Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies

Thyroid hormone resistance affects the pituitary gland and a variety of other tissues. We studied a large kindred with this disorder and measured a number of clinical markers of tissue metabolism to determine if these markers were useful in elucidating the sites and degree of resistance.

A kindred of 89 persons in four generations was identified; 44 had thyroid function tests, and 14 (five to 67 years old) were found to have thyroid hormone resistance.

The inheritance pattern was autosomal dominant, with no common HLA haplotype. Physiologic measurements in five affected members showed marked heterogeneity. Four patients had normal baseline cardiac contractility, but only two experienced a shortening of their QKd interval into the hyperthyroid range with triiodothyronine (T3) therapy. Intrathyroidal 127I content was increased in two patients and was normal in two. Bone mineral content was normal in two men, but two women had marked osteopenia. The propositus, hypothyroid after inappropriate 131I therapy, had a hypothyroid ventilatory response to hypercapnea. This response became low normal during T3 (100 micrograms/day) administration but not during long-term thyroxine (T4) (300 micrograms/day) administration. Three other patients had values within normal limits and one had a hyperthyroid ventilatory response. Peripheral biochemical markers of thyroid hormone action were measured in 13 affected and 19 unaffected family members. Sex hormone-binding globulin was increased in zero of 13 affected patients (versus 19 of 20 hyperthyroid, chi 2:p less than 0.001); ferritin was elevated in two of 13 patients (versus 11 of 20 hyperthyroid, p less than 0.02); angiotensin converting enzyme activity was increased in one of 13 patients (versus 12 of 20 hyperthyroid, p less than 0.025). The eldest patient had marked cardiac sensitivity despite normal biochemical markers. We attempted to suppress the integrated thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) using T3 (72 and 100 percent suppression in two patients), dopamine (40 percent suppression in one), 3,5,3'-triiodothyroacetic acid (TRIAC) (94 percent suppression in one), and verapamil (10 percent and 40 percent suppression in two). Neuropsychologic function was studied in 14 individuals (11 affected, three unaffected). Although mild impairments were detected, they were not specific for thyroid hormone resistance.(ABSTRACT TRUNCATED AT 400 WORDS)