Abstract
DICER1 syndrome, known previously as the pleuropulmonary blastoma—familial tumor dysplasia syndrome (OMIM #601200, #138800, #180295), was first described clinically in 1996. In 2009, heterozygous pathogenic variants in DICER1 (OMIM *606241) were found to cause the syndrome now referred to as DICER1 syndrome; since then, numerous investigations have revealed that more than 25–30 phenotypes comprise DICER1 syndrome. The phenotypes are mostly rare to ultra-rare malignant and benign proliferative lesions, which occur from birth through ages 30–40 years. DICER1 syndrome is notably pleiotropic, but the most frequent and distinctive disorders are pleuropulmonary blastoma, cystic nephroma, and ovarian Sertoli-Leydig cell tumors, yet each has disease penetrance under 10%. In contrast, multinodular goiter, the least specific DICER1 phenotype, has penetrance approaching 75% in females and 20% in males. Other rare and highly characteristic conditions include pituitary blastoma, embryonal rhabdomyosarcoma of the uterine cervix, anaplastic renal sarcoma, as well as rare ocular and sinonasal tumors. Numerous reports of unusual rhabdomyosarcomatous tumors in young individuals, arising in the brain or in abdominal spaces, have DICER1 variants as the cause and reveal similar and characteristic histopathology. Conditions such as pineoblastoma, Wilms tumor, and juvenile hamartomatous intestinal polyps may also occur but do not on their own suggest DICER1 syndrome.
The predisposing DICER1 alterations are typically pathogenic loss-of-function variants in the germline. Termination and frameshift variants are common, but large and small deletions are also seen; mosaicism also causes DICER1 syndrome. In addition, most DICER1-related tumors harbor a highly characteristic somatic mutation in the second DICER1 allele impairing DICER1 protein’s RNase IIIb endonuclease function, which normally cleaves precursor microRNAs to their mature length. MicroRNAs function by targeted silencing and/or post-transcriptional degradation of specific messenger RNAs. Thus, DICER1 has emerged as an unusual tumor suppressor gene: the first molecular “hit” cripples one allele completely, whereas the somatic second “hit” is a single base substitution leading to an amino acid change in the RNase IIIb cleavage domain. This impairs the function of the protein, without overall protein loss, leading to unbalanced microRNA products.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Foulkes, W. D., Priest, J. R., & Duchaine, T. F. (2014). DICER1: Mutations, microRNAs and mechanisms. Nature Reviews. Cancer, 14(10), 662–672.
Hill, D. A., et al. (2009). DICER1 mutations in familial pleuropulmonary blastoma. Science, 325(5943), 965.
Priest, J. R., et al. (1996). Pleuropulmonary blastoma: A marker for familial disease. The Journal of Pediatrics, 128(2), 220–224.
Priest, J. R., et al. (2009). Pulmonary cysts in early childhood and the risk of malignancy. Pediatric Pulmonology, 44(1), 14–30.
Slade, I., et al. (2011). DICER1 syndrome: Clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. Journal of Medical Genetics, 48(4), 273–278.
de Kock, L., Wu, M. K., & Foulkes, W. D. (2019). Ten years of DICER1 mutations: Provenance, distribution, and associated phenotypes. Human Mutation, 40(11), 1939–1953.
Brenneman, M., et al. (2015). Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma/DICER1 syndrome: A unique variant of the two-hit tumor suppression model. F1000Res, 4(214), 214.
de Kock, L., et al. (2016). High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome. Journal of Medical Genetics, 53(1), 43–52.
de Kock, L., et al. (2018). Multiple DICER1-related tumors in a child with a large interstitial 14q32 deletion. Genes, Chromosomes & Cancer, 57(5), 223–230.
de Kock, L., et al. (2018). Further evidence that full gene deletions of DICER1 predispose to DICER1 syndrome. Genes, Chromosomes & Cancer, 58(8), 602–604.
Dehner, L. P. (1994). Pleuropulmonary blastoma is THE pulmonary blastoma of childhood. Seminars in Diagnostic Pathology, 11(2), 144–151.
Manivel, J. C., et al. (1988). Pleuropulmonary blastoma. The so-called pulmonary blastoma of childhood. Cancer, 62(8), 1516–1526.
McCluggage, W. G., et al. (2020). Embryonal rhabdomyosarcoma of the ovary and fallopian tube: Rare neoplasms associated with germline and somatic DICER1 mutations. The American Journal of Surgical Pathology, 44(6), 738–747.
Warren, M., et al. (2020). Expanding the spectrum of dicer1-associated sarcomas. Modern Pathology, 33(1), 164–174.
de Kock, L., & Foulkes, W. D. (2016). Sarcoma and germ-line DICER1 mutations. The Lancet Oncology, 17(11), e470.
Kamihara, J., et al. (2020). DICER1-associated central nervous system sarcoma in children: Comprehensive clinicopathologic and genetic analysis of a newly described rare tumor. Modern Pathology, 33(10), 1910–1921.
Schultz, K. A. P., et al. (2020). Pleuropulmonary blastoma-like peritoneal sarcoma: A newly described malignancy associated with biallelic DICER1 pathogenic variation. Modern Pathology, 33(10), 1922–1929.
Khan, N. E., et al. (2017). Quantification of thyroid cancer and multinodular goiter risk in the DICER1 syndrome: A family-based cohort study. The Journal of Clinical Endocrinology and Metabolism, 102(5), 1614–1622.
Stewart, D. R., et al. (2019). Neoplasm risk among individuals with a pathogenic germline variant in DICER1. Journal of Clinical Oncology, 37(8), 668–676.
Klein, S., et al. (2014). Expanding the phenotype of mutations in DICER1: Mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome. Journal of Medical Genetics, 51(5), 294–302.
de Kock, L., et al. (2013). Germ-line and somatic DICER1 mutations in a pleuropulmonary blastoma. Pediatric Blood & Cancer, 60(12), 2091–2092.
de Kock, L., et al. (2014). Pituitary blastoma: A pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathologica, 128(1), 111–122.
de Kock, L., et al. (2014). Exploring the association Between DICER1 mutations and differentiated thyroid carcinoma. The Journal of Clinical Endocrinology and Metabolism, 99(6), E1072–E1077.
Doros, L., et al. (2012). DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatric Blood & Cancer, 59(3), 558–560.
Heravi-Moussavi, A., et al. (2012). Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. The New England Journal of Medicine, 366(3), 234–242.
Tomiak, E., et al. (2014). DICER1 mutations in an adolescent with cervical embryonal rhabdomyosarcoma (cERMS). Pediatric Blood & Cancer, 61(3), 568–569.
Witkowski, L., et al. (2013). DICER1 hotspot mutations in non-epithelial gonadal tumours. British Journal of Cancer, 109(10), 2744–2750.
Wu, M. K., et al. (2013). Biallelic DICER1 mutations occur in Wilms tumours. The Journal of Pathology, 230(2), 154–164.
Anglesio, M. S., et al. (2013). 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. The Journal of Pathology, 229(3), 400–409.
Gurtan, A. M., et al. (2012). In vivo structure-function analysis of human Dicer reveals directional processing of precursor miRNAs. RNA, 18(6), 1116–1122.
de Kock, L., Rivera, B., & Foulkes, W. D. (2020). Pineoblastoma is uniquely tolerant of mutually exclusive loss of DICER1, DROSHA or DGCR8. Acta Neuropathologica, 139(6), 1115–1118.
Nur, S., et al. (2007). Syndromic presentation of a pleuropulmonary blastoma associated with congenital cystic adenomatoid malformation. A case report. Journal of Pediatric Surgery, 42(10), 1772–1775.
Priest, J. R., et al. (2006). Type I pleuropulmonary blastoma: A report from the International Pleuropulmonary Blastoma Registry. Journal of Clinical Oncology, 24(27), 4492–4498.
Shaheen, I. S., et al. (2010). Bilateral progressive cystic nephroma in a 9-month-old male infant requiring renal replacement therapy. Pediatric Nephrology, 25(9), 1755–1758.
Boman, F., et al. (2006). Familial association of pleuropulmonary blastoma with cystic nephroma and other renal tumors: A report from the International Pleuropulmonary Blastoma Registry. The Journal of Pediatrics, 149(6), 850–854.
Klein, S. D., & Martinez-Agosto, J. A. (2020). Hotspot Mutations in DICER1 Causing GLOW Syndrome-Associated Macrocephaly via Modulation of Specific microRNA Populations Result in the Activation of PI3K/ATK/mTOR Signaling. Microrna, 9(1), 70–80.
Pontén, E., et al. (2020). A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1. Journal of Medical Genetics, https://doi.org/10.1136/jmedgenet-2020-107385.
Chong, A. S., et al. (2018). Revisiting pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child: DICER1 syndrome or not? Pediatric Blood & Cancer, 65(10), e27294.
Gao, J., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling, 6(269), pl1.
Cerami, E., et al. (2012). The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discovery, 2(5), 401–404.
Tate, J. G., et al. (2018). COSMIC: The catalogue of somatic mutations in cancer. Nucleic Acids Research, 47(D1), D941–D947.
Rivera, B., et al. (2019). DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis. The Journal of Clinical Investigation, 130(3), 1479–1490.
Uro-Coste, E., et al. (2018). ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors. Acta Neuropathologica, 137(1), 175–177.
Lambo, S., et al. (2019). The molecular landscape of ETMR at diagnosis and relapse. Nature, 576(7786), 274–280.
