Genetic Causes of Rare Pediatric Ovarian Tumors

Authors: Pavlína Plevová 1,2;  Hedvika Geržová 3
Authors‘ workplace: Oddělení lékařské genetiky, FN Ostrava 1;  Katedra biomedicínských oborů, LF Ostravské univerzity, Ostrava 2;  Gynekologicko-porodnická klinika FN Ostrava 3
Published in: Klin Onkol 2019; 32(Supplementum2): 79-91
Category: Review
doi: 10.14735/amko2019S79


Background: Ovarian tumors in childhood and adolescence are distinguished from those that arise in adulthood by their histological subtype. These tumors may arise as the first manifestation of a cancer predisposition syndrome. Correct diagnosis of the syndrome may offer the possibility of surveillance for other members of the patient’s family.

Purpose: To summarize current knowledge about paediatric ovarian tumors that may be associated with genetically defined cancer syndromes. Juvenile granulosa cell tumors occur in those with Ollier disease and Maffucci syndrome; they are caused by postzygotic IDH1 and IDH2 gene mutations. Sertoli–Leydig cell tumors usually arise in association with DICER1 syndrome, which is caused by germline DICER1 gene mutations. Sex cord tumors with annular tubules and Sertoli cell tumors may arise in patients with Peutz–Jeghers syndrome; this syndrome is caused by germline STK11 gene mutations. The majority of germ cell tumors develop in the context of gonadal dysgenesis. In XY gonadal dysgenesis, the presence of a Y chromosome material renders the patient at increased risk for developing gonadal malignancy. Characteristically, these patients develop gonadoblastoma, which has the potential to evolve into dysgerminoma and exhibit malignant behavior. Sex-chromosome aneuploidy syndromes or mutations in genes involved in gonadal development and differentiation may cause gonadal dysgenesis. Small cell carcinoma of the ovary of a hypercalcaemic type is usually caused by loss-of-function mutations in the SMARCA4 gene.

Conclusion: Ovarian tumors are uncommon during childhood and adolescence. It is always necessary to consider gonadal dysgenesis or any of the inherited cancer syndromes. These patients require interdisciplinary care, careful noting of personal and family history, precise clinical examination, laboratory testing, and differential diagnosis by a clinician with a good knowledge of genetic syndromes. Expert pathological review may be required for correct diagnoses. This is necessary for appropriate management and to establish an association with hereditary cancer syndromes.

The work was supported by the Ministry of Health of the Czech Republic – Conceptual Development of Research Organization, Faculty Hospital of Ostrava /2015.

We thank to Lenka Foretová, M.D., Ph.D., (MMCI, Brno) and Radoslava Tomanová, M.D., (Institute of Pathology, University Hospital Ostrava) for rewarding advice, Mrs. Jana Němcová (Department of Medical Genetics, University Hospital Ostrava), Bc. Ludmila Stuchlá and Mrs. Lenka Zivčáková (Medical Library, University Hospital Ostrava) for help during manuscript preparation.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted: 10. 3. 2019

Accepted: 16. 4. 2019


ovarian neoplasms – child – adolescent – hereditary cancer syndromes


1. Heo SH, Kim JW, Shin SS et al. Review of ovarian tumors in children and adolescents: radiologic-pathologic correlation. Radiographics 2014; 34 (7): 2039–1055. doi: 10.1148/rg.347130144.

2. Skinner MA, Schlatter MG, Heifetz SA et al. Ovarian neoplasms in children. Arch Surg 1993; 128 (8): 849–853.

3. Poynter JN, Amatruda JF, Ross JA. Trends in incidence and survival of pediatric and adolescent germ cell tumors in the United States, 1975–2006. Cancer 2010; 116 (20): 4882–4891.

4. Kurman RJ, Carcangiu ML, Herrington CS et al (eds). WHO classification of tumours of female reproductive organs. WHO Classification of Tumours. 4. ed. Lyon: IARC 2014.

5. Goudie C, Witkowski L, Vairy S et al. Paediatric ovarian tumours and their associated cancersusceptibility syndromes. J Med Genet 2018; 55 (1): 1–10. doi: 10.1136/jmedgenet-2017-104926.

6. Schultz KA, Sencer SF, Messinger Y et al. Pediatric ovarian tumors: a review of 67 cases. Pediatr Blood Cancer 2005; 44 (2): 167–173. doi: 10.1002/pbc.20233.

7. Wu H, Pangas SA, Eldin KW et al. Juvenile granulosa cell tumor of the ovary: a clinicopathologic study. J Pediatr Adolesc Gynecol 2017; 30 (1): 138–143. doi: 10.1016/j.jpag.2016.09.008.

8. Auguste A, Bessière L, Todeschini AL et al. Molecular analyses of juvenile granulosa cell tumors bearing AKT1 mutations provide insights into tumor biology and therapeutic leads. Hum Mol Genet 2015; 24 (23): 6687–6698. doi: 10.1093/hmg/ddv373.

9. Schneider DT, Calaminus G, Wessalowski R et al. Ovarian sex cord-stromal tumors in children and adolescents. J Clin Oncol 2003; 21 (12): 2357–2363. doi: 10.1200/JCO.2003.05.038.

10. Tamimi HK, Bolen JW. Enchondromatosis (Ollier’s disease) and ovarian juvenile granulosa cell tumor. Cancer 1984; 53 (7): 1605–1608.

11. Vaz RM, Turner C. Ollier disease (enchondromatosis) associated with ovarian juvenile granulosa cell tumor and precocious pseudopuberty. J Pediatr 1986; 108 (6): 945–947.

12. Tanaka Y, Sasaki Y, Nishihira H et al. Ovarian juvenile granulosa cell tumor associated with Maffucci’s syndrome. Am J Clin Pathol 1992; 97 (4): 523–527. doi: 10.1093/ajcp/97.4.523.

13. Herget GW, Strohm P, Rottenburger C et al. Insights into enchondroma, enchondromatosis and the risk of secondary chondrosarcoma. Review of the literature with an emphasis on the clinical behaviour, radiology, malignant transformation, and the follow up. Neoplasma 2014; 61 (4): 365–378. doi: 10.4149/neo_2014_046.

14. Burgetova A, Matejovsky Z, Zikan M et al. The association of enchondromatosis with malignant transformed chondrosarcoma and ovarian juvenile granulosa cell tumor (Ollier disease). Taiwan J Obstet Gynecol 2017; 56 (2): 253–257. doi: 10.1016/j.tjog.2017.02.002.

15. Tan CL, Vellayappan B, Wu B et al. Molecular profiling of different glioma specimens from an Ollier disease patient suggests a multifocal disease process in the setting of IDH mosaicism. Brain Tumor Pathol 2018; 35 (4): 202–208. doi: 10.1007/s10014-018-0327-y.

16. Leyva-Carmona M, Vázquez-López MA, Lendinez-Molinos F. Ovarian juvenile granulosa cell tumors in infants. J Pediatr Hematol Oncol 2009; 31 (4): 304–306. doi: 10.1097/MPH.0b013e318196a70e.

17. Gell JS, Stannard MW, Ramnani DM et al. Juvenile granulosa cell tumor in a 13-year-old girl with enchondromatosis (Ollier’s disease): a case report. J Pediatr Adolesc Gynecol 1998; 11 (3): 147–150.

18. Amary MF, Damato S, Halai D et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat Genet 2011; 43 (12): 1262–1265. doi: 10.1038/ng.994.

19. Akiyama M, Yamaoka M, Mikami-Terao Y et al. Somatic mosaic mutations of IDH1 and NPM1 associated with cup-like acute myeloid leukemia in a patient with Maffucci syndrome. Int J Hematol 2015; 102 (6): 723–728. doi: 10.1007/s12185-015-1892-z.

20. Kenny SL, Patel K, Humphries A et al. Ovarian cellular fibroma harbouring an isocitrate dehydrogenase 1 (1DH1) mutation in a patient with Ollier disease: evidence for a causal relationship. Histopathology 2013; 62 (4): 667–670. doi: 10.1111/his.12054.

