title: Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis.
abstract: BACKGROUND
  Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis.
  
  
  OBJECTIVE
  Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis.
  
  
  METHODS
  In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis.
  
  
  RESULTS
  By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct.
  
  
  CONCLUSIONS
  We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.
authors.affiliation: Institute of Experimental Pediatric Endocrinology (P.K., H.B., A.G., H.K.), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Department of Pediatric Endocrinology and Diabetes (S.T., T.G., S.A., A.B.), Marmara University Hospital, 34722 Istanbul, Turkey; and Max-Delbrück Center for Molecular Medicine (S.F., W.C.), 13092 Berlin-Buch, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kühnen
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fröhler
authors.forename: Tülay
authors.initials: T
authors.lastname: Güran
authors.forename: Saygin
authors.initials: S
authors.lastname: Abali
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bereket
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D015331:Cohort Studies; D003409:Congenital Hypothyroidism / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D000076988:Sulfate Transporters; D050033:Thyroid Dysgenesis / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D014421:Turkey
chemical_list: D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters