Thyroid hormone resistance from newborns to adults: a Spanish experience.

OBJECTIVE: Thyroid hormone resistance (RTH ß) is a rare genetic disorder characterized by an altered response of target tissue to the action of thyroid hormone. Few studies on RTH ß have been carried out in southern European populations. We aimed to describe the clinical and genetic characteristics at the time of diagnosis in a Spanish cohort of patients with genetically confirmed RTH ß, with ages ranging from newborns to adults. METHODS: Retrospective multicenter study of 28 patients who were genetically confirmed as RTH ß. Clinical and biochemical data were collected from the reference centers, and the studied variables included age, sex, anthropometric data, clinical characteristics and biochemical results. In the Basque country, a simultaneous analysis of TSH and T4 is carried out in the program for the screening of inborn errors of metabolism. A molecular analysis of the thyroid hormone beta (THRB) gene was performed. RESULTS: The total cohort included 20 adults and eight pediatric patients (six newborns). Of the total, 5 (17.8%) were diagnosed by clinical characteristics (goiter, hypertension or tachycardia), 13 (46.4%) were analyzed in the context of a family study and 10 (35.7%) were diagnosed after obtaining an altered fT4 and/or TSH level in a biochemical analysis performed due to clinical symptoms unrelated to RTH ß. Four of the newborns included in the series were diagnosed by the result of neonatal screening, which allows us to estimate a minimum local incidence of RTH ß of 1/18,750 live newborns. The genetic analysis showed the presence of 12 different heterozygous mutations in the THRB gene. CONCLUSIONS: We report the clinical and genetic characteristics of a Spanish RTH ß cohort, from neonates to adults. We also describe one novel mutation in the THRB gene as the cause of the disease. The simultaneous analysis of TSH and T4 carried out in the program for the screening of inborn errors of metabolism facilitates the early diagnosis of RTH ß in newborns and has allowed us to estimate a minimum local incidence of RTH of 1/18,750 live newborns.

Adverse effects of thyroid hormones.

The adverse health effects of thyrotoxicosis have been carefully documented and most practitioners are familiar with the clinical consequences for the patient. Until recently, many patients experienced the adverse effects of excessive thyroxine dosages. Which can now be avoided by the application of highly sensitive immunometric assays for monitoring serum thyrotrophin (thyroid-stimulating hormone; TSH) levels. However, sensitive monitoring of serum thyrotrophin levels has led to the frequent recognition of biochemical subclinical hyperthyroidism (isolated suppression of thyrotrophin). Because of the increased recognition of this condition, the adverse effects of thyroxine therapy can be divided into those associated with subclinical hyperthyroidism and those associated with the euthyroid state. Investigation of the potential clinical consequences of thyrotrophin-suppressing dosages of thyroxine has dominated studies over the last decade, with less attention being given to euthyroid patients. It appears that the adverse effects of thyroxine are considerably more common when serum thyrotrophin has been suppressed. They are usually manifested in older patients as increased bone mineral loss in postmenopausal women and as cardiac effects in patients with intrinsic heart disease. These patients may have subtle behavioural alterations and other clinically silent organ effects that occur infrequently. Children who are euthyroid while taking thyroxine occasionally develop pseudotumour cerebri shortly after starting hormone replacement for hypothyroidism. Otherwise, thyroxine dosages that render patients euthyroid, as evidenced by thyrotrophin values that are within the normal range, rarely cause adverse effects. Thus, avoidance of dosages that cause thyrotrophin suppression, when not clinically indicated, is the primary approach to the management of these adverse effects.