Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci.
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.
Grasberger
Helmut
H
Department of Medicine, The University of Chicago, MC3090, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
Mimouni-Bloch
Aviva
A
Vantyghem
Marie-Christine
MC
van Vliet
Guy
G
Abramowicz
Marc
M
Metzger
Daniel L
DL
Abdullatif
Hussein
H
Rydlewski
Catherine
C
Macchia
Paolo E
PE
Scherberg
Neal H
NH
van Sande
Jacqueline
J
Mimouni
Marc
M
Weiss
Roy E
RE
Vassart
Gilbert
G
Refetoff
Samuel
S
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
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