Cushing's disease in childhood as the first manifestation of multiple endocrine neoplasia syndrome type 1

OBJECTIVE: To describe three cases of Cushing's disease in children with multiple endocrine neoplasia type 1 (MEN1), as clinical manifestations of MEN1 are very rare in childhood. DESIGN AND METHODS: A retrospective review of three cases of Cushing's disease diagnosed between 1997 and 1999. Genetic screening for MEN1 gene mutation was performed in each patient. RESULTS: An ACTH-secreting microadenoma was diagnosed in three children, aged 11-13 years, presenting with growth retardation and weight gain over a period of 3-4 years. All patients had successful transsphenoidal adenomectomies. Primary hyperparathyroidism was subsequently diagnosed in two of the patients, and in the monozygotic twin of one of the patients. A new mutation in the MEN1 gene (Tyr351His) was identified in two of the patients and the affected members of their families. In the third patient a de novo MEN1 gene mutation (Leu444Pro) was found. CONCLUSIONS: MEN1 has to be considered in all children with tumours of the pituitary gland, and in those presenting with primary hyperparathyroidism. The children and their families should be advised to seek genetic counselling. We suggest that careful growth records be kept for children at risk of developing inherited MEN1 and, in the event of a decelerating growth rate, further diagnostic evaluation be undertaken with regards to ACTH-secreting pituitary tumours.     

Inhibition of the morning cortisol peak abolishes the expected morning decrease in serum osteocalcin in normal males: evidence of a controlling effect of serum cortisol on the circadian rhythm in serum osteocalcin.

Osteocalcin (OC) in serum varies in a remarkably constant circadian rhythm with zenith at night and nadir in the morning. The factors controlling this rhythm are unknown, but several studies indicate that serum cortisol could be of major importance. We tested this hypothesis in a double-blind, placebo-controlled, cross-over study comprising 10 normal male volunteers (aged 23-31 yr) by measuring the response in serum OC and cortisol rhythms to a single dose of metyrapone (30 mg/kg body weight) administered at midnight. During placebo, serum cortisol consistently peaked early in the morning before 0730 h. Ingestion of metyrapone at 2400 h significantly postponed and flattened this peak (P less than 0.01). On both occasions, serum OC increased towards peak levels around 0300 h (P less than 0.01) with no overall differences in the OC profiles. However, when the serum OC time series were synchronized according to the individual cortisol nadirs, we found a significant (P less than 0.01) decrease in serum OC on the placebo day approximately 4 h after the cortisol nadir, whereas no significant changes (P greater than 0.50) were seen on the metyrapone day. Moreover, the mean serum OC level tended to be higher (P less than 0.10 in the interval 0-12 h, and P = 0.06 in the interval 4-8 h) on the metyrapone day compared with the placebo day. On the placebo day, the mean level of serum cortisol during the interval 0-4 h correlated inversely with the mean level of serum OC in the interval 4-8 h (r = 0.77, P less than 0.05). This relation was not found on the metyrapone day. In conclusion, administration of metyrapone, which reduced and postponed the early morning cortisol peak, abolished the normal morning decrease in serum OC. This strongly supports that changes in endogenous serum cortisol are of major importance for the circadian rhythm in serum OC.     

Relations between diurnal variations in serum osteocalcin, cortisol, parathyroid hormone, and ionized calcium in normal individuals

Serum osteocalcin varies in a diurnal rhythm, with peak values during the night and minimum levels before noon, but the factors controlling this rhythm are unknown. In this study, we evaluated the temporal relations between the osteocalcin rhythm and variations in serum concentrations of cortisol, intact parathyroid hormone (PTH(1-84)), and ionized calcium (Ca2+) in 15 normal volunteers, aged 22-46 years. Serum cortisol varied in a typical way preceding inverse changes in serum osteocalcin by about 4 h (r = 0.78, p less than 0.0001). Changes in serum osteocalcin following the early morning increase in serum cortisol were statistically indistinguishable from the changes seen after oral administration of 2.5 or 10 mg of prednisone. Serum PTH (1-84) showed a diurnal rhythm (p less than 0.01) with peak values (4.06 +/- 0.42 pmol/l) at 20.30 h and nadir (2.81 +/- 0.10 pmol/l) around 10.30 h, preceding changes in serum osteocalcin in the same direction by 5 h (r = 0.55, p less than 0.02). Prednisone at a dose of 10 mg did not change the time course significantly. Serum Ca2+ varied in an almost bi-phasic pattern (p less than 0.01) with maximal mean levels around 16.30 and 09.30 h and minimal levels around 05.30 and 14.30 h. Serum Ca2+ correlated inversely with PTH (1-84) (r = 0.53, p less than 0.01), and serum osteocalcin was inversely related to Ca2+ at concurrent time points (r = 0.59, p less than 0.005). Prednisone caused a 2-3 h lasting increase in serum Ca2+ 3-5 h after ingestion (p less than 0.001). In conclusion, our results suggest that cortisol is strongly associated to the diurnal rhythm in serum osteocalcin. The biological relevance of the reported relation between serum osteocalcin and PTH (1-84) and serum Ca2+ is uncertain.     

Changes in bone mineral density of the acetabulum, femoral neck and femoral shaft, after hip resurfacing and total hip replacement: two-year results from a randomised study

It is accepted that resurfacing hip replacement preserves the bone mineral density (BMD) of the femur better than total hip replacement (THR). However, no studies have investigated any possible difference on the acetabular side. Between April 2007 and March 2009, 39 patients were randomised into two groups to receive either a resurfacing or a THR and were followed for two years. One patient's resurfacing subsequently failed, leaving 19 patients in each group. Resurfaced replacements maintained proximal femoral BMD and, compared with THR, had an increased bone mineral density in Gruen zones 2, 3, 6, and particularly zone 7, with a gain of 7.5% (95% confidence interval (CI) 2.6 to 12.5) compared with a loss of 14.6% (95% CI 7.6 to 21.6). Resurfacing replacements maintained the BMD of the medial femoral neck and increased that in the lateral zones between 12.8% (95% CI 4.3 to 21.4) and 25.9% (95% CI 7.1 to 44.6). On the acetabular side, BMD was similar in every zone at each point in time. The mean BMD of all acetabular regions in the resurfaced group was reduced to 96.2% (95% CI 93.7 to 98.6) and for the total hip replacement group to 97.6% (95% CI 93.7 to 101.5) (p = 0.4863). A mean total loss of 3.7% (95% CI 1.0 to 6.5) and 4.9% (95% CI 0.8 to 9.0) of BMD was found above the acetabular component in W1 and 10.2% (95% CI 0.9 to 19.4) and 9.1% (95% CI 3.8 to 14.4) medial to the implant in W2 for resurfaced replacements and THRs respectively. Resurfacing resulted in a mean loss of BMD of 6.7% (95% CI 0.7 to 12.7) in W3 but the BMD inferior to the acetabular component was maintained in both groups. These results suggest that the ability of a resurfacing hip replacement to preserve BMD only applies to the femoral side.     

Birth Weight and Adult Bone Metabolism Are Unrelated: Results From Birth Weight–Discordant Monozygotic Twins

Low birth weight (BW) has been associated with poor bone health in adulthood. The aim of this study was to investigate the association between BW and bone mass and metabolism in adult BW‐discordant monozygotic (MZ) twins. A total of 153 BW–extremely discordant MZ twin pairs were recruited from the Danish Twin Registry. Serum vitamin D (25‐hydroxyvitamin D [25OHD]) and bone turnover markers (BTMs) amino‐terminal propeptide of type I procollagen (P1NP), pyridinoline cross‐linked carboxyterminal telopeptide of type I collagen (1CTP), and cross‐linked C‐telopeptide (CTX) were quantified. Femoral neck (FN), total hip (TH), lumbar spine (LS), and whole‐body (WB) bone mineral density (BMD) (ie, FN‐BMD, TH‐BMD, LS‐BMD, and WB‐BMD, respectively) were measured using dual‐energy X‐ray absorptiometry (DXA). Twins were studied as single individuals using regression analyses with or without adjustment for height, weight, age, sex, and intrapair correlation. Within‐pair differences were assessed using Student's t test and fixed‐regression models. BW was not associated with BTMs, LS‐BMD, TH‐BMD, FN‐BMD, or WB‐BMD, but BW was associated with WB‐BMC, and WB‐Area after adjustments. Compared to the co‐twin, twins with the highest BW were heavier and taller in adulthood (mean differences ± SD): 3.0 ± 10.5 kg; 1.6 ± 2.6 cm; both p < 0.001). Within‐pair analyses showed that LS‐BMD, TH‐BMD, and FN‐BMD tended to be higher in twins with highest BW (for all: mean difference 0.01 ± 0.1 g/cm²; p = 0.08, 0.05, and 0.10, respectively). No difference was observed after adjustment for adult body size. Intrapair differences in BW were not associated with differences in any of the biochemical parameters or BMD. Small differences between twins in BMD were explained by dissimilarities in body size. These results suggest that BW and adult bone metabolism are unrelated. © 2013 American Society for Bone and Mineral Research.     

人体1型糖尿病中的关键免疫细胞

1型糖尿病患者胰岛β细胞被破坏与胰岛自身反应性T细胞之间的直接联系从未被证明,对诊断后的疾病进程也所知无几.最近美国科学家的研究第一次对此有了直接的证据.冷冻胰腺样本来自病程在1周到超过50年的45例死亡患者的遗体捐赠,14例非糖尿病患者对照样本,5例有自身抗体的非糖尿病患者样本,2例孕期糖尿病患者样本,以及6例2型糖尿病患者样本.系统检查样本的组织切片是否存在有足够胰岛素的β细胞、CD8阳性的胰岛病变和1型HLA过度表达.最后,对表达HLA-A2的样本的连续切片用四聚体染色法针对6种已知确定的与1型糖尿病有关的胰岛自身抗原进行CD8 T细胞反应性检查.在临床确诊后最长达8年的分组患者胰岛样本中单一和多种CD8 T细胞反应性都检测到了.1型糖尿病特有的1型HLA过度表达和胰岛炎等病理特征存在于一小部分病程很长的患者中.在受影响的器官中.胰岛病变持续存在,表现为不同程度的浸润和β细胞丢失.该研究为人体胰岛自身反应性提供了第一个直接证据并强调了发病历程的异质性和长期性.     

PREPARING THE MALE URETHRA FOR TRANSURETHRAL PROCEDURES

SUMMARY The antiseptic and analgesic effectiveness of different preparations of lignocaine gel used prior to flexible cystoscopy were studied in patients recruited over a 12-month period. This random study involved 106 patients in four groups. There appeared to be no difference in bacterial colonisation of the urethra between the groups. Urethral analgesia was improved when higher volumes of gel were used. It was concluded that high-volume gel preparations (>20 ml) with no antiseptic provided optimal conditions for flexible cystoscopy.