Apellaniz-Ruiz, M., et al. (2019). Mesenchymal hamartoma of the liver and DICER1 syndrome. The New England Journal of Medicine, 380(19), 1834–1842.
Kapur, R. P., et al. (2014). Activation of the chromosome 19q microRNA cluster in sporadic and androgenetic-biparental mosaicism-associated hepatic mesenchymal hamartoma. Pediatric and Developmental Pathology, 17(2), 75–84.
Keller, R. B., et al. (2015). Methylation status of the chromosome arm 19q MicroRNA cluster in sporadic and androgenetic-Biparental mosaicism-associated hepatic mesenchymal hamartoma. Pediatric and Developmental Pathology, 18(3), 218–227.
McCluggage, W. G., & Foulkes, W. D. (2020). DICER1-associated sarcomas: Towards a unified nomenclature. Modern Pathology.
Vujanic, G. M., et al. (2007). Anaplastic sarcoma of the kidney: A clinicopathologic study of 20 cases of a new entity with polyphenotypic features. The American Journal of Surgical Pathology, 31(10), 1459–1468.
Messinger, Y. H., et al. (2015). Pleuropulmonary blastoma: A report on 350 central pathology-confirmed pleuropulmonary blastoma cases by the International Pleuropulmonary Blastoma Registry. Cancer, 121(2), 276–285.
Priest, J. R., et al. (1997). Pleuropulmonary blastoma: A clinicopathologic study of 50 cases. Cancer, 80(1), 147–161.
Guillerman, R. P., Foulkes, W. D., & Priest, J. R. (2019). Imaging of DICER1 syndrome. Pediatric Radiology, 49(11), 1488–1505.
Hill, D. A., et al. (2008). Type I pleuropulmonary blastoma: Pathology and biology study of 51 cases from the international pleuropulmonary blastoma registry. The American Journal of Surgical Pathology, 32(2), 282–295.
Dehner, L. P., et al. (2015). Pleuropulmonary blastoma: Evolution of an entity as an entry into a familial tumor predisposition syndrome. Pediatric and Developmental Pathology, 18(6), 504–511.
Schultz, K. A., et al. (2014). Judicious DICER1 testing and surveillance imaging facilitates early diagnosis and cure of pleuropulmonary blastoma. Pediatric Blood & Cancer, 61(9), 1695–1697.
Schultz, K. A. P., et al. (2018). DICER1 and associated conditions: Identification of at-risk individuals and recommended surveillance strategies. Clinical Cancer Research, 24(10), 2251–2226.
Weinberg, A. G., et al. (1980). Mesenchymal neoplasia and congenital pulmonary cysts. Pediatric Radiology, 9(3), 179–182.
Dosios, T., et al. (2004). Pleuropulmonary blastoma in childhood. A malignant degeneration of pulmonary cysts. Pediatric Surgery International, 20(11–12), 863–865.
Messinger, Y.H., et al. (2012). Outcome of 116 cases of pleuropulmonary blastoma type I and type Ir (regressed): A report from the International PPB Registry (IPPBR). Journal of Clinical Oncology (suppl; abstr 9522).
Pugh, T. J., et al. (2014). Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences. Oncogene, 33(45), 5295–5302.
Seki, M., et al. (2014). Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma. Cancer Research, 74(10), 2742–2749.
Murray, M. J., et al. (2014). Serum levels of mature microRNAs in DICER1-mutated pleuropulmonary blastoma. Oncogene, 3, e87.
Schultz, K. A., et al. (2014). Pleuropulmonary blastoma familial tumor predisposition syndrome: A unique constellation of neoplastic conditions. Pathology Case Reviews, 19(2), 90–100.
Zuker, N. B., et al. (2007). Unusual survival of an adult with pleuropulmonary blastoma and neurofibromatosis. The Journal of Thoracic and Cardiovascular Surgery, 134(2), 541–542.
Li, Q., et al. (2019). Biphasic pulmonary blastomas in the context of neurofibromatosis 1. Int J Clin Exp Med, 12(6):7852–7860.
de Kock, L., et al. (2016). Somatic DICER1 mutations in adult-onset pulmonary blastoma. The European Respiratory Journal, 47(6), 1879–1882.
Javert, C. T., & Finn, W. F. (1951). Arrhenoblastoma; the incidence of malignancy and the relationship to pregnancy, to sterility, and to treatment. Cancer, 4(1), 60–77.
Jensen, R. D., Norris, H. J., & Fraumeni, J. F., Jr. (1974). Familial arrhenoblastoma and thyroid adenoma. Cancer, 33(1), 218–223.
Vanderpump, M. P., et al. (1995). The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clinical Endocrinology, 43(1), 55–68.
Bignell, G. R., et al. (1997). Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. American Journal of Human Genetics, 61(5), 1123–1130.
Rio Frio, T., et al. (2011). DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA, 305(1), 68–77.
