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PH Kvistad, K Lovas, H Boman and OL Myking

OBJECTIVE: Thyroid hormone resistance (RTH) is characterised by variable tissue hyporesponsiveness to thyroid hormone. The disorder is usually caused by mutations in the thyroid hormone receptor beta (TR beta). We describe a large family with this disorder. SUBJECTS AND MEASUREMENT: We identified 36 family members with RTH in four generations by screening relatives of patients with the diagnosis. The diagnosis was verified by identification of a mutation in the thyroid hormone receptor beta (TR beta) gene. Symptoms, clinical findings and laboratory tests of 29 affected individuals were compared with those of 16 first-degree relatives. RESULTS: Bone maturation in children with RTH was delayed. The height was lower both in children and in adults with RTH than in the controls. Children with RTH had lower birth weight than the controls, particularly when the condition was inherited from the father. We did not observe increased prevalence of neuropsychological symptoms associated with RTH in this family. Palpitations and increased pulse rate indicated mild cardiac hyperthyroidism. Direct sequence analysis of the TR beta gene revealed a novel point mutation, a heterozygous transition c.1031G>C in exon 9 theoretically substituting Gly344Ala. CONCLUSIONS: We found evidence of skeletal tissue hypothyroidism that resulted in permanent growth retardation from prenatal to adult life. We found substantial variations in thyroid hormone levels and clinical presentation, but most individuals were without symptoms of thyroid disorder.

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K Lovas, ES Husebye, F Holsten and B Bjorvatn

OBJECTIVE: The standard replacement therapy in Addison's disease does not restore normal nocturnal levels of the hormones of the hypothalamic-pituitary-adrenal axis. The aim of the study was to describe the prevalence and characteristics of sleep disturbances in patients with Addison's disease. METHODS: Sixty patients completed a self-administered sleep questionnaire and the Epworth Sleepiness Scale (ESS) questionnaire. Activity-based monitoring (actigraph recordings) and sleep diaries were obtained from eight patients. RESULTS: Thirty-four percent reported weekly sleep disturbances (difficulties falling asleep in 13%; repeated awakenings in 14%; early morning awakenings in 20%). The sleep need was 8.21 h (s.d. 1.34; range 6-14 h), and sleep onset latency was 29 min (s.d. 29, range 2-150 min). Forty percent of the patients were tired during daily activities more than once a week, but the scores of the ESS were 6.0 (s.d. 3.5), which is not higher than normal. The actigraph recordings showed higher sleep efficiency than the subjective recordings. CONCLUSION: We did not identify specific sleep disturbances which were characteristic for patients with Addison's disease. Patients with Addison's disease have increased daytime fatigue, but no more daytime sleepiness than normal.

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Kristian Løvås, Clara G Gjesdal, Monika Christensen, Anette B Wolff, Bjørg Almås, Johan Svartberg, Kristian J Fougner, Unni Syversen, Jens Bollerslev, Jan A Falch, Penelope J Hunt, V Krishna K Chatterjee and Eystein S Husebye

Context

Patients with primary adrenal insufficiency (Addison's disease) receive more glucococorticoids than the normal endogenous production, raising concern about adverse effects on bone.

Objective

To determine i) the effects of glucocorticoid replacement therapy on bone, and ii) the impact of glucocorticoid pharmacogenetics.

Design, setting and participants

A cross-sectional study of two large Addison's cohorts from Norway (n=187) and from UK and New Zealand (n=105).

Main outcome measures

Bone mineral density (BMD) was measured; the Z-scores represent comparison with a reference population. Blood samples from 187 Norwegian patients were analysed for bone markers and common polymorphisms in genes that have been associated with glucocorticoid sensitivity.

Results

Femoral neck BMD Z-scores were significantly reduced in the patients (Norway: mean −0.28 (95% confidence intervals (CI) −0.42, −0.16); UK and New Zealand: −0.21 (95% CI −0.36, −0.06)). Lumbar spine Z-scores were reduced (Norway: −0.17 (−0.36, +0.01); UK and New Zealand: −0.57 (−0.78, −0.37)), and significantly lower in males compared with females (P=0.02). The common P-glycoprotein (ABCB1) polymorphism C3435T was significantly associated with total BMD (CC and CT>TT P=0.015), with a similar trend at the hip and spine.

Conclusions

BMD at the femoral neck and lumbar spine is reduced in Addison's disease, indicating undesirable effects of the replacement therapy. The findings lend support to the recommendations that 15–25 mg hydrocortisone daily is more appropriate than the higher conventional doses. A common polymorphism in the efflux transporter P-glycoprotein is associated with reduced bone mass and might confer susceptibility to glucocorticoid induced osteoporosis.