American Journal of Part C (Seminars in Medical Genetics) 172C:296–306 (2016) ARTICLE

A Tumor Profile in Edwards Syndrome ( 18) DANIEL SATGE,* MOTOI NISHI, NICOLAS SIRVENT, AND MICHEL VEKEMANS

Constitutional trisomy 18 causes Edwards syndrome, which is characterized by and a particular set of malformations. Although this condition carries high mortality during prenatal and early postnatal life, some of the rare who survive the first months develop benign and malignant tumors. To determine the tumor profile associated with Edwards syndrome, we performed a systematic review of the literature. This review reveals a tumor profile differing from those of Down (trisomy 21) and Patau (trisomy 13) syndromes. The literature covers 45 malignancies: 29 were liver cancers, mainly hepatoblastomas found in Japanese females; 13 were kidney tumors, predominantly nephroblastomas; 1 was neuroblastoma; 1 was a Hodgkin disease; and 1 was acute myeloid in an with both trisomy 18 and type 1 neurofibromatosis. No instances of the most frequent malignancies of early life—cerebral tumors, germ cell tumors, or leukemia—are reported in children with pure trisomy 18. Tumor occurrence does not appear to correlate with body weight, tissue growth, or cancer mapping to 18. Importantly, the most recent clinical histories report successful treatment; this raises ethical concerns about cancer treatment in infants with Edwards syndrome. In conclusion, knowledge of the Edwards’ syndrome tumor profile will enable better clinical surveillance in at-risk organs (i.e., liver, kidney). This knowledge also provides clues to understanding oncogenesis, including the probably reduced frequency of some neoplasms in infants and children with this genetic condition. © 2016 Wiley Periodicals, Inc.

KEY WORDS: Edwards syndrome; trisomy 18; hepatoblastoma; nephroblastoma; cancer; cancer protection How to cite this article: Satge D, Nishi M, Sirvent N, Vekemans M. 2016. A tumor profile in Edwards syndrome (trisomy 18). Am J Med Genet Part C Semin Med Genet 172C:296–306.

INTRODUCTION condition carries a short life expectancy, understanding of this distribution will with only 5–10% of affected infants enable appropriate surveillance measures Trisomy 18 results in Edwards syndrome living beyond the first year [Cereda and for infants with this condition. We [Edwards et al., 1960], which is the Carey, 2012]. present the first systematic review of second most frequent constitutional Trisomic conditions—trisomy 18 as the literature describing tumor occur- autosomal syndrome, occurring in 1/ well as trisomy 21 () and rence in children with Edwards syn- 6,000 to 1/8,000 live births. Edwards trisomy 13 ()—are asso- drome, with the aim of providing a syndrome is characterized by a constel- ciated with a particular distribution of foundation for clinical follow-up of these lation of major and minor malforma- neoplasms [Satge and Van den Berghe, children. The findings of these reports tions, growth deficiency, and a marked 1996]. However, the distribution of reveal a particular distribution of neo- psychomotor and cognitive impairment tumors in Edwards syndrome has not plasms that raises questions on oncogen- [Pont et al., 2006]. Importantly, the yet been profiled in detail. A better esis in this well-defined genetic

Motoi Nishi, M.D., Ph.D., is Full Professor of Epidemiology in the Department of Fundamental Health Sciences, Health Sciences University of Hokkaido. He has concentrated his work on childhood cancers and childhood cancer screening. He is responsible for the Registry of Childhood Malignancies in Hokkaido, Japan. Daniel Satge, M.D. Pathology, Ph.D. Neurosciences, has worked for 20 years on cancers affecting people with intellectual disabilities. He is the Co- Creator and currently Director of Oncodefi association in Montpellier France www.oncodefi.org, dedicated to the care of cancer in these people; and co-editor of a book on cancer in children and adults with intellectual disabilities. Nicolas Sirvent, M.D., Ph.D., is Full Professor of , Head of Pediatric Oncology Unit, CHU Montpellier, France. His work is focused on childhood , and is an active member of the EORTC-Children Leukemia Group, and currently coordinator of Leukemia Committee of the French Society against Childhood Cancer. Michel Vekemans, M.D., Ph.D., is Full Professor of Human Genetics at Universite Paris Descartes and Director of the Department of Laboratory Medicine and Pathology at Hopital^ Necker-Enfants Malades. He is the author or the co-author of more than 400 publications in peer-reviewed journals. He is the Editor-in-Chief of Birth Defects Research: Clinical and Molecular Teratology and is a member of the Editorial Board of the journal Clinical Genetics. *Correspondence to: Daniel Satge, M.D., Ph.D., Oncodefi, and Epidemiology and Biostatistics Department (EA 2415), University Institute for Clinical Research Montpellier, 209 avenue des apothicaires, 34090 Montpellier, France. E-mail: [email protected] DOI 10.1002/ajmg.c.31511 Article first published online 30 July 2016 in Wiley Online Library (wileyonlinelibrary.com).

ß 2016 Wiley Periodicals, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 297 condition. Surprisingly, it seems that trisomy 18 and 1 had both trisomy 18 well-differentiated hepatoblastoma or fe- trisomy 18 could protect infants against and type 1 neurofibromatosis. tal-type hepatoblastoma, rarely - some of the most common malignancies nal-type hepatoblastoma or mixed fetal- of early childhood. embryonal-type. In one patient the two Hepatoblastoma nodules were slightly different histologi- is the most frequently cally; a molecular examination showed — reported malignancy in infants and chil- two different clones [Yokoyama et al., Trisomic conditions trisomy dren with trisomy 18. Table I summarizes 1999]. Interestingly, in one patient the 18 as well as trisomy 21 29 reports comprising 26 histologically tumor tissue had a 47,XX þ 18 (Down syndrome) and trisomy documented hepatoblastomas and three while the normal liver tissue had a 46,XX other liver tumors without histological karyotype [Tanaka et al., 1992]. In 13 (Patau syndrome)—are diagnosis. A 30th patient [Bove et al., contrast, a child with trisomy 18 associated with a particular 1996] insufficiently documented is not exhibited a 46,XX karyotype in tumor included. Patients in this group were ages cells; the karyotype of normal liver tissue distribution of neoplasms. 3 months to 10 years at diagnosis. was not indicated [Pereira et al., 2012]. In However, the distribution of Excluding one patient for whom gender a third patient the tumor karyotype was tumors in Edwards syndrome was not given, the majority of patients complex, with unusual anomalies of were female (25 vs. 3 males). As hepato- observed in hepatoblas- has not yet been profiled in blastoma is more frequent in males in toma [Tan et al., 2014]. detail. A better understanding Japan(MN,datafromtheJapanese government years 2005–2014)thisgender of this distribution will enable distribution may be explained, at least in appropriate surveillance part, by the better survival of females with Liver cancer is the most trisomy 18 [Cereda and Carey, 2012]. We measures for infants with this are not aware of an established suscepti- frequently reported condition. bility for hepatoblastoma in Japanese malignancy in infants and individuals; however, 21/29 patients children with trisomy 18. were reported from Japan. Accordingly, Table I summarizes 29 MATERIALS AND METHODS among a series of 43 autopsies performed in infants and fetuses with trisomy 18 in a reports comprising 26 After a previous extensive review of the single Japanese institution, the three literature conducted on all autosomal reported tumors were hepatoblastoma histologically documented constitutional [Satge and Van [Matsuoka and Miaushi, 2000]. This hepatoblastomas and three den Berghe, 1996], one author (DS) ethnic susceptibility is unique to hepato- followed the literature (PubMed) on blastoma and was not reported for other other liver tumors without tumorsinEdwardssyndromefor20years. tumors seen in trisomy 18. Four children histological diagnosis. We used the terms “Edwards syndrome,” had trisomy 18 mosaicism [Tanaka et al., “trisomy 18,”“neoplasms,”“cancer,” 1992; Takahashi et al., 2004; Fernandez “benign tumors,” without language et al., 2011a; Pereira et al., 2012]. This is Typical treatment protocols were limitation and whithout limitation of expected since children with mosaic occasionally modified due to the date (i.e., before and after 1996). We trisomy 18 have a longer life expectancy physical disposition of children with excluded hyperplasias and cysts. Case compared to children with full trisomy 18. trisomy 18, for example, because of reports from Japan were searched by one In six children the tumor was an autopsy growth deficiency, cardiac insuffi- author (MN) on Pubmed and Igaku finding; in some others the tumor was an ciency, or potential renal toxicity of Chuo Zassi (Japanese Central Journal of unexpected finding on routine examina- chemotherapy. Some patients did not Medicine), which is a search tool for tion [Maruyama et al., 2001; Pereira et al., receive oncotherapy and died from medical articles written in Japanese and 2012] or was discovered during an their tumors, or from other causes English. All cases found in the Japanese abdominal ultrasound [Tan et al., 2014]. [Dasouki and Barr, 1987; Maruyama literature were translated to English More commonly, symptoms such as et al., 2001; Ito et al., 2004; Ogawa language by MN. abdominal distention, hepatomegaly, or et al., 2006; Kitanovski et al., 2009]. a palpable mass revealed the tumor. Conventional or adjuvant chemother- RESULTS Tumors ranged from 0.3 to 18 cm in apy was discarded [Teraguchi et al., diameter, sometimes occupying most of 1994; Bove et al., 1996; Tan et al., The search could find 45 cancers and 12 the liver [Ariwa et al., 1992; Ito et al., 2014], delivered at lower doses, or benign tumors in 56 fetuses, infants or 2004]. Multiple foci were found in seven abbreviated due to -related children. Five patients has a mosaic children. The histological type was mainly complications [Uekusa et al., 2008; 298 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE I. Liver Tumors Documented in Infants and Children With Trisomy 18

Reference Sex, age KT Tumors Treatment and outcome Abe et al. [1983a,b] F, 9 m Full Two nodules, well-differentiated Autopsy finding hepatoblastoma Mamlok et al. [1989] F, 4 m Full 0.4 0.3 cm, embryonal-type Autopsy finding hepatoblastoma Tanaka et al. [1992] F, 2 y Mos 8 7 6 cm, fetal-type Surgery and chemotherapy. Alive at hepatoblastoma 9y 9ma Ariwa et al. [1992] F, 8 m Full 18 13 5 cm, well-differentiated Chemotherapy (vincristine, endoxan) hepatoblastoma and radiotherapy. Death 10 m Teraguchi et al. [1994] F, 7 m Full 9 6 4 and 4 cm, fetal-type Surgery, chemotherapy discarded. Teraguchi et al. [1997] hepatoblastomas Died 5 y, encephalitis Iiyama et al. [1997] Hamada et al. [1997] Takada et al. [2007] Bove et al. [1996] F, 1 y 9 m Full 9 4 cm, fetal-embryonal-type Surgery, bone metastases 5 week after hepatoblastoma surgery; chemotherapy discarded Yokoyama et al. [1999] F, 11 m Full Two micro hepatoblastomas Autopsy finding Suzuki et al. [1999] F, 4 m Full 9 8 6 cm, well-differentiated Chemotherapy JPLT protocol 91B2 hepatoblastoma tumor reduction surgery at 1 y 1 m. Alive 8 m after surgery Hino et al. [1999] M, 10 m Full 5 5 cm, well-differentiated No treatment. Death at 1 y 1 m Suzuya et al. [2000] hepatoblastoma Ishibashi et al. [2009] case 1 Uemura et al. [2000a,b] F, 5 m Full Four nodules 2.1, 2.0, 1.7, 0.8 cm, Autopsy finding fetal-type hepatoblastomas Matsuoka and Miauchi [2000] F, 4 m Full Multiple tumors 1.5–0.5 cm Autopsy findingb Nishimura et al. [2000] F, 6 m Full Well-differentiated hepatoblastoma Autopsy finding Maruyama et al. [2001] F, 3 m Full 2, 4.5, and 3.5 cm, fetal-type No treatment. Died 5 m heart failure hepatoblastomas Takagi et al. [2004] NI, NI Full NI Surgery, age not indicated. Alive 3 m after surgery Ito et al. [2004] F, 6 m Full Tumor occupied nearly all abdominal No treatment cavity, presumed hepatoblastoma Takahashi et al. [2004] F, 10 m Mos 7 6.4 cm, hepatoblastoma Chemotherapy (cisplatin, adrianicine), tumor disappearance. Surgery discarded (parents refusal) Watanabe et al. [2006] F, 10 m Full 2.7 2.6 cm, hepatoblastoma Chemotherapy (vincristine and 5-FU no CDDP (renal toxicity). Surgery planed Nishi et al. [2006] F, 1 y Full 3 cm, presumed hepatoblastoma No surgery, chemotherapy (VP-16). Sudden death 9 days after chemotherapy starting. Ogawa et al. [2006] F, 9 m Full 4 cm, well-differentiated No treatment. Death 10 m, Oohashi et al. [2012] hepatoblastoma pulmonary hypertension-hypoxia ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 299

TABLE I. (Continued)