Lee, Y. A., et al. (2020). Predominant DICER1 pathogenic variants in pediatric follicular thyroid carcinomas. Thyroid, 30(8), 1120–1131.
de Kock, L., et al. (2016). Deep sequencing reveals spatially distributed distinct hot spot mutations in DICER1-related multinodular goiter. The Journal of Clinical Endocrinology and Metabolism, 101(10), 3637–3645.
van der Tuin, K., et al. (2018). Clinical and molecular characteristics may alter treatment strategies of thyroid malignancies in DICER1-syndrome. The Journal of Clinical Endocrinology and Metabolism, 104(2), 277–284.
Costa, V., et al. (2015). New somatic mutations and WNK1-B4GALNT3 gene fusion in papillary thyroid carcinoma. Oncotarget, 6(13), 11242–11251.
Rath, S. R., et al. (2014). Multinodular Goiter in children: An important pointer to a germline DICER1 mutation. The Journal of Clinical Endocrinology and Metabolism, 99(6), 1947–1948.
Rome, A., et al. (2008). Pediatric thyroid cancer arising as a fourth cancer in a child with pleuropulmonary blastoma. Pediatric Blood & Cancer, 50(5), 1081.
Shin, S. H., et al. (2012). Follicular thyroid carcinoma arising after hematopoietic stem cell transplantation in a child with pleuropulmonary blastoma. Thyroid, 22(5), 547–551.
Rutter, M. M., et al. (2016). DICER1 mutations and differentiated thyroid carcinoma: Evidence of a direct association. The Journal of Clinical Endocrinology and Metabolism, 101(1), 1–5.
Wasserman, J. D., et al. (2018). DICER1 mutations are frequent in adolescent-onset papillary thyroid carcinoma. The Journal of Clinical Endocrinology and Metabolism, 103(5), 2009–2015.
Chernock, R. D., et al. (2020). Poorly differentiated thyroid carcinoma of childhood and adolescence: A distinct entity characterized by DICER1 mutations. Modern Pathology, 33, 1264–1274.
Zhang, G., et al. (2019). Genetic analysis of a hereditary medullary thyroid carcinoma case with normal preoperative serum calcitonin levels. Pathology, Research and Practice, 215(10), 152529.
Agaimy, A., et al. (2020). Malignant teratoid tumor of the thyroid gland: An aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations-is the term “thyroblastoma” more appropriate? Virchows Archiv, 477(6), 787–798.
Rabinowits, G., et al. (2017). Successful management of a patient with malignant thyroid teratoma. Thyroid, 27(1), 125–128.
Rooper, L. M., et al. (2020). Recurrent DICER1 hotspot mutations in malignant thyroid gland teratomas: Molecular characterization and proposal for a separate classification. The American Journal of Surgical Pathology, 44(6), 826–833.
Priest, J. R., et al. (2007). Cerebral metastasis and other central nervous system complications of pleuropulmonary blastoma. Pediatric Blood & Cancer, 49(3), 266–273.
Nakano, Y., et al. (2019). Successful treatment of metastatic cerebral recurrence of pleuropulmonary blastoma. Pediatric Blood & Cancer, 66(5), e27628–e27628.
Scheithauer, B. W., et al. (2012). Pituitary blastoma: A unique embryonal tumor. Pituitary, 15(3), 365–373.
Scheithauer, B. W., et al. (2008). Pituitary blastoma. Acta Neuropathologica, 116(6), 657–666.
Sahakitrungruang, T., et al. (2014). Germline and somatic DICER1 mutations in a pituitary blastoma causing infantile-onset Cushing’s disease. The Journal of Clinical Endocrinology and Metabolism, 99(8), E1487–E1492.
Gresh, R., Piatt, J., & Walter, A. (2015). A report of a child with a pituitary blastoma and DICER1 syndrome. 2015 ASPHO Abstracts. Pediatric Blood & Cancer, 62(S2), S72–S73.
Kalinin, A., et al. (2017). A novel DICER1 gene mutation in a 10-month-old boy presenting with ACTH-secreting pituitary blastoma and lung cystic dysplasia. Endocrine Abstracts, 49, EP1025.
Salunke, P., et al. (2010). Congenital immature teratoma mimicking Cushing’s disease. Pediatric Neurosurgery, 46(1), 46–50.
Chhuon, Y., et al. (2020). Pituitary blastoma in a 19-year-old woman: A case report and review of literature. World Neurosurgery, 139, 310–313.
Sabbaghian, N., et al. (2012). Germline DICER1 mutation and associated loss of heterozygosity in a pineoblastoma. Journal of Medical Genetics, 49(7), 417–419.
de Kock, L., et al. (2014). Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathologica, 128(4), 583–595.
Li, B. K., et al. (2019). Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: A Rare Brain Tumor Consortium registry study. Acta Neuropathologica, 139(2), 223–241.
Liu, A. P. Y., et al. (2019). Risk-adapted therapy and biological heterogeneity in pineoblastoma: Integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials. Acta Neuropathologica, 39(2), 259–271.
Pfaff, E., et al. (2019). Molecular subgrou** of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations. Acta Neuropathologica, 139(2), 243–257.
de Kock, L., et al. (2020). An update on the central nervous system manifestations of DICER1 syndrome. Acta Neuropathologica, 139(4), 689–701.
Koelsche, C., et al. (2018). Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations. Acta Neuropathologica, 136(2), 327–337.
Sakaguchi, M., et al. (2019). Two cases of primary supratentorial intracranial rhabdomyosarcoma with DICER1 mutation which may belong to a “spindle cell sarcoma with rhabdomyosarcoma-like feature, DICER1 mutant”. Brain Tumor Pathology, 36(4), 174–182.
Lee, J. C., et al. (2019). Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1. Acta Neuropathologica, 137(3), 521–525.
Das, A., et al. (2019). Germline DICER1-mutant intracranial sarcoma with dual chondroid and spindle cell morphology and pulmonary metastases treated with multimodal therapy. Pediatric Blood & Cancer, 66(7), e27744.
Lambo, S., et al. (2020). ETMR: A tumor entity in its infancy. Acta Neuropathologica, 140, 249–266.
Cross, S. F., et al. (2010). Familial pleuropulmonary blastoma in Australia. Pediatric Blood & Cancer, 55(7), 1417–1419.
Kramer, G. D., et al. (2014). Ciliary body medulloepithelioma association with pleuropulmonary blastoma in a familial tumor predisposition syndrome. Journal of Pediatric Ophthalmology and Strabismus, 51, e48–e50.
Kaliki, S., et al. (2013). Ciliary body medulloepithelioma: Analysis of 41 cases. Ophthalmology, 120(12), 2552–2559.
Korshunov, A., et al. (2015). Comparative integrated molecular analysis of intraocular medulloepitheliomas and central nervous system embryonal tumors with multilayered rosettes confirms that they are distinct nosologic entities. Neuropathology, 35(6), 538–544.
Priest, J. R., et al. (2011). Ciliary body medulloepithelioma: Four cases associated with pleuropulmonary blastoma—A report from the International Pleuropulmonary Blastoma Registry. The British Journal of Ophthalmology, 95(7), 1001–1005.
Stathopoulos, C., et al. (2020). Successful treatment of ciliary body medulloepithelioma with intraocular melphalan chemotherapy: A case report. BMC Ophthalmology, 20(1), 239.
Ramasubramanian, A., et al. (2013). Medulloepithelioma in DICER1 syndrome treated with resection. Eye, 27(7), 896–897.
Huryn, L. A., et al. (2018). DICER1 syndrome: Characterization of the ocular phenotype in a family-based cohort study. Ophthalmology, 126(2), 296–304.
Durieux, E., et al. (2015). Somatic DICER1 gene mutation in sporadic intraocular medulloepithelioma without pleuropulmonary blastoma syndrome. Human Pathology, 46(5), 783–787.
Sahm, F., et al. (2016). Somatic mutations of DICER1 and KMT2D are frequent in intraocular medulloepitheliomas. Genes, Chromosomes & Cancer, 55(5), 418–427.
Johnson, C., et al. (2007). Nasal chondromesenchymal hamartoma: Radiographic and histopathologic analysis of a rare pediatric tumor. Pediatric Radiology, 37(1), 101–104.
McDermott, M. B., Ponder, T. B., & Dehner, L. P. (1998). Nasal chondromesenchymal hamartoma: An upper respiratory tract analogue of the chest wall mesenchymal hamartoma. The American Journal of Surgical Pathology, 22(4), 425–433.
Priest, J. R., et al. (2010). Nasal chondromesenchymal hamartoma in children with pleuropulmonary blastoma—A report from the International Pleuropulmonary Blastoma Registry registry. International Journal of Pediatric Otorhinolaryngology, 74(11), 1240–1244.
Stewart, D. R., et al. (2014). Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder. Human Genetics, 133(11), 1443–1450.
Stringer, M. D., & Alizai, N. K. (2005). Mesenchymal hamartoma of the liver: A systematic review. Journal of Pediatric Surgery, 40(11), 1681–1690.
Nguyen, V. H., Bouron-Dal Soglio, D., & Foulkes, W. D. (2019). Mesenchymal hamartoma of the liver and DICER1 syndrome. Reply. The New England Journal of Medicine, 381(6), 587.
Vargas, S. O., & Perez-Atayde, A. R. (2019). Mesenchymal hamartoma of the liver and DICER1 syndrome. The New England Journal of Medicine, 381(6), 586–587.
