title: Goitrous congenital hypothyroidism and hearing impairment associated with mutations in the TPO and SLC26A4/PDS genes.
abstract: BACKGROUND
  Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses.
  
  
  METHODS
  The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected.
  
  
  METHODS
  We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro.
  
  
  RESULTS
  Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro.
  
  
  CONCLUSIONS
  These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.
authors: Children's Hospital, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Building 109, D-55101 Mainz, Germany. pohlenz@kinder.klinik.uni-mainz.de.
authors: Nicole
authors: N
authors: Pfarr
authors: Guntram
authors: G
authors: Borck
authors: Andrew
authors: A
authors: Turk
authors: Ulrike
authors: U
authors: Napiontek
authors: Annerose
authors: A
authors: Keilmann
authors: Wibke
authors: W
authors: Müller-Forell
authors: Peter
authors: P
authors: Kopp
authors: Joachim
authors: J
authors: Pohlenz