Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

OBJECTIVE: Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. METHODS: Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. RESULTS: Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. CONCLUSIONS: Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.

Role of the corticotropin-releasing factor receptor type 2 in the control of food intake in mice: a meal pattern analysis.

The actions of corticotropin-releasing factor (CRF) and related peptides are mediated by two receptors (CRF(1) and CRF(2)). The respective role of each subtype in the control of food intake remains poorly known. In the present study, we examined the quantity and microstructure of ingestive behavior of knockout (KO) mice lacking CRF(2) receptors and their wild-type (WT) littermates. Under basal conditions, CRF(2) KO mice showed increased nocturnal food intake, evident as an increased zenith in circadian cosinor analysis of food intake. Microstructure analysis revealed that this greater food intake reflected increased meal size, rather than meal frequency, suggesting a decreased satiating value of food. Following acute restraint stress, CRF(2) KO mice showed an intact immediate anorectic response with increased latency to eat and decreased meal size. However, CRF(2) deletion abolished the prolonged phase of restraint-induced anorexia. CRF(2) KO mice did not differ from WT controls in feeding responses to food deprivation or injection of ghrelin receptor agonists. Independent of genotype, food deprivation increased food intake, with dramatic changes in meal size, meal frequency, water : food ratio and eating rate. Acyl-ghrelin or BIM-28131, a potent ghrelin analog, dose-dependently stimulated food intake by increasing meal size (ghrelin, BIM-28131) and meal number (BIM-28131), while slowing the average eating rate (BIM-28131) similarly in WT and KO mice. These results suggest that the CRF(2) receptor is involved in the control of meal size during the active phase of eating and following acute exposure to stress.

A novel thyroid hormone receptor-beta mutation, not anticipated to occur in resistance to thyroid hormone, causes variable phenotypes.

Resistance to thyroid hormones (RTH) is a syndrome characterized by a variable tissue hyposensitivity to thyroid hormones and is linked to mutations in the thyroid hormone receptor-beta (TRbeta) gene. We report here for the first time in vivo the mutation R429W (CCG-->TCG) located in the exon 10. The artificial mutant obtained in vitro displayed a normal T(3)-binding affinity and transactivation function. Therefore, it was thought to produce little, if any, clinical effect and to escape to clinical detection. The present report is at least in part discordant with this prediction since the propositus and his grandmother had an authentic hyperthyroidism with high FT(4) plasma level in the presence of inappropriate TSH. On the other hand, spontaneous variations of clinical features and - interestingly - of plasma FT(4) concentrations with time in the propositus, and the phenotype observed in his mother who never complained with thyrotoxic symptoms, confirmed the in vitro binding and functional predictions. The most intriguing is the clinical course of the grandmother as she first presented with predominant pituitary RTH and a diffuse goiter and finally with a toxic multinodular goiter with normal T(3) and T(4) plasma concentrations and suppressed TSH. In conclusion, we report a novel mutation in the gene encoding the thyroid hormone receptor responsible for predominant pituitary RTH already described in vitro but not in vivo. The fluctuant phenotype of the propositus suggests that other factors modulate the degree of tissue resistance that is under genetic control. Toxic multinodular goiter, possibly due to chronic TSH stimulation during RTH, in addition to the phenotype variability, increases the difficulty to diagnose this thyroid disorder.