Donovan, M. J., Kozakewich, H., & Perez-Atayde, A. (1995). Solitary nonparasitic cysts of the liver: The Boston Children’s Hospital experience. Pediatric Pathology & Laboratory Medicine, 15(3), 419–428.
Foulkes, W. D., et al. (2011). Extending the phenotypes associated with DICER1 mutations. Human Mutation, 32(12), 1381–1384.
Young, R. H. (2005). Sex cord-stromal tumors of the ovary and testis: Their similarities and differences with consideration of selected problems. Modern Pathology, 18(Suppl 2), S81–S98.
Young, R. H., & Scully, R. E. (1985). Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases. The American Journal of Surgical Pathology, 9(8), 543–569.
Schultz, K. A., et al. (2011). Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: A report from the International Pleuropulmonary Blastoma Registry. Gynecologic Oncology, 122(2), 246–250.
de Kock, L., et al. (2017). DICER1 mutations are consistently present in moderately and poorly differentiated Sertoli-Leydig cell tumors. The American Journal of Surgical Pathology, 41(9), 1178–1187.
Goulvent, T., et al. (2015). DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: A GINECO Group study. Histopathology, 68(2), 279–285.
Conlon, N., et al. (2015). A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors. Modern Pathology, 28(12), 1603–1612.
Kato, N., et al. (2017). DICER1 hotspot mutations in ovarian Sertoli-Leydig cell tumors: A potential association with androgenic effects. Human Pathology, 59, 41–47.
Schultz, K. A. P., et al. (2017). DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry. Gynecologic Oncology, 147(3), 521–527.
Karnezis, A. N., et al. (2019). DICER1 and FOXL2 mutation status correlates with clinicopathologic features in ovarian Sertoli-Leydig cell tumors. The American Journal of Surgical Pathology, 43(5), 628–638.
**ao, Y. X., et al. (2020). Ovarian Sertoli-Leydig cell tumors: DICER1 hotspot mutations and associated clinicopathological features. Zhonghua Bing Li Xue Za Zhi, 49(5), 441–447.
McCluggage, W. G., et al. (2020). Somatic tumour testing establishes that bilateral DICER1-associated ovarian Sertoli-Leydig cell tumours represent independent primary neoplasms. Histopathology, 77(2), 223–230.
Chen, K. S., et al. (2018). Distinct DICER1 hotspot mutations identify bilateral tumors as separate events. JCO Precision Oncology, 2, 1–9.
Wang, Y., et al. (2018). DICER1 hotspot mutations in ovarian gynandroblastoma. Histopathology, 73(2), 306–313.
de Kock, L., et al. (2015). Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome. Human Pathology, 46(6), 917–922.
Schultz, K. A., et al. (2016). Ovarian tumors related to intronic mutations in DICER1: A report from the international ovarian and testicular stromal tumor registry. Familial Cancer, 15(1), 105–110.
Kebudi, R., et al. (2018). PO-500. Germline DICER1 mutation and sarcoma of the ovary. Abstract from the 50th Congress of the International Society of Paediatric Oncology (SIOP) Kyoto, Japan. Pediatric Blood & Cancer, 65(Suppl 2), e27455.
Melendez-Zajgla, J., et al. (2018). Genomics of a pediatric ovarian fibrosarcoma. Association with the DICER1 syndrome. Scientific Reports, 8(1), 3252.
de Boer, C. M., et al. (2012). DICER1 RNase IIIb domain mutations are infrequent in testicular germ cell tumours. BMC Research Notes, 5, 569.
Daya, D. A., & Scully, R. E. (1988). Sarcoma botryoides of the uterine cervix in young women: A clinicopathological study of 13 cases. Gynecologic Oncology, 29(3), 290–304.
Golbang, P., et al. (1997). Cervical sarcoma botryoides and ovarian Sertoli-Leydig cell tumor. Gynecologic Oncology, 67(1), 102–106.
Rosenberg, P., et al. (2012). Cervical sarcoma botryoides and ovarian Sertoli-Leydig cell tumor: A case report and review of literature. Archives of Gynecology and Obstetrics, 285(3), 845–848.
McClean, G. E., et al. (2007). Cervical embryonal rhabdomyosarcoma and ovarian Sertoli-Leydig cell tumour: A more than coincidental association of two rare neoplasms? Journal of Clinical Pathology, 60(3), 326–328.
de Kock, L., et al. (2016). Adult-onset cervical embryonal rhabdomyosarcoma and DICER1 mutations. Journal of Lower Genital Tract Disease, 20(1), e8–e10.
Dehner, L. P., Jarzembowski, J. A., & Hill, D. A. (2012). Embryonal rhabdomyosarcoma of the uterine cervix: A report of 14 cases and a discussion of its unusual clinicopathological associations. Modern Pathology, 25(4), 602–614.
Stewart, C. J., Charles, A., & Foulkes, W. D. (2016). Gynecologic manifestations of the DICER1 syndrome. Surgical Pathology Clinics, 9(2), 227–241.