Reference Sex, age KT Tumors Treatment and outcome Uekusa et al. [2008] M, 1 y 2 m Full 11.7 10.7 cm, fetal-type Chemotherapy THP-ADR CDDR Habu et al. [2009a,b] hepatoblastoma lower doses. Tumor decreases in Uekusa et al. [2012] size. Surgical resection. Postoperative chemotherapy. Alive 1 y 6 m post therapy Ishibashi et al. [2009] case 2 F, 5 m Full Four well-differentiated Surgery. Alive at 11 m Ishibashi et al. [2010] hepatoblastomas Kunikata et al. [2009] NI, 6 m Full Hepatoblastoma Chemotherapy, Doxorubicin. Death at 7 m Kitanovski et al. [2009] F, 6 m Full 3, 8.3, 3.7, 3.2 cm, fetal-type No treatment. (Parent refusal) death hepatoblastomas 7 m, probable disease progression Fernandez et al. [2011b] M, 9 m Mos 4.3 4.3 4 cm, fetal-type Surgery. Chemotherapy cisplatin, hepatoblastoma 5-FU, vincristine. Two recurrences. Liver transplant. Alive 28 m after transplantation Pereira et al. [2012] F, 10 y Mos 13 10 8.9 cm, fetal-type Chemotherapy, cispaltin 5-FU, hepatoblastoma vincristine shortened. Surgery. Alive at 12 y Sugitate et al. [2012] F, 2 y Full Hepatoblastoma Surgery. No chemotherapy. Alive 5 m post surgery Tan et al. [2014] case 1 F, 1 y Full 6.3 6 cm, fetal-type hepatoblastoma Complete surgical resection; stage 1 presurgical chemotherapy discarded Tan et al. [2014] case 2 F, 7 m Full 5.3 5 4.3 cm, feta-embryonal- Complete surgical resection. type hepatoblastoma stage 1 Presurgical chemotherapy discarded. No recurrence. Death at 13 months, cardiopulmonary collapse

NI, not indicated; Mos, trisomy 18 mosaicism; KT, karyotype. aPersonal communication with Dr. Teraguchi [1987]. bAlso had micro nodular hyperplasia adrenals.

Pereira et al., 2012]. Tumor response to 1997]. However, the most recent does not include the observation of a 47, chemotherapy was variable, with par- publications report a better outcome, XX þ 18 tumor karyotype in a nephro- tial or complete regression [Suzuki with survival between 6 and 28 months blastoma since the child’s phenotype was et al., 1999; Takahashi et al., 2004; after various treatments using surgery not reported [Wang-Wuu et al., 1990]. Nishi et al., 2006; Uekusa et al., 2008]. alone, including one liver transplant, or Additionally, nephroblastomatosis has One individual’s tumor displayed re- associated with chemotherapy [Suzuki been described as a common feature in sistance to 5-fluorouracil (5-FU), et al., 1999; Fernandez et al., 2011a; kidneys of infants with trisomy 18 [Bove which was attributed to the triplication Pereira et al., 2012; Sugitate et al., et al., 1969; Scott et al., 2006]. As for of the thymidilate synthetase map- 2012; Uekusa et al., 2012]. hepatoblastoma, there was an imbalance ping to [Fernandez in the female to male ratio of patients. et al., 2011b]. Surgery was also Further, and strikingly, the mean age at Renal Tumors discarded in some patients [Hino diagnosis for the three male patients was et al., 1999; Takahashi et al., 2004; Nephroblastoma, reported in 12 children 11 months, while the mean age for the Nishi et al., 2006]. Initial reports (Table II), is currently the second most nine females was 8 years 2 months. If this indicate a poor outcome, except for frequent solid malignancy in children age difference is confirmed by further one long-term survival up to 9 years with trisomy 18. The tumor was usually cases, it may suggest that the life [Tanaka et al., 1992; Teraguchi et al., revealed by an abdominal mass. Table II expectancy in females does not help to 300 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE understand the lack of renal tumors in The lesions, which could have been Heart Tumors females under 5 years. In the general nephroblastomatosis or an early Wilms population the mean age at diagnosis of tumor, were successfully treated with Four intracardiac papillary tumors have renal tumors exhibits a smaller difference: 19 weeks of chemotherapy using been reported in three infants and one 42 months in males, and 47 months in Daptomycin and Vincristin [Starr et al., fetus with documented [Rosenfield females [Fernandez et al., 2011a]. In 2014]. Additionally, the kidneys of a et al., 1962; Anderson et al., 1977; contrast to hepatoblastoma, only one 4-month-old infant with trisomy 18 Rehder, 1982] or suspected [Flenker, patient was Japanese [Suzuki et al., 1992]. contained focal bilateral hamartomas of 1972] trisomy 18. These small, benign This patient was also the only child with renal tubules at autopsy [Rosenfield papillary tumors were situated on the renal tumors who had mosaic trisomy 18. et al., 1962]. tricuspid or aortic valves, and in one Five patients died from chemotherapy- infant on the margin of a ventricular related sepsis, post-operative cardiopul- septal defect [Flenker, 1972]. Beyond monary failure, or advanced disease at different names given to these papillary diagnosis [Olson et al., 1995; Anderson Nephroblastoma, reported in nodules—myxoma, valvular hamar- et al., 2003]. Three other children had 12 children (Table II), is toma, papillary tumor, fibrous vegeta- prolonged survival to ages 8, 11, and tions—they presented similar papillary 20 years, one of them despite metastatic currently the second most architecture with loose mesenchymal disease [Geiser and Schindler, 1969]. frequent solid malignancy in axis devoid of vessels in the three Abdominal ultrasounds performed at patients with available histology. They 15 months of age in a male with large children with trisomy 18. The differ from polyvalvular diseases fre- duplication of the chromosome 18q tumor was usually revealed by quently reported in patients with and nearly full Edwards syndrome an abdominal mass. Edwards syndrome. Currently, given phenotype revealed multiple cortical the potential risk for fatal outcome, renal masses that were not biopsied. these benign tumors are treated by

