title: Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci.
abstract: BACKGROUND
  Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. OBJECTIVE, SETTING, AND PARTICIPANTS: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected.
  
  
  RESULTS
  Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1.
  
  
  CONCLUSIONS
  These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.
authors.affiliation: Department of Medicine, The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.forename: Aviva
authors.initials: A
authors.lastname: Mimouni-Bloch
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.forename: Guy
authors.initials: G
authors.lastname: van Vliet
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Metzger
authors.forename: Hussein
authors.initials: H
authors.lastname: Abdullatif
authors.forename: Catherine
authors.initials: C
authors.lastname: Rydlewski
authors.forename: Paolo E
authors.initials: PE
authors.lastname: Macchia
authors.forename: Neal H
authors.initials: NH
authors.lastname: Scherberg
authors.forename: Jacqueline
authors.initials: J
authors.lastname: van Sande
authors.forename: Marc
authors.initials: M
authors.lastname: Mimouni
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010375:Pedigree; D018382:Thyroid Hormone Resistance Syndrome / Q000097:blood / Q000235:genetics*; D013972:Thyrotropin / Q000097:blood*; D015534:Trans-Activators / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D015534:Trans-Activators; D013972:Thyrotropin