title: DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association.
abstract: BACKGROUND
  DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.
  
  
  METHODS
  We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.
  
  
  CONCLUSIONS
  This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Meilan M
authors.initials: MM
authors.lastname: Rutter
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Pranati
authors.initials: P
authors.lastname: Jha
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Kris Ann P
authors.initials: KA
authors.lastname: Schultz
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Amy
authors.initials: A
authors.lastname: Sheil
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Harris
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bauer
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Field
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: James
authors.initials: J
authors.lastname: Geller
authors.affiliation: Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Hill
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary; D002648:Child; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D020518:Focal Nodular Hyperplasia / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D043244:Ribonuclease III / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D013965:Thyroidectomy
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases