Jean-Marc Kuhn

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

OBJECTIVEnLimited 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.nnnMETHODSnAnalysis 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.nnnRESULTSnAdrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10u200amm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40u200amm 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.nnnCONCLUSIONSnAdrenal 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.

Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly

Backgroundu2002 An essential criterion for control of acromegaly is normalization of IGF‐I levels. Somatostatin analogues act to suppress IGF‐I and GH levels.

Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism.

CONTEXTnHyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant syndrome with incomplete penetrance that can associate in a single patient parathyroid adenoma or carcinoma, fibro-osseous jaw tumor, cystic kidney lesion, and uterine tumor. Germline mutations of the HRPT2 gene (CDC73) coding for parafibromin are identified in approximately 50%-75% of HPT-JT cases and in approximately 14% of familial isolated hyperparathyroidism. A whole deletion of this gene has recently been reported in 1 sporadic case and in a family presenting with HPT-JT.nnnOBJECTIVEnThe objective of the study was to report molecular abnormalities of the HRPT2 gene in patients with primary hyperparathyroidism in a French National cohort from the Groupe dÉtude des Tumeurs Endocrines.nnnMETHODSnPatients genomic DNA was screened by PCR-based sequencing for point mutations affecting HRPT2 and real-time quantitative PCR analysis for gross deletions.nnnRESULTSnWe report 20 index patients with a germinal HRPT2 abnormality. Median age at diagnosis of primary hyperparathyroidism was 23 years (range 14-65 years). Median serum total calcium level at diagnosis was 3.19 mmol/L (range 2.8-4.3 mmol/L). Thirteen different mutations were identified by routine sequencing, including 7 mutations never reported. Seven patients (35%) carried a gross deletion of this gene (3 complete and 4 partial deletions). No genotype-phenotype correlation could be identified. A gross deletion of the HRPT2 gene was identified in 7% of patients for whom a routine screening by direct sequencing came up as negative.nnnCONCLUSIONnGross deletion analysis of the HRPT2 gene is indicated for all patients negative for mutation, presenting with HPT-JT or familial isolated hyperparathyroidism, parathyroid carcinoma, or in patients with apparently sporadic parathyroid adenoma diagnosed at a young age, having a severe hypercalcemia.

MEN1 Disease Occurring Before 21 Years Old: A 160-Patient Cohort Study From the Groupe d'étude des Tumeurs Endocrines

CONTEXTnMultiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports.nnnOBJECTIVEnTo improve the knowledge of MEN1 natural history before 21 years old.nnnMETHODSnObtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the Groupe détude des Tumeurs Endocrines MEN1 cohort.nnnRESULTSnThe first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases.nnnCONCLUSIONSnVarious MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

ACTH-Independent Cushing’s Syndrome with Bilateral Micronodular Adrenal Hyperplasia and Ectopic Adrenocortical Adenoma

CONTEXTnBilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma are two rare causes of ACTH-independent Cushings syndrome.nnnOBJECTIVEnThe aim of the study was to evaluate a 35-yr-old woman with ACTH-independent hypercortisolism associated with both micronodular adrenal hyperplasia and ectopic pararenal adrenocortical adenoma.nnnDESIGN AND SETTINGnIn vivo and in vitro studies were performed in a University Hospital Department and academic research laboratories.nnnINTERVENTIONnMutations of the PRKAR1A, PDE8B, and PDE11A genes were searched for in leukocytes and adrenocortical tissues. The ability of adrenal and adenoma tissues to synthesize cortisol was investigated by immunohistochemistry, quantitative PCR, and/or cell culture studies.nnnMAIN OUTCOME MEASUREnDetection of 17alpha-hydroxylase and 21-hydroxylase immunoreactivities, quantification of CYP11B1 mRNA in adrenal and adenoma tissues, and measurement of cortisol levels in supernatants by radioimmunological assays were the main outcomes.nnnRESULTSnHistological examination of the adrenals revealed nonpigmented micronodular cortical hyperplasia associated with relative atrophy of internodular cortex. No genomic and/or somatic adrenal mutations of the PRKAR1A, PDE8B, and PDE11A genes were detected. 17alpha-Hydroxylase and 21-hydroxylase immunoreactivities as well as CYP11B1 mRNA were detected in adrenal and adenoma tissues. ACTH and dexamethasone activated cortisol secretion from adenoma cells. The stimulatory action of dexamethasone was mediated by a nongenomic effect involving the protein kinase A pathway.nnnCONCLUSIONnThis case suggests that unknown molecular defects can favor both micronodular adrenal hyperplasia and ectopic adrenocortical adenoma associated with Cushings syndrome.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study

BACKGROUNDnMEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe détude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.nnnMETHODSnThe study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.nnnRESULTSnIntrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.nnnCONCLUSIONnThe present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Effect of the serotonin4 receptor agonist cisapride on plasma aldosterone levels in cirrhotic patients with secondary hyperaldosteronism

We have previously shown in vitro that serotonin (5HT), produced by the human adrenal cortex, stimulates corticosteroid secretion through the activation of a serotonergic type-4 receptor [1, 2]. In agreement with this observation, 5-HT4 receptor agonists are able to stimulate aldosterone secretion in man, both in vitro and in vivo [2, 3]. In particular, the oral administration of 10 mg cisapride, a 5-HT4 receptor agonist commonly used for the treatment of gastro-oesophagal re ̄ux, leads to a signi®cant increase in plasma aldosterone levels in healthy volunteers [3] and in patients with primary hyperaldosteronism [4]. The stimulatory ex80ect of cisapride on aldosterone secretion appears to be additive to that of angiotensin II [3], suggesting that cisapride is capable of aggravating mineralocorticoid excess in conditions with secondary (angiotensin II-induced) hyperaldosteronism, such as cirrhosis. In the present study, we investigated the ex80ect of cisapride on plasma aldosterone levels in eight cirrhotic patients with ascites. None had taken diuretics and/or spironolactone during the 6 weeks preceding the study. Secondary hyperaldosteronism was assessed by low natriuresis (<10 mmol per day) and high plasma levels of renin and aldosterone after 2 h of recumbency. Sodium intake (30 mmol per day) was kept constant throughout the study. The study was approved by the regional ethics committee. During the day preceding the experimentation, the patients were pretreated with dexamethasone (0.5 mg, orally, every 6 h) in order to suppress adrenocorticotrophic hormone (ACTH)-induced changes in aldosterone production throughout the study. After 2 h of recumbency, a single dose of 10 mg cisapride (Prepulsid, Janssen-Cilag, Boulogne-Billancourt, France) was administered orally at 0800 hours (t0). Blood samples for aldosterone, renin ACTH and cortisol measurements were obtained at 0 and 30 min, and 1, 1.5, 2, 2.5 and 3 h. Patients remained recumbent throughout the study. Potassium concentrations were measured at 0, 1, 1.5 and 3 h. Analysis of variance (ANOVA) was used to detect time-related variations in mean plasma aldosterone values. Cisapride induced a signi®cant increase of mean plasma aldosterone concentration from 2490 pmol á l (SD 1900) to 4720 pmol á l (4200) at t180 (P < 0.05). The analysis of individual data revealed that the aldosterone response to cisapride was observed in all patients, although basal aldosterone levels and the amplitudes of the responses showed important variation between patients (Fig. 1). Cisapride did not modify either plasma renin or potassium levels in cirrhotic patients. Plasma ACTH and cortisol levels remained suppressed throughout the study (data not shown). The present data indicate that acute administration of the 5-HT4 receptor agonist cisapride, in patients with secondary hyperaldosteronism, is followed by an increase in plasma aldosterone levels. Our results are consistent with previous ®ndings showing that cisapride stimulates aldosterone secretion in healthy volunteers Eur J Clin Pharmacol (1998) 53: 479±480 Ó Springer-Verlag 1998

A step towards cinacalcet testing for the diagnosis of primary hyperparathyroidism: comparison with the standardized intravenous calcium loading. A pilot study.

A calcium load to suppress parathyroid hormone (PTH) secretion can help to perform the diagnosis in some case of primary hyperparathyroidism (PHPT) with atypical presentation. A similar test with calcimimetic, which avoids hypercalcaemia, would be of interest. Our proof of concept study was conducted to compare firstly the results of a single‐dose cinacalcet testing with those of the standardized short‐time calcium load in healthy control (HC) and secondly the results of the single‐dose cinacalcet testing in HC and in PHPT.