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.

OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-␣ (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS-Missense mutations prevailed in the dimerizationand DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P ϭ 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P ϭ 10 Ϫ4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P ϭ 0.03). MODY3 is characterized by a severe insulin secretion defect, a retained sensitivity to sulfonylureas, a decreased renal threshold for glucose reabsorption, and, in rare families, the occurrence of liver adenomatosis (3-6). CONCLUSIONS-TheseThe clinical expression of MODY3 is highly variable from one family to another or even within the same family (7). HNF1A mutation carriers may be normoglycemic while their siblings may be hyperglycemic at a comparable age (8). Symptoms at diagnosis may be variable. Some patients have metabolic decompensation, while in others diabetes is diagnosed by systematic screening. The severity and the course of insulin secretion defect also vary since approximately one-third of the patients are treated with insulin after 15 years of diabetes duration, whereas others control their diabetes by diet or oral hypoglycemic agents (9).As in other monogenic diseases, this phenotype variability may be explained by environmental and/or additional genetic factors. Two studies have shown that age at diagnosis of diabetes in offspring carrying a HNF1A mutation was lower by 5-10 years when maternal diabetes was diagnosed before pregnancy, suggesting the role of exposure of the fetus to maternal hyperglycemia (10,11). Modifier genetic factors may also modulate the phenotype of the disease. Age at onset of diabetes is partly inheritable within MODY3 families, and putative genetic modifier loci have been mapped but not identified yet (12). In the same vein, it has been recently shown that germ line CYP1B1 Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.HNF1A, hepatocyte nuclear factor 1-␣; MODY, maturity-onset diabetes of the young.

Hypothesis: Completion pancreatectomy in patients with pancreatic leakage associated with postoperative peritonitis after pancreaticoduodenectomy is a viable salvage procedure.

Bone is the second most frequent target of distant metastases in patients with differentiated thyroid cancer, and such forms carry a very poor prognosis. The impact of 131 I therapy in this setting is controversial. We describe the diagnostic circumstances and outcome of patients with bone metastases recently managed in two institutions. Among 921 consecutive thyroid cancer patients who had total thyroidectomy and 131 I ablation between January 2000 and December 2004 and who were subsequently monitored, bone metastases had been diagnosed in 16 patients. In three cases, the bone metastases were non-functioning (negative 131 I uptake) . These patients were treated with surgery and radiotherapy but progressed rapidly. The other 13 patients had functioning (positive 131 I uptake) bone metastases. In five of them, thyroid cancer was revealed by signs of distant involvement (bone pain, nZ4; dyspnea, nZ1). The bone metastases progressed in these five patients, despite local therapy and multiple courses of 131 I. The bone metastases in the remaining eight patients were discovered on the postsurgery 131 I therapy scan. Complementary radiological studies were negative except in one patient in whom one of the metastases (a 5 mm lesion of the right humerus) was visible on magnetic resonance imaging (MRI). Six of these patients showed a good response to 131 I therapy, with 131 I uptake and Tg levels becoming undetectable or showing a sharp fall. One patient refused 131 I therapy; bone metastases became visible on MRI within 1 year and the Tg level rose tenfold. The disease progressed in one patient despite 131 I therapy. Post-surgical 131 I ablation can contribute to early detection of bone metastases at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by 131 I therapy.