ARAGANGLIOMA SYNDROME(PGL) is a clinical term that has been introduced to describe a group of diseases in which patients may have neoplasias of several paraganglia. 1,2 For at least 4 decades, it has been known that such conditions may be heritable. 3 In addition, thoracic, retroperitoneal, and adrenal lo-cations (eg, extra-adrenal or adrenal pheochromocytomas) are also wellrecognized components of PGL. 4,5 Thus, Author Affiliations and a complete list of the members of the European-American Paraganglioma Study Group appear at the end of this article.

Objective: To analyze the penetrance and clinical course of isolated nonfunctioning tumors of the pancreas (NFTP) in MEN 1 patients, and to propose a strategy for managing them. Summary Background Data: Pancreaticoduodenal tumors develop in a majority of MEN 1 patients and are a major cause of death. The natural history of NFTP is poorly defined, and no clear-cut guidelines have been widely accepted regarding treatment. Methods: Data on 108 patients with isolated NFTP among 579 MEN 1 patients from the French Endocrine Tumor Study Group (GTE) were analyzed. Survival rates were calculated using the Kaplan-Meier method. Results: The penetrance of NFTP was 34% at age 50, making it the most frequent pancreaticoduodenal tumor in MEN 1 patients. Fortythree patients (40%) underwent surgery, 32 of them curatively. No patient died because of surgery. Average life expectancy for patients with NFTP was shorter than that for MEN 1 patients who did not have pancreaticoduodenal tumors. Thirteen patients died during follow-up, 10 due to NFTP. Tumor size was correlated with the risks of metastasis and death. These risks were low for patients with tumors Յ20 mm. Conclusions: NFTP are currently the most common tumors of the pancreaticoduodenal region in patients with MEN 1. Prevention of tumor spread by surgery should be balanced with potential operative mortality and morbidity. We do not recommend routine surgery for NFTP Յ20 mm. (Ann Surg 2006;243: 265-272) M ultiple endocrine neoplasia type 1 (MEN 1) is a rare autosomal dominant condition characterized by the development of endocrine parathyroid, pancreaticoduodenal, and pituitary tumors. In addition, MEN 1 patients are also prone to developing adrenal tumors, neuroendocrine tumors (in particular of the thymus or bronchus), dermal lesions, thyroid disease, and meningeal tumors. 1-7Pancreaticoduodenal tumors are often multiple, have been shown at autopsy to have developed in up to 80% of patients with MEN 1, and are a major cause of premature death in these patients. 8 -12 Most pancreaticoduodenal tumors are functioning tumors, the most frequent of which are gastrinomas and insulinomas, followed by the rare glucagonomas, VIPomas, GRFomas, and somatostatinomas. Surgical resection is the treatment of choice for functioning tumors of the pancreas, although controversy exists regarding the timing of surgery for gastrinomas. [13][14][15][16][17][18] In the absence of hormonal symptoms, nonfunctioning tumors of the pancreas (NFTP) have been recognized as a separate entity whose penetrance in the MEN 1 population is not well known. 19,20 In addition, because large surgical series of patients presenting with isolated NFTP are lacking and few clinical series have followed patients with NFTP, no clear-cut treatment guidelines have been widely accepted. Some authors have recommended a conservative approach for asymptomatic NFTP less than 1, 2, or 3 cm. [21][22][23][24] Others have recommended early surgical excision of all tumors as soon as they are found on imaging studies, or even ea...

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs fUS$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

This study suggests that surgery may not be beneficial for MEN1 patients with NFPET < or = 2 cm.

Our data show that maternal transmission of a SDHD-linked PGL, even if a rare event, can occur. Therefore, we propose that children who inherited a pathogenic mutation from their mother should be considered as at risk of PGL.

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Objectives: The aims of this study were to determine the performance of each variable, to define the optimal diagnostic thresholds and to determine the relative value of assaying chromogranin A (CgA). Design: Prospective study. Methods: Two groups of patients were studied: a control group of 71 patients and a group of 63 patients with a histologically-proven pheochromocytoma (52 pheochromocytomas and 14 paragangliomas). Fourteen of the patients had a family history of the disease. Eleven variables were assayed in each patient, i.e. the plasma and urinary concentrations of amines and their derivatives, and the CgA serum concentration.Results: The study of the control group showed that all the serum assays gave false positive results (from 6 to 23%), as did four of the six urinary assays (from 2.9 to 12.3%). The areas under the receiver operating characteristic curves varied from 0.689 to 0.992. The variables relating to the epinephrine pathway were significantly less expressed in the hereditary diseases than in the sporadic cases. The diagnostic thresholds of the three most efficient variables have been raised. Conclusions: Plasma determinations of metanephrines are now an easy and convenient tool for the diagnosis of pheochromocytoma. However, in our study the best specificity was obtained with the urinary tests rather than with the plasma assays while the highest sensitivities were for the normetanephrine assays. The assay of CgA was highly efficient in diagnosing pheochromocytomas in the absence of renal insufficiency. By combining it with fractionated metanephrine assays, the sensitivities of the latter were increased.European Journal of Endocrinology 156 569-575