Zhang, L., et al. (2020). Somatic DICER1 mutations in a pubertal girl with cervical embryonal rhabdomyosarcoma and papillary thyroid adenoma. Journal of Pediatric and Adolescent Gynecology, 33(6), 742–744.
Yoon, J., et al. (2020). The value of DICER1 mutation analysis in “subtle” diagnostically challenging embryonal rhabdomyosarcomas of the uterine cervix. International Journal of Gynecological Pathology, in press.
de Kock, L., et al. (2020). Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Modern Pathology, 33(6), 1207–1219.
Dural, O., et al. (2019). DICER1-related embryonal rhabdomyosarcoma of the uterine corpus in a prepubertal girl. Journal of Pediatric and Adolescent Gynecology, 33(2), 173–176.
de Kock, L., et al. (2017). Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma. British Journal of Cancer, 116(12), 1621–1626.
Bahubeshi, A., et al. (2010). Germline DICER1 mutations and familial cystic nephroma. Journal of Medical Genetics, 47(12), 863–866.
Doros, L. A., et al. (2014). DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Modern Pathology, 27(9), 1267–1280.
Cajaiba, M. M., et al. (2016). Pediatric cystic nephromas: Distinctive features and frequent DICER1 mutations. Human Pathology, 48, 81–87.
Joshi, V. V., & Beckwith, J. B. (1989). Multilocular cyst of the kidney (cystic nephroma) and cystic, partially differentiated nephroblastoma. Terminology and criteria for diagnosis. Cancer, 64(2), 466–479.
Khan, N. E., et al. (2018). Structural renal abnormalities in the DICER1 syndrome: A family-based cohort study. Pediatric Nephrology, 33(12), 2281–2288.
Nakano, Y., et al. (2019). Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation. Modern Pathology, 32(12), 1744–1750.
Wu, M. K., et al. (2016). Tumor progression in DICER1-mutated cystic nephroma-witnessing the genesis of anaplastic sarcoma of the kidney. Human Pathology, 53, 114–120.
Abbo, O., et al. (2018). Wilms tumor, pleuropulmonary blastoma, and DICER1: Case report and literature review. World Journal of Surgical Oncology, 16(1), 164.
Herriges, J. C., et al. (2018). Identification of two 14q32 deletions involving DICER1 associated with the development of DICER1-related tumors. European Journal of Medical Genetics, 62(1), 9–14.
Palculict, T. B., et al. (2016). Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour. Journal of Medical Genetics, 53(6), 385–388.
Gambale, A., et al. (2019). Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition. Clinical Genetics, 96(4), 359–365.
Gadd, S., et al. (2017). A Children’s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nature Genetics, 49(10), 1487–1494.
Rakheja, D., et al. (2014). Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nature Communications, 2, 4802.
Torrezan, G. T., et al. (2014). Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour. Nature Communications, 5, 4039.
Walz, A. L., et al. (2015). Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell, 27(2), 286–297.
Wegert, J., et al. (2015). Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer Cell, 27(2), 298–311.
Fremerey, J., et al. (2017). Embryonal rhabdomyosarcoma in a patient with a heterozygous frameshift variant in the DICER1 gene and additional manifestations of the DICER1 syndrome. Familial Cancer, 16(3), 401–405.
Apellaniz-Ruiz, M., et al. (2020). DICER1 screening in 15 paediatric paratesticular sarcomas unveils an unusual DICER1-associated sarcoma. The Journal of Pathology. Clinical Research, 6(3), 185–194.
Sabbaghian, N., et al. (2013). Germ-line DICER1 mutations do not make a major contribution to the etiology of familial testicular germ cell tumours. BMC Research Notes, 6, 127.
Yüksel, S., et al. (2006). The association of cystic nephroma with pulmonary sequestration: Is it a coincidence or not? Pediatric Nephrology, 21(7), 1041–1044.
Bickel, S., et al. (2016). Type I pleuropulmonary blastoma originating from an extralobar sequestration. European Respiratory & Pulmonary Diseases, 2, 23–25.
Tanaka, M., et al. (2014). Pleuropulmonary blastoma in extrapulmonary lung tissue: A case report. Journal of Pediatric Surgery Case Reports, 2(7), 360–362.
Sabbaghian, N., et al. (2018). Analysis of DICER1 in familial and sporadic cases of transposition of the great arteries. Congenital Heart Disease, 13(3), 401–406.
Ozer, E., et al. (2004). Congenital cystic adenomatoid malformation type 4 and aneurysm of the vein of Galen: A rare coincidence or possibly related association. Pediatric and Developmental Pathology, 7(3), 268–272.
Saskin, A., et al. (2018). A case of neuroblastoma in DICER1 syndrome: Chance finding or noncanonical causation? Pediatric Blood & Cancer, 65(1).
