title: Clinical and genetic characteristics of congenital hypothyroidism due to mutations in the thyroid peroxidase (TPO) gene in Israelis.
abstract: OBJECTIVE
  Iodide organification defect (IOD) is characterized by a reduced ability of the thyroid gland to retain iodide and results in hypothyroidism. Mutations in the thyroid peroxidase (TPO) gene are a frequent cause of IOD. While TPO mutations have been identified in various populations, none have been reported in Israeli patients with IOD. The objectives of this study were to characterize the molecular basis of IOD in an Israeli Arab-Muslim population and to analyse the clinical, neurological and imaging data of patients with TPO mutations followed for up to 29 years.
  
  
  METHODS
  Twenty-two patients from six core families with congenital hypothyroidism (CH) and IOD living in the same region.
  
  
  METHODS
  All subjects underwent clinical, hormonal and imaging evaluation. The TPO gene was directly sequenced and the presence of specific mutations among family members was determined by restriction fragment length polymorphism (RFLP).
  
  
  RESULTS
  All patients had congenital and persistent primary hypothyroidism. The thyroid gland was demonstrated in all subjects by technetium (99mTc) scans. A positive perchlorate discharge test (mean 87%) was indicative of IOD. Enlargement of the thyroid gland was shown in 64% of our patients, mostly with multinodular appearance, and in some with retrosternal invasion. Neurological complications were observed in 13 patients (59%). Four subjects, who carry two different TPO mutations, had sensorineural deafness. Two previously described TPO gene mutations [G1567A (G493S) and C1708T (R540X)] and one novel TPO gene mutation [C965T (S292F)] were identified. The two previously described mutations were present in 90% of the subjects. Haplotyping suggested a distant common ancestry for each of these two mutations.
  
  
  CONCLUSIONS
  Three different TPO gene mutations were found to be responsible for IOD in a consanguineous Israeli population. The high rate of development of multinodular glands (MNGs) in our cohort of patients indicates the need for long-term follow-up of patients with TPO gene mutations.
authors: Paediatric Endocrine Unit, Ha'Emek Medical Centre, Afula, Israel. rakover_y@clalit.org.il
authors: Yardena
authors: Y
authors: Tenenbaum-Rakover
authors: Sunee
authors: S
authors: Mamanasiri
authors: Carrie
authors: C
authors: Ris-Stalpers
authors: Alina
authors: A
authors: German
authors: Joseph
authors: J
authors: Sack
authors: Stavit
authors: S
authors: Allon-Shalev
authors: Joachim
authors: J
authors: Pohlenz
authors: Samuel
authors: S
authors: Refetoff
mesh_terms: D000293:Adolescent; D000328:Adult; D018912:Arabs; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000208:ethnology / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D007514:Islam; D007557:Israel; D008297:Male; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D007453:Iodide Peroxidase