TABLE II. Kidney Tumors Documented in Infants and Children With Trisomy 18

Authors Sex, age KT Tumors Treatment and outcome Geiser and Schindler M, 1 y Full Typical nephroblastoma Surgical resection 23 months. Well at [1969] 11 y 6m Karayalcin et al. [1981] F, 11 y Full Nephroblastoma, 15 12 cm Radiotherapy, surgery, chemotherapy, plus radiotherapy on metastases. Death 20 y 5 m cardio pulmonary arrest Shanske [2006] Faucette and Carey [1991] F, 9 y NI Nephroblastoma, NOS NI F, 5 y NI Nephroblastoma, NOS NI Suzuki et al. [1992] M, 7 m Mos Nephroblastoma, stage I Surgery and chemotherapy. Death from relapse in the right orbit at 8 y Olson et al. [1995] F, 13 y 9 m NI Nephroblastoma diffuse blastema, Death attributed to cancer, stage III unresectable tumor, lung metastases F, 5 y 8 m Full Nephroblastoma, mixed type stage III Death, chemotherapy-related sepsis F, 8 y 7 m NI Nephroblastoma diffuse blastema, Death, chemotherapy-related sepsis stage III F, 5 y 8 m Full Nephroblastoma tubular epithelial Death, chemotherapy-related sepsis differentiated stage III Kullendorff and Wiebe F, 5 y 6 m NI Bilateral nephroblastoma, stage V Death, no treatment [1997] Anderson et al. [2003] F, 9 y 5 m NI Nephroblastoma, stage I Post-operative death, cardio pulmonary failure

NI, not indicated; Mos, mosaicism; KT, karyotype; NOS, no other specification. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 301 surgical resection [Shahian, 2000]. [Kinoshita et al., 1989]. The pancreas syndrome. On the other hand, clinicians Papillary intracardiac tumors are very of a 7-day-old male contained a are more prone to report patients with rare during childhood in the general microcystic adenoma [Hashida et al., Edwards syndrome and a malignancy than population [Shahian, 2000]. They have 1983]. Proliferative hamartomatous patients without a malignancy. This bias not been described in trisomy 13 or lesions have been described in pancreas must be kept in mind for the evaluation of trisomy 21. Thus, these cardiac tumors of fetuses [Rehder, 1982]. The testes of tumor frequency in Edwards syndrome. appear specific to Edwards syndrome. one fetus contained gonadoblastoma- On the basis of the few reported cases, and Hemangiomas of the pulmonary and like tubular hamartomas [Coerdt et al., until a large international study is available, mitral valves were reported in a 33- 1985]. Two adrenal lesions, which are we conclude that cancer could be week fetus with trisomy 18 [Shanklin not true neoplasms, have been ob- relatively rare in infants with Edwards and Sotelo-Avila, 1969]. served in trisomy 18, a cortical micro- syndrome. nodular hyperplasia in a 4-month-old [Matsuoka and Miauchi, 2000], and Skin Tumors cytomegaly of the fetal adrenal cortex Benign skin tumors have been reported in a 3-day-old [Bove et al., 1969]. One study on cancer in rarely in trisomy 18. A small 0.5-cm Finally, a 17-month-old Japanese fe- children with birth defects capillary hamartoma was observed on male with trisomy 18 and likely the left arm of a newborn female associated type 1 neurofibromatosis found no case of cancer in the [Townes et al., 1964]. Two pedoncu- died from juvenile myelomonocytic small cohort of 378 infants lated skin tags were found anterior to leukemia [Tateishi et al., 2005]. No with trisomy 18. The fact that the left ear in a 2-month-old female information was provided on treat- [Smith et al., 1960]. A recent study ment. This hematopoietic malignancy just 5–10% of infants with reported preauricular tags, which are is strongly associated with type 1 trisomy 18 live beyond the age usually considered as malformative neurofibromatosis. It is one of the benign tumors, in 10% of children two hematopoietic malignancies we of 1 year may explain the with trisomy 18 [Rosa et al., 2013]. A uncovered in this review. small number of observed red pedonculated hamartoma occupied the left cheek of a newborn girl who tumors. DISCUSSION later developed hepatoblastomas [Kitanovski et al., 2009]. Tumor Frequency and It is not easy to evaluate the tumor Distribution profile of a particular condition on the Other Tumors The frequency of tumors in Edwards basis of case reports and small series only. A 4-cm mediastinal solid functional syndrome is not known. Given the However, since no large series or large neurogenic tumor (probably a neuro- prevalence of trisomy 18, estimated at epidemiological study yet exists, there is blastoma, a ganglioneuroblastoma, or a around 1/6,000 live births, and the value in determining the tumor types in ganglioneuroma) was discovered at incidence of pediatric cancer in 1/500 Edwards syndrome. In assuming that the ultrasound examination of a newborn children under 15 years, the 45 cancers cancer distribution is similar in infants female. The patient’s parents refused identified in this systematic review suggest and children with Edwards syndrome treatment. The tumor increased in size, that malignancies are rare. This would be and in the general population, we would and the patient died at 9 months particularly true if we exclude the 23 expect at least a few instances of the [Robinson and McCorquodale, Japanese cases. One study on cancer in most frequent pediatric malignancies 1981]. A stage IB Hodgkin children with birth defects found no case [Scheurer et al., 2011]. Yet, the 45 has been observed 17-year-old boy of cancer in the small cohort of 378 infants malignant tumors summarized in this with mosaic trisomy 18. He has been with trisomy 18 [Botto et al., 2013]. The review do not support this hypothesis. successfully treated by usual chemo- fact that just 5–10% of infants with Brain tumors are the most frequent solid therapy with four cycles of COPP trisomy 18 live beyond the age of 1 year tumors in childhood, accounting for (cyclophosphamide, vincristin, procar- may explain the small number of observed more than 20% of all neoplasms bazine, prednisone/ABU (adriamycin, tumors. It is also possible that some tumors [Scheurer et al., 2011], but no brain bleomycin, vinblastine) and local me- are not reported in the literature. How- tumor has been described in a fetus, diastinal radiotherapy with a total dose ever, a systematic and extensive examina- infant, or child with trisomy 18. of 14.4 Gy [Motta et al., 2016]. In the tion of organs in fetuses [Rehder, 1982; Leukemia, which is the predominant digestive tract, an adenomyosis of the Coerdt et al., 1985] and in newborns malignancy in children under 15 years stomach and a jejunal polyp, respec- [Kinoshita et al., 1989] uncovered benign and accounts for 25% of cancers, has not tively, were discovered at autopsy of a tumors, indicating that proliferation been reported in a child with pure 3-day-old and a 16-day-old infant anomalies are not so rare in Edwards trisomy 18 [Tateishi et al., 2005]. 302 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Neuroblastoma, the third most frequent and retinoblastoma are more frequent (8.7%) among various organ systems malignancy in children (7% of cancers) than in the general population, and investigated [Pont et al., 2006]. Finally, in the general population [Scheurer hepatoblastoma and nephroblastoma are despite a 62-fold increased risk for et al., 2011], has been reported only unusually rare [Satge et al., 1998a; Satge central nervous system malformations once [, 1981]. Additionally, no germ cell et al., 2003]. Further, the profile differs in trisomy 18 [Pont et al., 2006], not a tumor such as teratoma, usually ob- from that of children with Patau single case of cranial tumor has been served in infancy or early childhood, has syndrome (trisomy 13), in whom neu- reported. Thus, the link between cancer been described in a fetus or a child with roblastoma, germ cell tumors, cerebral and malformation does not seem con- Edwards syndrome, though germ cell tumors, epithelial tumors, and renal clusive in this context. tumors are reported in trisomy 21 [Satge tumors are the most frequently reported et al., 2003] and in trisomy 13 [Satge and malignancies [Satge and Van den Abnormal growth Van den Berghe, 1996]. Berghe, 1996]. The risk for hepatoblastoma is increased through an unknown mechanism among children with low birth weight and particularly with very low birth It is not easy to evaluate the Despite the poor survival of weight, [Spector et al., 2009]. Thus, the infants with Edwards rate of hepatoblastoma in trisomy 18 is tumor profile of a particular probably linked to prenatal and postnatal syndrome, we gathered 57 condition on the basis of case growth retardation, which characterizes reports of benign (12) and Edwards syndrome [Cereda and Carey, reports and small series only. malignant (45) neoplasms. 2012]. One study found a possible slight However, since no large series excess of retinoblastoma and glioma as The compilation of these or large epidemiological study well as a reduced frequency of Wilms reports indicates a particular tumors in very low birth weight children yet exists, there is value in [Spector et al., 2009]. As this tumor determining the tumor types tumor profile compared to that distribution has not been observed in occurring in normal fetuses, our review, the body weight of children in Edwards syndrome. with trisomy 18 does not seem able to infants, and children. explain the observed tumor profile. On the other hand, two evaluations of Despite the poor survival of infants visceral growth and weight in mid- with Edwards syndrome, we gathered 57 gestation fetuses [Barr, 1994] and new- Tumor Causes reports of benign (12) and malignant borns [Naeye, 1967] found that the (45) neoplasms. The compilation of Malformations spleen and kidneys are over-weighted in these reports indicates a particular tumor A link between cancer, particularly in individuals with trisomy 18. As kidney profile compared to that occurring in childhood, and malformations has long over-weight/nephromegaly and neph- normal fetuses, infants, and children. been suspected [Bleeker et al., 2014]. roblastomatosis favor Wilms’ tumor Hepatoblastoma and nephroblastoma, Cardiac tumors, particularly papillary [Fernandez et al., 2011b], kidney devel- which together make up nearly 5% of neoplasms, are very rare in children. opment in trisomy 18 could be a risk all malignancies in euploid children Thus, reports of five affected infants in a factor for embryonal renal tumors. [Scheurer et al., 2011], account for 38 syndrome where cardiac malformations of the 41 malignancies with docu- are estimated to be 120-fold more Supernumerary chromosome 18 and mented histology reported in children frequent than in the general population supernumerary genetic material with trisomy 18. Conversely, the most [Pont et al., 2006] would suggest a link; Trisomy 18 within tumors as a sole frequent malignancies of childhood— however, cardiac papillary tumors are abnormality or associated with other brain tumors, leukemia, neuroblastoma, benign proliferations. On the other tumor karyotype abnormalities is con- and germ cell tumors—which make up hand, hepatoblastoma is the most fre- sidered non-specific [Van Dyke, 2003]. more than 65% of childhood tumors quent malignancy in children with Trisomy 18 has been found mainly in [Scheurer et al., 2011], are strikingly trisomy 18, but hepatobiliary malfor- hematopoietic malignancies such as underrepresented. One neuroblastic tu- mations are not common in Edwards acute and chronic lymphocytic leuke- mor and one Hodgkin lymphoma are syndrome; indeed, few cases have been mia, , and reported in this population; the other reported [Ikeda et al., 1999, Kahramaner [Van Dyke, 2003]. It has also been common cancers are not reported. This et al., 2013]. The second most frequent observed in non-hematopoietic tumors tumor profile also differs from that of type of cancer in trisomy 18 is renal, such as breast cancer in adults [Buller- children with Down syndrome, in whereas the risk for urinary tract diek et al., 1994], the benign cutaneous whom leukemia, germ cell tumors, malformation is one of the lowest tumor pilomatricoma in children ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 303

[Agoston et al., 2010], and other frequency of cancers in individuals germ cell tumors, and testicular can- tumors. As children with Edwards with trisomy 18. Indeed, the rarity of cer. Another control with trisomy 13 syndrome have a short life expectancy, some tumors in individuals with tri- reveal only two tumors not reported it is not possible to evaluate whether somy 18 or trisomy 21 [Satge et al., in Pubmed. We believe that numerous constitutional trisomy 18 increases the 1998b, 2001, 2013] argues against an cases of hepatoblastoma in this review risk of adult tumors. Nonetheless, as our increased tumorigenesis. A recent ex- reveal a specific excess of this tumor in review yielded only one case of he- periment showed that various consti- Japanese infants and children with matopoietic tumor, although these tu- tutional trisomies, including trisomy trisomy 18. Further, other publication mors are the most frequent cancers in 18, induce moderate chromosome bias may not produce an accurate children in the general population, a instability that is estimated to be representation of tumor occurrences. lack of clear correspondence between insufficient to generate cancer-like We hope that this review will prompt constitutional and tumor karyotype is levels [Valind et al., 2013]. pediatricians to report their experi- likely. This challenges the direct link ences to help overcome such limita- between constitutional and tumor kar- tions in the future. A systematic Treatment, Tumor Screening, and yotype predicted by the somatic muta- review of published cases in fetuses, Ethical Problems tion theory of cancer. For instance, the children, and adults with Down increased expression of MIB1 and BCL2 Therapeutic successes reported for syndrome [Satge et al., 1998a] was genes, which map to chromosome 18, hepatoblastoma, nephroblastoma and largely confirmed by epidemiological should increase the risk for hematopoi- Hodgkin lymphoma show that cancer studies reported during the following etic tumors [Van Dyke, 2003]. The treatment is possible for infants and decade [Hasle et al., 2000; Patja et al., evidence does not support this. Benign children with trisomy 18, with survival 2006; Sullivan et al., 2007], demon- tumors, like a microcystic adenoma of 9 years after surgery for nephro- strating that important foundation [Hashida et al., 1983] and pancreatic blastoma and at least 2 years for provided by such studies. hamartoma-like lesions [Rehder, 1982], hepatoblastoma. The high risk for have been found in a newborn and in these tumors in children with trisomy CONCLUSION fetuses with trisomy 18. Interestingly, a 18 who survive the first week of life team has shown that GATA6, which prompted a recommendation for peri- This first systematic review of tumors in maps to chromosome 18 and is a odic screening with abdominal ultra- Edwards syndrome reveals a particular regulator of and func- sounds every 6 months [Carey et al., distribution of malignancies. While tion of the normal pancreas, is amplified 2002; Cereda and Carey, 2012]. Given awaiting a large international study in pancreato-biliary cancer [Kwei et al., the short life expectancy of newborns that has the power to extend the 2008]. Actually constitutional trisomy with Edwards syndrome, it has been knowledge of the tumor profile in induces more complex variations in suggested that invasive procedures and individuals with trisomy 18, the col- transcription with a particular transcrip- surgery may be avoided for these lected data are useful for two main tional response pattern independent of children [Goc et al., 2006]. However, reasons. The first is that they can enable the type of , possibly involved treatment may be considered in a an understanding of how a supernumer- in carcinogenesis [Durrbaum€ et al., context of collaborative physician– ary copy of genes on chromosome 18 2014]. However, the role of these parent decision-making, taking into favors a given subset of tumors, and seem anomalies remains to be understood to account the benefits, and burdens of to protect against other tumors. A explain the very different tumor distri- care options [Lorenz and Hardart, simple correlation with data on tumor bution observed in constitutional tri- 2014]. Treatment with surgery, che- genetics as predicted by the somatic somy 13, 18, and 21. motherapy, and radiotherapy should be theory of cancer is not likely. Aneuploidy has been proposed to the same as for ordinary children, when The oncogenetic mechanism could be favor oncogenesis by increasing chro- possible, particularly for milder phe- more complex through chronic func- mosome instability in human cells notypes. It should be adapted case by tional and metabolic modifications on [Duesberg et al., 2011]. If this mecha- case for children who have particular tissues that could lead to malignant nism is effective, we should expect an organ and/or metabolic weaknesses. transformation. The second reason, excess of cancer in constitutional We recognize that this systematic and most important from a medical such as autosomal triso- review lacks the power of an epide- point of view, is that knowledge of the mies, in which all cells have the same miological study for assessing the particular distribution of cancers will supernumerary . Such global tumor profile in trisomy 18. 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