title: Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy.
abstract: BACKGROUND
  Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T(3)) and low/normal thyroxine (T(4)). MCT8 contributes to hormone release from the thyroid gland.
  
  
  OBJECTIVE
  To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice.
  
  
  METHODS
  Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8(-/y) model.
  
  
  RESULTS
  We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (l-T(4)), the preoperative, inadequately low T(4) and free T(4) remained, while increasing the l-T(4) dosage led to T(3) serum concentrations above the normal range.
  
  
  CONCLUSIONS
  Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities.
authors.affiliation: Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Eva K
authors.initials: EK
authors.lastname: Wirth
authors.forename: Sien-Yi
authors.initials: SY
authors.lastname: Sheu
authors.forename: Jazmin
authors.initials: J
authors.lastname: Chiu-Ugalde
authors.forename: Remy
authors.initials: R
authors.lastname: Sapin
authors.forename: Marc O
authors.initials: MO
authors.lastname: Klein
authors.forename: Ilona
authors.initials: I
authors.lastname: Mossbrugger
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Martin Hrabĕ
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: Thomas
authors.initials: T
authors.lastname: Riebel
authors.forename: Karin
authors.initials: K
authors.lastname: Rothe
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018265:Carcinoma, Papillary, Follicular / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D002648:Child; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007453:Iodide Peroxidase / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D027981:Symporters; D013961:Thyroid Gland / Q000000981:diagnostic imaging / Q000473:pathology* / Q000601:surgery; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000601:surgery; D013965:Thyroidectomy; D013974:Thyroxine / Q000097:blood*; D016896:Treatment Outcome; D014284:Triiodothyronine / Q000097:blood*; D014463:Ultrasonography
chemical_list: D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D012313:RNA; D007453:Iodide Peroxidase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D013974:Thyroxine