References

• 1 Vogelstein B, Kinzler KW. The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill; 2002
• 2 Fleming AJ, Chi SN. Brain tumors in children. Curr Probl Pediatr Adolesc Health Care 2012; 42 (4) 80-103
• 3 Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol 2005; 23 (2) 276-292
• 4 Ponder BA. Cancer genetics. Nature 2001; 411 (6835) 336-341
• 5 Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68 (4) 820-823
• 6 Foulkes WD. Inherited susceptibility to common cancers. N Engl J Med 2008; 359 (20) 2143-2153
• 7 Eng C, Ponder BA. The role of gene mutations in the genesis of familial cancers. FASEB J 1993; 7 (10) 910-919
• 8 Hennekam RCM, Allanson JE, Krantz ID. Gorlin's Syndromes of the Head and Neck. 5th ed. New York, NY: Oxford University Press Inc.; 2010
• 9 Agha MM, Williams JI, Marrett L, To T, Zipursky A, Dodds L. Congenital abnormalities and childhood cancer. Cancer 2005; 103 (9) 1939-1948
• 10 Altmann AE, Halliday JL, Giles GG. Associations between congenital malformations and childhood cancer. A register-based case-control study. Br J Cancer 1998; 78 (9) 1244-1249
• 11 Merks JH, Ozgen HM, Koster J, Zwinderman AH, Caron HN, Hennekam RC. Prevalence and patterns of morphological abnormalities in patients with childhood cancer. JAMA 2008; 299 (1) 61-69
• 12 Merks JH, Caron HN, Hennekam RC. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet A 2005; 134A (2) 132-143
• 13 Bourdeaut F, Lequin D, Brugières L , et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 2011; 17 (1) 31-38
• 14 Merks JH, Ozgen HM, Cluitmans TL , et al. Normal values for morphological abnormalities in school children. Am J Med Genet A 2006; 140 (19) 2091-2109
• 15 Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-oncol 2012; 14 (Suppl. 05) v1-v49
• 16 Howlader N, Noone AM, Krapcho M , et al. SEER Cancer Statistics Review, 1975–2010. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2010/ based on November 2012 SEER data submission, posted to the SEER web site, April 2013.
• 17 Kieran MW, Walker D, Frappaz D, Prados M. Brain tumors: from childhood through adolescence into adulthood. J Clin Oncol 2010; 28 (32) 4783-4789
• 18 Semerci CN, Bebitoglu I, Kaçar A , et al. An unusual fetus with complete absence of thoracic, lumbar and sacral vertebrae, bilateral renal agenesis, VSD, meningomyelocele, imperforate anus, and teratoma. Clin Dysmorphol 2001; 10 (1) 57-60
• 19 Blount JP, Elton S. Spinal lipomas. Neurosurg Focus 2001; 10 (1) e3
• 20 Goyal N, Singh PK, Kakkar A, Sharma MC, Mahapatra AK. Mature teratoma in association with neural tube defect (occipital encephalocele): series of four cases and review of the literature. Pediatr Neurosurg 2012; 48 (2) 67-72
• 21 Villavicencio EH, Walterhouse DO, Iannaccone PM. The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet 2000; 67 (5) 1047-1054
• 22 Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science 2013; 341 (6141) 1237758
• 23 Winter RM, Baraitser M. The London Dysmorphology Database. J Med Genet 1987; 24 (8) 509-510
• 24 Louis DN, Ohgaki H. WHO Classification of Tumours of the Central Nervous System. Lyon, France: IARC Press; 2007
• 25 Hopman SM, Merks JH, de Borgie CA , et al. The development of a clinical screening instrument for tumour predisposition syndromes in childhood cancer patients. Eur J Cancer 2013; 49 (15) 3247-3254
• 26 Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International classification of childhood cancer, third edition. Cancer 2005; 103: 1457-1467
• 27 Lubs ML, Bauer MS, Formas ME, Djokic B. Lisch nodules in neurofibromatosis type 1. N Engl J Med 1991; 324 (18) 1264-1266
• 28 Carli M, Ferrari A, Mattke A , et al. Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 2005; 23 (33) 8422-8430
• 29 Porter DE, Prasad V, Foster L, Dall GF, Birch R, Grimer RJ. Survival in Malignant Peripheral Nerve Sheath Tumours: A Comparison between Sporadic and Neurofibromatosis Type 1-Associated Tumours. Sarcoma 2009; 2009: 756395
• 30 Wilding A, Ingham SL, Lalloo F , et al. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet 2012; 49 (4) 264-269
• 31 Ruggieri M, Iannetti P, Polizzi A , et al. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics 2005; 36 (1) 21-34
• 32 Evans DG, Birch JM, Ramsden RT. Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child 1999; 81 (6) 496-499
• 33 Asthagiri AR, Parry DM, Butman JA , et al. Neurofibromatosis type 2. Lancet 2009; 373 (9679) 1974-1986
• 34 Evans DG. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II] Genet Med 2009; 11 (9) 599-610
• 35 Baser ME, Friedman JM, Aeschliman D , et al. Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet 2002; 71 (4) 715-723
• 36 De Amorim Bernstein K, Sethi R, Trofimov A , et al. Early clinical outcomes using proton radiation for children with central nervous system atypical teratoid rhabdoid tumors. Int J Radiat Oncol Biol Phys 2013; 86 (1) 114-120
• 37 Hasselblatt M, Gesk S, Oyen F , et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 2011; 35 (6) 933-935
• 38 Sévenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 1999; 65 (5) 1342-1348
• 39 Gessi M, Giangaspero F, Pietsch T. Atypical teratoid/rhabdoid tumors and choroid plexus tumors: when genetics “surprise” pathology. Brain Pathol 2003; 13 (3) 409-414
• 40 Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 2007; 80 (4) 805-810
• 41 Plotkin SR, Blakeley JO, Evans DG , et al. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am J Med Genet A 2013; 161A (3) 405-416
• 42 MacCollin M, Chiocca EA, Evans DG , et al. Diagnostic criteria for schwannomatosis. Neurology 2005; 64 (11) 1838-1845
• 43 van den Munckhof P, Christiaans I, Kenter SB, Baas F, Hulsebos TJ. Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. Neurogenetics 2012; 13 (1) 1-7
• 44 Tsurusaki Y, Okamoto N, Ohashi H , et al. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nat Genet 2012; 44 (4) 376-378
• 45 Santen GWE, Aten E, Vulto-van Silfhout AT , et al; Coffin-Siris consortium. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat 2013; 34 (11) 1519-1528
• 46 Kanno H, Kuratsu J, Nishikawa R , et al. Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease. Acta Neurochir (Wien) 2013; 155 (1) 1-7
• 47 Ahlsén G, Gillberg IC, Lindblom R, Gillberg C. Tuberous sclerosis in Western Sweden. A population study of cases with early childhood onset. Arch Neurol 1994; 51 (1) 76-81
• 48 Ichikawa T, Wakisaka A, Daido S , et al. A case of solitary subependymal giant cell astrocytoma: two somatic hits of TSC2 in the tumor, without evidence of somatic mosaicism. J Mol Diagn 2005; 7 (4) 544-549
• 49 Russell-Swetek A, West AN, Mintern JE , et al. Identification of a novel TP53 germline mutation E285V in a rare case of paediatric adrenocortical carcinoma and choroid plexus carcinoma. J Med Genet 2008; 45 (9) 603-606
• 50 Schniederjan MJ, Shehata B, Brat DJ, Esiashvili N, Janss AJ. De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system. Pediatr Blood Cancer 2009; 53 (7) 1352-1354
• 51 Rausch T, Jones DT, Zapatka M , et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 2012; 148 (1-2) 59-71
• 52 Zhukova N, Ramaswamy V, Remke M , et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol 2013; 31 (23) 2927-2935
• 53 Villani A, Tabori U, Schiffman J , et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011; 12 (6) 559-567
• 54 Garrè ML, Cama A, Bagnasco F , et al. Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome—a new clinical perspective. Clin Cancer Res 2009; 15 (7) 2463-2471
• 55 Brugières L, Remenieras A, Pierron G , et al. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol 2012; 30 (17) 2087-2093
• 56 Merks JH, de Vries LS, Zhou XP , et al. PTEN hamartoma tumour syndrome: variability of an entity. J Med Genet 2003; 40 (10) e111
• 57 Turcot J, Despres JP, St Pierre F. Malignant tumors of the central nervous system associated with familial polyposis of the colon: report of two cases. Dis Colon Rectum 1959; 2: 465-468
• 58 Hamilton SR, Liu B, Parsons RE , et al. The molecular basis of Turcot's syndrome. N Engl J Med 1995; 332 (13) 839-847
• 59 Schulmann K, Brasch FE, Kunstmann E , et al; German HNPCC Consortium. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 2005; 128 (3) 590-599
• 60 Merlo A, Rochlitz C, Scott R. Survival of patients with Turcot's syndrome and glioblastoma. N Engl J Med 1996; 334 (11) 736-737
• 61 Vasen HF, Sanders EA, Taal BG , et al. The risk of brain tumours in hereditary non-polyposis colorectal cancer (HNPCC). Int J Cancer 1996; 65 (4) 422-425