Diets, I. J., et al. (2018). High yield of pathogenic germline mutations causative or likely causative of the cancer phenotype in selected children with cancer. Clinical Cancer Research, 24(7), 1594–1603.
Apellaniz-Ruiz, M., et al. (2020). A child with neuroblastoma and metachronous anaplastic sarcoma of the kidney: Underlying DICER1 syndrome? Pediatric Blood & Cancer, 67(12), e28488.
Liu, D. J., et al. (2016). Metachronous Type I pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child. Pediatric Blood & Cancer, 63(12), 2240–2242.
de Kock, L., et al. (2016). Germline and somatic DICER1 mutations in a well-differentiated fetal adenocarcinoma of the lung. Journal of Thoracic Oncology, 11(3), e31–e33.
Cotton, E., & Ray, D. (2018). DICER1 mutation and pituitary prolactinoma. Endocrinology, Diabetes & Metabolism Case Reports, 2018, 18-0087.
Caimari, F., & Korbonits, M. (2016). Novel genetic causes of pituitary adenomas. Clinical Cancer Research, 22(20), 5030–5042.
Khan, N. E., et al. (2017). Macrocephaly associated with the DICER1 syndrome. Genetics in Medicine, 19, 244–248.
Choi, S., et al. (2019). Dental abnormalities in individuals with pathogenic germline variation in DICER1. American Journal of Medical Genetics. Part A, 179(9), 1820–1825.
Sabbaghian, N., et al. (2014). Germ-line deletion in DICER1 revealed by a novel MLPA assay using synthetic oligonucleotides. European Journal of Human Genetics, 22(4), 564–567.
van Engelen, K., et al. (2018). DICER1 syndrome: Approach to testing and management at a large pediatric tertiary care center. Pediatric Blood & Cancer, 65(1), e26720.
Choong, C. S., Priest, J. R., & Foulkes, W. D. (2012). Exploring the endocrine manifestations of DICER1 mutations. Trends in Molecular Medicine, 18(9), 503–505.
Schultz, K. A. P., et al. (1993). DICER1 tumor predisposition. In M. P. Adam, H. H. Ardinger, R. A. Pagon, et al. (Eds.), GeneReviews®. University of Washington, Seattle.
McCluggage, W. G., & Foulkes, W. D. (2020). DICER1-associated sarcomas: towards a unified nomenclature. Modern Pathology. https://doi.org/10.1038/s41379-020-0602-4
Kommoss, F. K. F., et al. (2021). Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: Evidence for a distinct DICER1-associated subgroup. Modern Pathology. https://doi.org/10.1038/s41379-021-00804-y
González, I. A., et al. (2021). Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): A report from the International Pleuropulmonary Blastoma/DICER1 Registry. Modern Pathology. https://doi.org/10.1038/s41379-021-00804-y.
Liu, A. P. Y., et al. (2021). Clinical outcomes and complications of pituitary blastoma. The Journal of Clinical Endocrinology and Metabolism, 106(2), 351–363.
Nadaf, J., et al. (2021). Molecular characterization of DICER1-mutated pituitary blastoma. Acta Neuropathologica. https://doi.org/10.1007/s00401-021-02283-6
See, S. C., et al. (2021). Primary biphasic hepatic sarcoma in DICER1 syndrome. Pediatric and Developmental Pathology. https://doi.org/10.1177/10935266211008443
Golmard, L., et al. (2021). Testicular Sertoli cell tumour and potentially testicular Leydig cell tumour are features of DICER1 syndrome. Journal of Medical Genetics. https://doi.org/10.1136/jmedgenet-2020-107434.
Pancaldi, A., et al. (2020). DICER1-associated metastatic abdominopelvic primitive neuroectodermal tumor with an EWSR1 rearrangement in a 16-yr-old female. Cold Spring Harbor Molecular Case Studies, 2020, 6(5).
Acknowledgments
We thank Catherine Choong, MBBS, MD, FRACP, and Gillian Northcott, B.A., for their assistance with Fig. 9.1; Maria Apellaniz-Ruiz, PhD, for compilation of Fig. 9.2 and its legend; Marc Fabian, PhD, for comments on Fig. 9.2; and Eric Carolan, MD, for expert radiologic input on Fig. 9.5. We also wish to thank the many physicians who provide cases that have helped us describe the DICER1 syndrome. We particularly thank all the families that have taken part in our studies described here.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Editor(s) (if applicable) and The Author(s) under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Foulkes, W.D., de Kock, L., Priest, J.R. (2021). DICER1 Syndrome. In: Malkin, D. (eds) The Hereditary Basis of Childhood Cancer. Springer, Cham. https://doi.org/10.1007/978-3-030-74448-9_9
Download citation
DOI: https://doi.org/10.1007/978-3-030-74448-9_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-74446-5
Online ISBN: 978-3-030-74448-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)