21. Foulkes WD, Gore M, McCluggage WG. Rare non-epithelial ovarian neoplasms: Pathology, genetics and treatment. Gynecol Oncol 2016; 142 (1): 190–198. doi: 10.1016/j.ygyno.2016.04.005.

22. Plon SE, Pirics ML, Nuchtern J et al. Multiple tumors in a child with germ-line mutations in TP53 and PTEN. N Engl J Med 2008; 359 (5): 537–539. doi: 10.1056/NEJMc0800627.

23. Schultz KA, Pacheco MC, Yang J et al. Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: a report from the International Pleuropulmonary Blastoma Registry. Gynecol Oncol 2011; 122 (2): 246–50. doi: 10.1016/j.ygyno.2011.03.024.

24. Kalfa N, Ecochard A, Patte C et al. Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab 2006: 91 (5): 1842–1847. doi: 10.1210/ jc.2005-2710.

25. Bessière L, Todeschini AL, Auguste A et al. A hot-spot of in-frame duplications activates the oncoprotein AKT1 in juvenile granulosa cell tumors. EBioMedicine 2015: 2 (5): 421–431. doi: 10.1016/j.ebiom.2015.03.002.

26. Shah SP, Köbel M, Senz J et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009: 360 (26): 2719–2729. doi: 10.1056/NEJMoa0902542.

27. Fuller PJ, Leung D, Chu S. Genetics and genomics of ovarian sex cord-stromal tumors. Clin Genet 2017; 91 (2): 285–291. doi: 10.1111/cge.12917.

28. Gui T, Cao D, Shen K et al. A clinicopathological analysis of 40 cases of ovarian Sertoli-Leydig cell tumors. Gynecol Oncol 2012; 127 (2): 384–389. doi: 10.1016/j.ygyno.2012.07.114.

29. Pommert L, Bradley W. Pediatric gynecologic cancers. Curr Oncol Rep 2017; 19 (7): 44. doi: 10.1007/s11912-017-0604-7.

30. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases. Am J Surg Pathol 1985; 9 (8): 543–569.

31. Horta M, Cunha TM, Marques RC et al. Ovarian Sertoli-Leydig cell tumor with heterologous elements of gastrointestinal type associated with elevated serum alpha-fetoprotein level: an unusual case and literature review. J Radiol Case Rep 2014; 8 (11): 30–41. doi: 10.3941/jrcr.v8i11.2272.

32. Hill DA, Ivanovich J, Priest JR et al. Germline DICER1 mutations in familial pleuropulmonary blastoma. Science 2009; 325 (5943): 965. doi: 10.1126/science.1174334.

33. Slade I, Bacchelli C, Davies H et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 2011; 48 (4): 273–278. doi: 10.1136/jmg.2010.083790.

34. Schultz KA, Rednam SP, Kamihara J et al. PTEN, DICER1, FH and their associated tumor susceptibility syndromes: clinical features, genetics and surveillance recommendations in childhood. Clin Cancer Res 2017; 23 (12): e76-e82. doi: 10.1158/1078-0432.CCR-17-0629.

35. Choong CS, Priest JR, Foulkes WD. Exploring the endocrine manifestations of DICER1 mutations. Trends Mol Med 2012; 18 (9): 503–505. doi: 10.1016/j.molmed.2012.07.003.

36. Foulkes WD, Priest JR, Duchaine TF. DICER1: mutations, microRNAs and mechanisms. Nat Rev Cancer 2014; 14 (10): 662–672. doi: 10.1038/nrc3802.

37. Kim J, Schultz KA, Hill DA et al. The prevalence of germline DICER1 pathogenic variation in cancer populations. Mol Genet Genomic Med 2019: e555. doi: 10.1002/mgg3.555.

38. de Kock L, Terzic T, McCluggage WG et al. DICER1 mutations are consistently present in moderately and poorly differentiated sertoli-leydig cell tumors. Am J Surg Pathol 2017; 41 (9): 1178–1187. doi: 10.1097/PAS.0000000000000895.

39. Khan NE, Bauer AJ, Schultz KAP et al. Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: a family-based cohort study. J Clin Endocrinol Metab 2017; 102 (5): 1614–1622. doi: 10.1210/jc.2016-2954.

40. Rutter MM, Jha P, Schultz KA et al. DICER1 mutations and differentiated thyroid carcinoma: evidence of a direct association. J Clin Endocrinol Metab 2016; 101 (1): 1–5. doi: 10.1210/jc.2015-2169.

41. Durieux E, Descotes F, Mauduit C et al. The co-occurrence of an ovarian Sertoli-Leydig cell tumor with a thyroid carcinoma is highly suggestive of a DICER1 syndrome. Virchows Arch 2016; 468 (5): 631–636. doi: 10.1007/s00428-016-1922-0.

42. Brenneman M, Field A, Yang J et al. Temporal order of RNase IIIb and loss-of-function mutations during development determinesphenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hittumor suppression model. F1000Res 2015; 4: 214. doi: 10.12688/f1000research.6746.2.

43. Anglesio MS, Wang Y, Yang W et al. Cancer-associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse-strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage. J Pathol 2013; 229 (3): 400–409. doi: 10.1002/path.4135.

44. Witkowski L, Mattina J, Schönberger S et al. DICER1 hotspot mutations in non-epithelial gonadal tumours. Br J Cancer 2013; 109 (10): 2744–2750. doi: 10.1038/bjc.2013.637.

45. Heravi-Moussavi A, Anglesio MS, Cheng SW et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med 2012; 366 (3): 234–242. doi: 10.1056/NEJMoa1102903.

46. Howell L, Bader A, Mullassery D et al. Sertoli Leydig cell ovarian tumour and gastric polyps as presenting features of Peutz-Jeghers syndrome. Pediatr Blood Cancer 2010; 55 (1): 206–207. doi: 10.1002/pbc.22433.

47. Ravishankar S, Mangray S, Kurkchubasche A et al. Unusual sertoli cell tumor associated with sex cord tumor with annular tubules in peutz-jeghers syndrome: report of a case and review of the literature on ovarian tumors in peutzjeghers syndrome. Int J Surg Pathol 2016; 24 (3): 269–273. doi: 10.1177/1066896915620663.

48. Brown J, Sood AK, Deavers MT et al. Patterns of metastasis in sex cord-stromal tumors of the ovary: can routine staging lymphadenectomy be omitted? Gynecol Oncol 2009; 113 (1): 86-90. doi: 10.1016/j.ygyno.2008.12.007.

49. Young RH, Welch WR, Dickersin GR et al. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 1982; 50 (7): 1384–1402.

50. Qian Q, You Y, Yang J et al. Management and prognosis of patients with ovarian sex cord tumor with annular tubules: a retrospective study. BMC Cancer 2015; 15: 270. doi: 10.1186/s12885-015-1277-y.

51. Han Y, Li S, Wu L et al. Non-Peutz-Jeghers syndrome-associated ovarian sex cord tumor with annular tubules: report of a malignant case. J Obstet Gynaecol Res 2016; 42 (2): 224–227. doi: 10.1111/jog.12883.

52. Scully RE. Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 1970; 25 (5): 1107–1121.

53. Puchmajerová A, Vasovčák P, Křepelová A. Peutz-Jeghersův syndrom. Klin Onkol 2009; 22 (Suppl 1): S36–S37.

54. Meserve EE1, Nucci MR2. Peutz-Jeghers syndrome: pathobiology, pathologic manifestations, and suggestions for recommending genetic testing in pathology reports. Surg Pathol Clin 2016; 9 (2): 243–268. doi: 10.1016/j.path.2016.01.006.

55. Schreibman IR, Baker M, Amos C et al. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 2005; 100 (2): 476–490. doi: 10.1111/j.1572-0241.2005.40237.x.

56. Connolly DC, Katabuchi H, Cliby WA et al. Somatic mutations in the STK11 / LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz-Jegher’ s syndrome. Cancer 2000; 156 (1): 339–345. doi: 10.1016/S0002-9440 (10) 64735-9.

57. Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol 2005; 18 (Suppl 2): S81–S98. doi: 10.1038/modpathol.3800311.

58. Oliva E, Alvarez T, Young RH. Sertoli cell tumors of the ovary: a clinicopathologic and immunohistochemical study of 54 cases. Am J Surg Pathol 2005; 29 (2): 143–156.

59. Tavassoli FA, Norris HJ. Sertoli tumors of the ovary. A clinicopathologic study of 28 cases with ultrastructural observations. Cancer 1980; 46 (10): 2281–2297.

60. Massa G, Roggen N, Renard M et al. Germline mutation in the STK11 gene in a girl with an ovarian Sertoli cell tumour. Eur J Pediatr 2007; 166 (10): 1083–1085. doi: 10.1007/s00431-006-0352-4.

61. Poynter JN, Amatruda JF, Ross JA. Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006. Cancer 2010; 116 (20): 4882–4891. doi: 10.1002/cncr.25454.

62. Scully RE: Gonadoblastoma: a review of 74 cases. Cancer 1970, 25 (6): 1340–1356.

63. Hung W, Randolph JG, Chandra R: Gonadoblastoma in dysgenetic testis causing male pseudohermaphroditism in newborn. Urology 1981; 17 (6): 584–587.

64. King TF, Conway GS. Swyer syndrome. Curr Opin Endocrinol Diabetes Obes 2014; 21 (6): 504–510. doi: 10.1097/MED.0000000000000113.

65. Hart WR, Burkons DM. Germ cell neoplasms arising in gonadoblastomas. Cancer 1979; 43 (2): 669–678.

66. Jorgensen A, Lindhardt Johansen M, Juul A et al. Pathogenesis of germ cell neoplasia in testicular dysgenesis and disorders of sex development. Semin Cell Dev Biol 2015; 45: 124–137. doi: 10.1016/j.semcdb.2015.09.013.

67. De Backer A, Madern GC, Oosterhuis JW et al. Ovarian germ cell tumors in children: a clinical study of 66 patients. Pediatr Blood Cancer 2006; 46 (4): 459–464. doi: 10.1002/pbc.20633.

68. Kurman RJ, Norris HJ. Embryonal carcinoma of the ovary: a clinicopathologic entity distinct from endodermal sinus tumor resembling embryonal carcinoma of the adult testis. Cancer 1976; 38 (6): 2420–2433.

69. Scully RE. Gonadoblastoma; a gonadal tumor related to the dysgerminoma (seminoma) and capable of sex-hormone production. Cancer 1953; 6 (3): 455–463.

70. Skakkebaek NE, Berthelsen JG, Giwercman A. Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987; 10 (1): 19–28.

71. Abaci A, Catli G, Berberoglu M. Gonadal malignancy risk and prophylactic gonadectomy in disorders of sexual development. J Pediatr Endocrinol Metab 2015; 28 (9–10): 1019–1027. doi: 10.1515/jpem-2014-0522.

72. McCann-Crosby B, Mansouri R, Dietrich JE et al. State of the art review in gonadal dysgenesis: challenges in diag-nosis and management. Int J Pediatr Endocrinol 2014; 2014 (1): 4. doi: 10.1186/1687-9856-2014-4.

73. MacLaughlin DT, Donahoe PK. Sex determination and differentiation. N Engl J Med 2004; 350 (4): 367–378. doi: 10.1056/NEJMra022784.

74. Fallat ME, Donahoe PK. Intersex genetic anomalies with malignant potential. Curr Opin Pediatr 2006; 18 (3): 305–311. doi: 10.1097/01.mop.0000193316.60580.d7.

75. Priya PK, Mishra VV, Choudhary S et al. A case of primary amenorrhea with Swyer syndrome. J Hum Reprod Sci 2017; 10 (4): 310–312. doi: 10.4103/jhrs.JHRS_128_17.

76. Bastian C, Muller JB, Lortat-Jacob S et al. Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis. Fertil Steril 2015; 103 (5): 1297–1304. doi: 10.1016/j.fertnstert.2015.01.043.

77. Wong YS, Tam YH, Pang KKY et al. Clinical heterogeneity in children with gonadal dysgenesis associated with non-mosaic 46,XY karyotype. J Pediatr Urol 2017; 13 (5): 508.e1–508.e6. doi: 10.1016/j.jpurol.2017.03.021.

78. Swyer GI. Male pseudohermaphroditism: a hitherto undescribed form. Br Med J 1955; 2 (4941): 709–712. doi: 10.1136/bmj.2.4941.709.

79. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine; c1966-2019. [online]. Dostupné z: https: //

80. Michala L, Creighton SM. The XY female. Best Prac Res Clin Obstet Gynaecol 2010; 24 (2): 139–148. doi: 10.1016/j.bpobgyn.2009.09.009.

81. Rocha VB, Guerra-Junior G, Marques-de-Faria AP et al. Complete gonadal dysgenesis in clinical practice: the 46,XY karyotype accounts for more than one third of cases. Fertil Steril 2011; 96 (6): 1431–1434. doi: 10.1016/j.fertnstert.2011.09.009.

82. Cameron FJ, Sinclair AH. Mutations in SRY and SOX9: testis-determining genes. Hum Mutat 1997; 9 (5): 388–395. doi: 10.1002/ (SICI) 1098-1004 (1997) 9: 5<388:: AID-HUMU2>3.0.CO; 2-0.

83. Wilhelm D, Koopman P. The makings of maleness: towards an integrated view of male sexual development. Nat Rev Genet 2006; 7 (8): 620–631. doi: 10.1038/nrg1903.

84. Cui X, Cui Y, Shi L et al. A basic understanding of Turner syndrome: incidence, complications, diagnosis, and treatment. Intractable Rare Dis Res 2018; 7 (4): 223–228. doi: 10.5582/irdr.2017.01056.

85. Schoemaker MJ, Swerdlow AJ, Higgins CD et al. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 2008; 9 (3): 239–246. doi: 10.1016/S1470-2045 (08) 70033-0.

86. Gravholt CH, Fedder J, Naeraa RW et al. Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study. J Clin Endocrinol Metab 2000; 85 (9): 3199–3202. doi: 10.1210/jcem.85.9.6800.

87. Matsushita M, Kitoh H, Kaneko H et al. A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome. Am J Med Genet 2013; 161A: 2528–2534. doi: 10.1002/ajmg.a.36134.

88. Tam YH, Wong YS, Pang KK et al. Tumor risk of children with 45,X/46,XY gonadal dysgenesis in relation to their clinical presentations: further insights into the gonadal management. J Pediatr Surg 2016; 51 (9): 1462–1466. doi: 10.1016/j.jpedsurg.2016.03.006.

89. Morozumi K, Ainoya K, Takemoto J et al. Newly identified t (2; 17) (p15; q24.2) chromosomal translocation is associated with dysgenetic gonads and multiple somatic anomalies. Tohoku J Exp Med 2018; 245 (3): 187–191. doi: 10.1620/tjem.245.187.

90. Mueller RF. The Denys-Drash syndrome. J Med Genet 1994; 31 (6): 471–477. doi: 10.1136/jmg.31.6.471.

91. Kreidberg JA, Sariola H, Loring JM et al. WT-1 is required for early kidney development. Cell 1993; 74 (4): 679–691.

92. Call KM, Glaser T, Ito CY et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 1990; 60 (3): 509–520.

93. Ezaki J, Hashimoto K, Asano T et al. Gonadal tumor in Frasier syndrome: a review and classification. Cancer Prev Res 2015; 8 (4): 271–276. doi: 10.1158/1940-6207.CAPR-14-0415.

94. Pelletier J, Bruening W, Kashtan CE et al. Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991; 67 (2): 437–447.

95. Little M, Wells C. A clinical overview of WT1 gene mutations. Hum Mutat 1997; 9 (3): 209–225. doi: 10.1002/ (SICI) 098-1004 (1997) 9: 3<209:: AID-HUMU2>3.0.CO; 2-2.

96. Barbaux S, Niaudet P, Gubler MC et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 1997; 17 (4): 467–470. doi: 10.1038/ng1297-467.

97. Huynh MT, Boudry-Labis E, Duban B et al. WAGR syndrome and congenital hypothyroidism in a child with a Mosaic 11p13 deletion. Am J Med Genet A 2017; 173 (6): 1690–1693. doi: 10.1002/ajmg.a.38206.

98. Frasier SD, Bashore RA, Mosier HD. Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J Pediatr 1964; 64: 740–745.

99. Haning RV Jr, Chesney RW, Moorthy AV et al. A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without genital ambiguity. Am J Kidney Dis 1985; 6 (1): 40–48.

100. Kinberg JA, Angle CR, Wilson RB. Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one. Am J Kidney Dis 1987; 9 (6): 507–510.

101. Joki-Erkkila MM, Karikoski R, Rantala I et al. Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: a case of Frasier syndrome. J Pediatr Adolesc Gynecol 2002; 15 (3): 145–149.

102. Melo KF, Martin RM, Costa EM et al. An unusual phenotype of Frasier syndrome due to IVS9+4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis. J Clin Endocrinol Metab 2002; 87 (6): 2500–2505. doi: 10.1210/jcem.87.6.8521.

103. Kitsiou-Tzeli S, Deligiorgi M, Malaktari-Skarantavou S et al. Sertoli cell tumor and gonadoblastoma in an untreated 29-year-old 46,XY phenotypic male with Frasier syndrome carrying a WT1 IVS9+4C>T mutation. Hormones (Athens) 2012; 11 (3): 361–367. doi: 10.14310/horm.2002.1366.

104. Patel PR, Pappas J, Arva NC et al. Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy. J Pediatr Endocrinol Metab 2013; 26 (9–10): 971–974. doi: 10.1515/jpem-2012-0409.

105. Andersen SR, Geertinger P, Larsen HW et al. Aniridia, cataract and gonadoblastoma in a mentally retarded girl with deletion of chromosome II. A clinicopathological case report. Ophthalmologica 1977; 176 (3): 171–177. doi: 10.1159/000308711.

106. Kaneko Y, Okita H, Haruta M et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. Br J Cancer 2015; 112 (6): 1121–1133. doi: 10.1038/bjc.2015.13.

107. Fleming A, Vilain E. The endless quest for sex determination genes. Clin Genet 2005; 67 (1): 15–25. doi: 10.1111/j.1399-0004.2004.00376.x.

108. Wilkie AO, Zeitlin HC, Lindenbaum RH et al. Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. II. Cases without detectable abnormality of the alpha globin complex. Am J Hum Genet 1990; 46 (6): 1127–1140.

109. Giambartolomei C, Mueller CM, Greene MH et al. A mini-review of familial ovarian germ cell tumors: an additional manifestation of the familial testicular germ cell tumor syndrome. Cancer Epidemiol 2009; 33 (1): 31–36. doi: 10.1016/j.canep.2009.04.015.

110. Bajčiová V. Nádory ovarií u dětí a adolescentních dívek. Onkologie 2014; 8 (2): 54–61.

111. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol 1994; 18 (11): 1102–1116.

112. Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer 1982; 49 (1): 188–197.

113. Lin DI, Chudnovsky Y, Duggan B et al. Comprehensive genomic profiling reveals inactivating SMARCA4 mutations and low tumor mutational burden in small cell carcinoma of the ovary, hypercalcemic-type. Gynecol Oncol 2017; 147 (3): 626–633. doi: 10.1016/j.ygyno.2017.09.031.

114. Harrison ML, Hoskins P, du Bois A et al. Small cell of the ovary, hypercalcemic type – analysis of combined experience and recommendation for management. A GCIG study. Gynecol Oncol 2006; 100 (2): 233–238. doi: 10.1016/j.ygyno.2005.10.024.

115. Florell SR, Bruggers CS, Matlak M et al. Ovarian small cell carcinoma of the hypercalcemic type in a 14 month old: the youngest reported case. Med Pediatr Oncol 1999; 32 (4): 304–307.

116. Witkowski L, Goudie C, Ramos P et al. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type. Gynecol Oncol 2016; 141 (3): 454–460. doi: 10.1016/j.ygyno.2016.03.013.

