Endocrine Abstracts

Mice with dominant-negative mutations of thyroid hormone receptor α1 (TRα1) are euthyroid but display growth retardation and delayed bone age as juveniles and increased bone mass during adulthood, indicating impaired skeletal thyroid hormone responsiveness. The first autosomal dominant mutations affecting TRα1 in humans were recently described in two unrelated children and one parent who were euthyroid apart from a low T₄:T₃ ratio. Consistent with the mouse phenotype both children exhibited skeletal dysplasia and growth retardation but information about the affected parent was limited. The type 2 deiodinase (D2) converts the prohormone T₄ to the active hormone T₃, thus controlling the intracellular supply of T₃ to target tissues. Detailed analysis of D2 knockout mice demonstrated high bone mass and mineralisation resulting from impaired T₃ action in osteoblasts. However, no individuals with mutations affecting D2 have been described.

These data demonstrate that impaired T₃ action in bone results in high bone mineral density (BMD) despite normal circulating thyroid status. Thus, we hypothesised that euthyroid adults with mutations affecting TRα1 or D2 would exhibit high BMD.

We defined a subgroup of 1278 healthy euthyroid postmenopausal women (hip standardised BMD: 863±145; Lumbar spine standardised BMD: 1022±138; mean±S.D., mg/cm²; fT₄:fT₃ ratio: 3.58±0.79) from the osteoporosis and ultrasound study (OPUS) population. The THRA gene (exons 2-10) was sequenced in 100 subjects with the highest BMD in whom DNA was available (n=200 alleles; hip BMD: 1105±112; LS BMD: 1325±156; fT₄:fT₃ ratio: 3.45±0.57) and the DIO2 gene (exons 1, 2, a, b, SECIS) was sequenced in 48 of these individuals (n=96 alleles; hip BMD: 1118±123; LS BMD: 1321±159; fT₄:fT₃ ratio: 3.52±0.67).

The T₄:T₃ ratio did not correlate with hip or lumbar spine BMD and no THRA or DIO2 mutations were identified. These data demonstrate that mutations affecting TRα1 or D2 are not a common cause of high bone mass in humans.

Declaration of funding

This work was supported by the Medical Research Council (grant number G800261).