Context: 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 subclincial 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 due to borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In 4 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 etiologic 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.