117. Estel R, Hackethal A, Kalder M et al. Small cell carcinoma of the ovary of the hypercalcaemic type: an analysis of clinical and prognostic aspects of a rare disease on the basis of cases published in the literature. Arch Gynecol Obstet 2011; 284 (5): 1277–1282. doi: 10.1007/s00404-011-1846-5.

118. Chan-Penebre E, Armstrong K, Drew A et al. Selective killing of SMARCA2-and SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type cells by inhibition of EZH2: in vitro and in vivo preclinical models. Mol Cancer Ther 2017; 16 (5): 850–860. doi: 10.1158/1535-7163.MCT-16-0678.

119. Lu B, Shi H. An in-depth look at small cell carcinoma of the ovary, hypercalcemic type (SCCOHT): clinical implications from recent molecular findings. J Cancer 2019; 10 (1): 223–237. doi: 10.7150/jca.26978.

120. Hodges HC, Stanton BZ, Cermakova K et al. Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 2018; 25 (1): 61–72. doi: 10.1038/s41594-017-0007-3.

121. Bourgo RJ, Siddiqui H, Fox S et al. SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Mol Biol Cell 2009; 20 (14): 3192–3199. doi: 10.1091/mbc.E08-12-1224.

122. Jelinic P, Mueller JJ, Olvera N et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet 2014; 46 (5): 424–426. doi: 10.1038/ng.2922.

123. Ramos P, Karnezis AN, Craig DW et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 2014; 46 (5): 427–429. doi: 10.1038/ng.2928.

124. Witkowski L, Carrot-Zhang J, Albrecht S et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet 2014; 46 (5): 438–443. doi: 10.1038/ng. 2931.

125. Schneppenheim R, Frühwald MC, Gesk S et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 2010; 86 (2): 279–284. doi: 10.1016/j.ajhg.2010.01.013.

126. 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. doi: 10.1097/PAS.0b013e3182196a39.

127. Foulkes WD, Clarke BA, Hasselblatt M et al. No small surprise – small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Path 2014; 233 (3): 209–214. doi: 10.1002/path.4362.

128. Nemes K, Bens S, Bourdeaut F et al. Rhabdoid tumor predisposition syndrome. In: Adam MP, Ardinger HH, Pagon RA et al (eds). Seattle: University of Washington 1993–2018.

129. Hasselblatt M, Nagel I, Oyen F et al. SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 2014; 128 (3): 453–456. doi: 10.1007/s00401-014-1323-x.

130. Witkowski L, Donini N, Byler-Dann R et al. The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases. Fam Cancer 2017; 16 (3): 395–399. doi: 10.1007/s10689-016-9957-6.

131. Bögershausen N, Wollnik B. Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders. Front Mol Neurosci 2018; 11: 252. doi: 10.3389/fnmol.2018.00252.

132. Coffin GS, Siris E. Mental retardation with absent fifth fingernail and terminal phalanx. Am J Dis Child 1970; 119 (5): 433–439.

133. Santen GW, Aten E, Vulto-van Silfhout AT et al. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat 2013; 34 (11): 1519–1528. doi: 10.1002/humu.22394.

134. Errichiello E, Mustafa N, Vetro A et al. SMARCA4 inactivating mutations cause concomitant Coffin-Siris syndrome, microphthalmia and small-cell carcinoma of the ovary hypercalcaemic type. J Pathol 2017; 243 (1): 9–15. doi: 10.1002/path.4926.

135. Berchuck A, Witkowski L, Hasselblatt M et al. Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type. Gynecol Oncol Rep 2015; 12: 20–22. doi: 10.1016/j.gore.2015.02.002.

136. Nasioudis D, Chapman-Davis E, Frey MK et al. Small cell carcinoma of the ovary: a rare tumor with a poor prognosis. Int J Gynecol Cancer 2018; 28 (5): 932–938. doi: 10.1097/IGC.0000000000001243.

137. Witkowski L, Goudie C, Foulkes WD et al. Small-cell carcinoma of the ovary of hypercalcemic type (malignant rhabdoid tumor of the ovary): a review with recent developments on pathogenesis. Surg Pathol Clin 2016; 9 (2): 215–226. doi: 10.1016/j.path.2016.01.005.

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