• 62 Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?. Hum Genet 2008; 124 (2) 105-122
• 63 Tan TY, Orme LM, Lynch E , et al. Biallelic PMS2 mutations and a distinctive childhood cancer syndrome. J Pediatr Hematol Oncol 2008; 30 (3) 254-257
• 64 Krüger S, Kinzel M, Walldorf C , et al. Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. Eur J Hum Genet 2008; 16 (1) 62-72
• 65 Van Meir EG. “Turcot's syndrome”: phenotype of brain tumors, survival and mode of inheritance. Int J Cancer 1998; 75 (1) 162-164
• 66 Nishisho I, Nakamura Y, Miyoshi Y , et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 1991; 253 (5020) 665-669
• 67 Gardner EJ. Follow-up study of a family group exhibiting dominant inheritance for a syndrome including intestinal polyps, osteomas, fibromas and epidermal cysts. Am J Hum Genet 1962; 14: 376-390
• 68 Bozbuga M, Turan Suslu H, Hicdonmez T, Bayindir C. Primary cerebellopontine angle craniopharyngioma in a patient with Gardner syndrome. J Clin Neurosci 2011; 18 (2) 300-301
• 69 Kenning TJ, Kanwar VS, Qian J, Deshaies EM. A de novo desmoid tumor of the surgical site following foramen magnum meningioma resection in a patient with Gardner's Syndrome: a case report and review of the literature. J Neurooncol 2009; 91 (1) 107-111
• 70 Leblanc R. Familial adenomatous polyposis and benign intracranial tumors: a new variant of Gardner's syndrome. Can J Neurol Sci 2000; 27 (4) 341-346
• 71 D'Orazio JA. Inherited cancer syndromes in children and young adults. J Pediatr Hematol Oncol 2010; 32 (3) 195-228
• 72 Knapke S, Nagarajan R, Correll J, Kent D, Burns K. Hereditary cancer risk assessment in a pediatric oncology follow-up clinic. Pediatr Blood Cancer 2012; 58 (1) 85-89
• 73 Méhes K. Malformations in children with cancer. Am J Med Genet A 2006; 140 (8) 932
• 74 Lindhurst MJ, Sapp JC, Teer JK , et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365 (7) 611-619
• 75 Huisman SA, Redeker EJ, Maas SM, Mannens MM, Hennekam RC. High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet 2013; 50 (5) 339-344
• 76 Listernick R, Mancini AJ, Charrow J. Segmental neurofibromatosis in childhood. Am J Med Genet A 2003; 121A (2) 132-135
• 77 Evans DG, Ramsden RT, Shenton A , et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet 2007; 44 (7) 424-428
• 78 Aavikko M, Li SP, Saarinen S , et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet 2012; 91 (3) 520-526
• 79 Zhang J, Wu G, Miller CP , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013; 45 (6) 602-612
• 80 Rogers L, Pattisapu J, Smith RR, Parker P. Medulloblastoma in association with the Coffin-Siris syndrome. Childs Nerv Syst 1988; 4 (1) 41-44
• 81 Wilhelm H. Primary optic nerve tumours. Curr Opin Neurol 2009; 22 (1) 11-18
• 82 Distel L, Neubauer S, Varon R, Holter W, Grabenbauer G. Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome. Med Pediatr Oncol 2003; 41 (1) 44-48
• 83 Schiffman JD, Geller JI, Mundt E, Means A, Means L, Means V. Update on pediatric cancer predisposition syndromes. Pediatr Blood Cancer 2013; 60 (8) 1247-1252
• 84 Alexandrov LB, Nik-Zainal S, Wedge DC , et al; Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain. Signatures of mutational processes in human cancer. Nature 2013; 500 (7463) 415-421
• 85 Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the tumor genome. JAMA 2013; 310 (8) 795-796
• 86 Cassidy SB, Allanson JE. Management of Genetic Syndromes. 3rd ed. Hoboken, NJ: Wiley-Blackwell; 2010
• 87 Ullrich NJ. Inherited disorders as a risk factor and predictor of neurodevelopmental outcome in pediatric cancer. Dev Disabil Res Rev 2008; 14 (3) 229-237
• 88 Kim A, Gillespie A, Dombi E , et al. Characteristics of children enrolled in treatment trials for NF1-related plexiform neurofibromas. Neurology 2009; 73 (16) 1273-1279
• 89 Mautner VF, Nguyen R, Kutta H , et al. Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro-oncol 2010; 12 (1) 14-18
• 90 Jóźwiak S, Nabbout R, Curatolo P ; participants of the TSC Consensus Meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): Clinical recommendations. Eur J Paediatr Neurol 2013; 17 (4) 348-352
• 91 Hennekam RC, Biesecker LG, Allanson JE , et al; Elements of Morphology Consortium. Elements of morphology: general terms for congenital anomalies. Am J Med Genet A 2013; 161A (11) 2726-2733