title: Studies of molecular mechanisms associated with increased deiodinase 3 expression in a case of consumptive hypothyroidism.
abstract: BACKGROUND
  Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to increased catabolic activity of type 3 iodothyronine deiodinase (DIO3) that can occur in large tumors. PATIENTs with CH typically present with markedly increased requirements for exogenous thyroid hormone and resolution after removal of the source of ectopic DIO3. DIO3 is encoded by DIO3, an imprinted gene expressed on the paternal allele that is located in a DIO3/delta-like 1 homolog (DLK1) gene locus regulated by a common control region, intergenic differentially methylated region (IGDMR). Because DIO3 is an imprinted gene, loss of imprinting at the IGDMR is thought to play a role in its increased expression; however, the molecular mechanism for DIO3 in CH currently is not known.
  
  
  OBJECTIVE
  The aim of the study was to determine the molecular mechanism for CH in an adult patient.
  
  
  METHODS
  The study was conducted in the Department of Endocrinology of a tertiary care center in Singapore.
  
  
  METHODS
  We report the case of an adult Asian female patient with a large intrathoracic fibrous tumor and severe hypothyroidism that resolved after tumor resection.
  
  
  RESULTS
  The patient's tumor expressed increased levels of DIO3 and DLK1 mRNA and protein levels. Methylation-specific PCR of the IGDMR showed similar hypomethylation in placenta, thyroid, leukocytes, and tumor. Western blotting showed activation of sonic hedgehog (SHH) and MAPK signaling pathways that can increase DIO3 and DLK1 expression.
  
  
  CONCLUSIONS
  Loss of imprinting did not account for overexpression of DIO3 in the patient's tumor. Instead SHH and MAPK/ERK pathway activation was associated with systemic thyroid hormone catabolism and growth of the tumor. These findings raise the possibility that other tumors that have increased SHH and MAPK/ERK signaling also may have intratumor or systemic effects on thyroid hormone function.
authors.affiliation: Laboratory of Hormonal Regulation (D.K.L.A., R.A.S., P.M.Y.), Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore 169857; Department of Endocrinology (H.C.T., L.M.L.), Singapore General Hospital, Singapore 169608; and Department of Clinical Medicine and Surgery (D.S.), University of Naples "Federico II," 80138 Naples, Italy.
authors.forename: Darius K L
authors.initials: DK
authors.lastname: Aw
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.forename: Hong Chang
authors.initials: HC
authors.lastname: Tan
authors.forename: Lih Ming
authors.initials: LM
authors.lastname: Loh
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D000368:Aged; D005260:Female; D018392:Genomic Imprinting; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D054364:Solitary Fibrous Tumors / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013899:Thoracic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase